1) The study examines the effects of acute and chronic hyperammonemia on antioxidant enzyme levels and oxidative damage in the cerebral cortex and cerebellum of rats.
2) Acute hyperammonemia decreased antioxidant enzyme levels in both brain regions but increased lipid peroxidation only in the cerebellum.
3) Chronic hyperammonemia increased antioxidant enzyme levels in the cerebral cortex but decreased levels in the cerebellum, suggesting the cerebellum is more susceptible to oxidative stress during chronic hyperammonemia.
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
"Glutathione supplementation attenuates lipopolysaccharide-induced mitochondrial dysfunction and apoptosis in a mouse model of acute lung injury" appeared in a 2012 issue of 'Physiology' and summarized the research Stephen M. Black and his team conducted into acute lung injury.
Learn more about his research on his blog: http://stephenmblack.com/blog/
Objective: To study the effects of resveratrol in neuronal structures in traumatic brain injury (TBI).
Study Design: Thirty rats were categorized as (1) control group (n=10), saline solution administered i.p. for 14 days, (2) TBI group (n=10), trauma induced by weight-drop model on brain, and (3) TBI+Resveratrol group (n=10), 15 minutes after injury the rats were given resveratrol (10 μmoL/kg/i.p.) for 14 days. At the end of the experiment the cerebellum was excised for routine paraffin tissue protocol. Blood samples were tested for serum biochemical markers (MDA, SOD, CAT, and GSH-x).
Results: SOD, GPx, and CAT values were lowest in the TBI group. MDA and histological scores of dilations in vessels, inflammation, degeneration in neurons, apoptosis in microglia, ADAMTS8, and GFAP expressions were highest in the TBI group. Sections of the control group showed normal cerebellar histology. The trauma group showed degenerated ganglion layer, pyknotic and apoptotic Purkinje cell nuclei. Vascular thrombus was seen in the substantia alba and substantia grisea. In the Trauma+Resveratrol group, most pa- thologies observed in the TBI group were improved. In the control group, GFAP protein was expressed in granular cells, axons, dendrites, Purkinje cells, and microglia cells. In the trauma group, increased GFAP expression was observed in glial processes, neurons, and Purkinje cells. In the Trauma+Resveratrol group, GFAP was expressed in molecular layer and glial processes. In the control group, ADAMTS-4 activity was observed in granulosa layer, glial cells, and Purkinje cells. In the trauma group, ADAMTS-4 expression was positive in Purkinje cells and glial cells. In the Trauma+ Resveratrol group, ADAMTS-4 was expressed in Purkinje cells, granular cells, and glial cells.
Conclusion: GFAP and ADAMTS-4 proteins may be involved in regeneration of damaged astroglial cells and other glial cells, Purkinje cells, and synaptic extensions. We suggest that antioxidative drugs such as resveratrol may be alternative target agents in neurological disease.
Keywords: ADAMTS-4, brain, cerebellum, GFAP, rat, resveratrol, traumatic brain injury
ABSTRACT- The aim of this study was to evaluate the pharmacological effect of EGb761 on the dynamic alterations of the level of magnesium,
glucose, and lactate in the brain cortex of gerbils during focal cerebral ischemia. A single-dose of EGb761 (100 mg/kg, i.p.) was given 30 min prior to
cerebral ischemic surgery. Cerebral ischemia was induced by occlusion of the right middle cerebral artery (RMCA) for 180 minutes. Two
microdialysis probes were stereotaxically implanted bilaterally into the brain cortex for auto-sampling the extracellular fluid. Experimental result
showed that pretreatment gerbil with EGb761 could preserve the highest Mg and glucose level in the contralateral (non-ischemic) brain. Meanwhile,
the lowest lactate concentration was observed in the contralateral (non-ischemic) brain in gerbils pretreated with EGb761. Interestingly, an opposite
result concerning the level of Mg, glucose, and lactate was found in the ipsilateral (ischemic) brain in EGb761 pretreated subject. Based on our
present finding, it seems likely that due to the pharmacological and compensatory effect, EGb761 can exert its biological effects by preserving more
Mg and glucose level but not the lactate concentration in the contralateral brain. Also, this phenomenon, at least in part, may be helpful for the nonischemic
brain not only in preserving more Mg and glucose level, but also in preventing the non-ischemic brain from further serious cerebral
ischemic challenge.
Key words- Cerebral ischemia, Microdialysis, Magnesium, Glucose, Lactate; EGb761
Morphohistometric analysis of the effects of Coriandrum sativum on cortical a...Prof. Hesham N. Mustafa
Objective: Natural compounds can act as metal chelators and oxygen free radical scavengers, which allows them to be used as bioactive antagonists to heavy metals neurotoxicity. The aim of the study to analyze the morphometric effects of Coriandrum sativum (C. sativum) on lead-induced neurotoxicity.
Materials and Methods: Forty Sprague-Dawley albino rats were divided into four equal groups (ten in each group): control group; coriander group: received aqueous C. sativum extracts (600 mg/kg BW for 60 days orally); lead (Pb) group: received a daily dose of lead acetate (Pb) (10 mg/kg BW for 60 days orally); Pb+ coriandrum group: received: aqueous C. sativum extract (600 mg/kg BW) prior to 10 mg/kg BW of Pb. The following parameters malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured. Layers thickness and nuclei density were analyzed.
Results: Lead levels in blood and tissues were decreased significantly in the Pb group and those findings were corrected significantly (p=0.001) with C. sativum addition. Data exhibited an increase in oxidative stress marker MDA and a decrease in antioxidant enzymes activities (SOD, CAT, and GPx) significantly in the Pb group and those effects were reversed significantly (p=0.001) by C. sativum administration. The cerebellar cortex and all layers of the somatosensory cortex thickness and nuclei density were diminished significantly in the Pb group. The morphometrical measurements were corrected significantly (p=0.001) by C. sativum.
Conclusion: From the findings of the current study, Pb caused noticeable structural and functional variations in the cerebellar cortex and somatosensory cortex. C. sativum corrected these parameters as it possesses chelating and antioxidant potentials.
Phytochemicals are considered as natural bio-active compounds with extraordinary bio-activities like free radical scavenging, enhancing mitochondrial integrity. preventing severe inflammation, regulating apoptosis and inhibiting toxic protein aggregations. This presentation deals with how phytochemicals are promoting brain health against various molecular assaults and wide range of diseases and disorders.
Liver ischemia/reperfusion injury, a setting in which the functional mass is ...Prof. Hesham N. Mustafa
Liver ischemia reperfusion is induced during sur-gical procedures like liver transplantation and re-section. Multiple mechanisms have been postulat-ed to liver damage following liver ischemia reperfu-sion injury, such as oxidative stress and inflamma-tory reactions. The present study declares the pos-sible mechanism of tadalafil, toward modulating the inflammatory response. Forty-eight rats were divided into 4 groups as follows; Sham group sub-jected to midline laparotomy only. Tadalafil group administered Tadalafil 10 mg/kg intraperitoneal 45 min before sham operation. I/R (Ischemia-reperfusion) group, rats undergo 60 min of hepatic ischemia followed by 60 min of reperfusion. Tada-lafil + I/R group rats undergo a similar pattern of I/R after the treatment with Tadalafil 10 mg/kg, 45 min before ischemia. At the end of the reperfusion, the blood samples were collected for estimation of biochemical markers including liver enzymes using colorimetric assay method and serum: TNF-α (tumor necrosis factor-α), IL-6 (interleukin 6) le-vels, ICAM- 1 (Intercellular Adhesion Molecule-1) were measured. Tissues were evaluated by semi-quantitative and morphometrical approaches. Ta-dalafil succeeded in restoring normal levels of liverenzymes and ameliorating the oxidative stress as evidenced by decreasing MDA and restoring redu-ced glutathione levels in liver tissue homogenate. Also, Tadalafil exhibits anti-inflammatory effects, as it significantly decreased the levels of TNF-α, IL6 and ICAM-1. The findings are supported by BCL-2, TNF-α immunomarkers. It is concluded that modulation of the inflammatory response might be one of the mechanisms of Tadalafil-mediated he-patoprotection, so it is recommended as an adju-vant therapy in liver surgery.Keywords: Ischemia/reperfusion injury – Oxidative stress – Apoptosis – TNF-α – BCL-2
Event Details
This webinar will introduce the Advanced MethylDetox Profile, discuss the scientific underpinnings of methylation and detoxifications, and explain how this test can benefit your patients. Our speakers have a diverse range of backgrounds from research to clinical practice.
Key Learning Points
-Discover the critical genes in the methylation pathway
-Understand each gene’s role in patient methylation function
-See how the MethylDetox Profile can be used clinically
-Learn how to monitor treatment progress
Objective: A spinal cord injury (SCI) is damage to the spinal cord either from trauma, loss of its normal blood supply, or compression from tumor or infection. In this study we focused on alterations in the bladder tissue with angiogenic and apoptotic aspects after spinal cord injury.
Study Design: Twenty Wistar Albino rats were categorized as control and SCI groups. At T7-T9 vertebras, a steel rod was dropped from 10 cm to create a spinal cord injury under anesthesia. Rats were decapitated and spinal tissue was processed to measure malondialdehyde (MDA), glutathione (GSH), and myeloperoxidase (MPO).
Results: MDA, MPO, epithelial degeneration, vascular dilation, inflammation, VEGF, and APAF-1 expressions in the SCI group were statistically higher than those in the control group. GSH content of the SCI group was statistically lower than that in the control group. In the hematoxylin-eosin–stained sections of the control group, normal histology was observed in bladder tissue. In the SCI group, degeneration epithelial cells, thinned epithelium, increased fibrosis, dilated and congested blood vessels, and hyperplastic endothelial cells were observed. In the control group, VEGF expression was slightly observed in some epithelial cells and vascular cells. In the SCI group, VEGF expression was increased in inflammatory and vascular endothelial cells. For APAF-1 expression, the control group showed no expression. In the SCI group, APAF-1 expression was positive in degenerated epithelial cells and connective tissue cells.
Conclusion: It is thought that the urination reflex was affected due to increased inflammation in the bladder tissue, leading to alterations in the regulation and function of the muscles.
Objective: To investigate the protective effect of lo- sartan, an angiotensin II type 1 receptor blocker with antioxidative effect on intestinal ischemia-reperfusion (I/R) injury in rats, against inflammation and apoptotic development.
Study Design: Forty male Wistar albino rats with a mean weight of 200–250 g each were divided into 4 groups: (1) Sham operation (laparotomy only, sham surgical preparation including isolation of the superior mesenteric artery [SMA] without occlusion), (2) Ischemia model with SMA closure for 2 hours, (3) I/R group (2 hours of ischemia followed by 3-hour reperfusion (SMA occlusion for 120 minutes followed by 240 minutes reperfusion), and (4) Losartan group (2 hours of ischemia, 40 mg/kg losartan was administered to the animals; losartan was dissolved in 1 mL distilled water and administered intraperitoneally after 2 hours of ischemia). Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were examined in jejunum tissue.
Results: Losartan treatment reduced the I/R-induced increase in MDA levels in the gut. Statistically, while SOD, CAT, and GSH activities decreased significantly in the I/R group, they increased in the I/R+Losartan group. Villus loss and increase in inflammation after ischemia persisted after reperfusion. Losartan treatment played a role in the reduction of inflammation and apoptosis and in the regulation of TNF-α and caspase-9 activity.
Conclusion: It has been thought that losartan in I/R may reduce mucosal damage and cell apoptosis in the direction of inflammation and may stabilize caspase-9 activity by inhibiting TNF-α stimulus.
Keywords: caspase-9, ischemia, ischemia/reperfusion, rat, reperfusion injury, TNF-α, tumor necrosis factor-alpha
"Glutathione supplementation attenuates lipopolysaccharide-induced mitochondrial dysfunction and apoptosis in a mouse model of acute lung injury" appeared in a 2012 issue of 'Physiology' and summarized the research Stephen M. Black and his team conducted into acute lung injury.
Learn more about his research on his blog: http://stephenmblack.com/blog/
Objective: To study the effects of resveratrol in neuronal structures in traumatic brain injury (TBI).
Study Design: Thirty rats were categorized as (1) control group (n=10), saline solution administered i.p. for 14 days, (2) TBI group (n=10), trauma induced by weight-drop model on brain, and (3) TBI+Resveratrol group (n=10), 15 minutes after injury the rats were given resveratrol (10 μmoL/kg/i.p.) for 14 days. At the end of the experiment the cerebellum was excised for routine paraffin tissue protocol. Blood samples were tested for serum biochemical markers (MDA, SOD, CAT, and GSH-x).
Results: SOD, GPx, and CAT values were lowest in the TBI group. MDA and histological scores of dilations in vessels, inflammation, degeneration in neurons, apoptosis in microglia, ADAMTS8, and GFAP expressions were highest in the TBI group. Sections of the control group showed normal cerebellar histology. The trauma group showed degenerated ganglion layer, pyknotic and apoptotic Purkinje cell nuclei. Vascular thrombus was seen in the substantia alba and substantia grisea. In the Trauma+Resveratrol group, most pa- thologies observed in the TBI group were improved. In the control group, GFAP protein was expressed in granular cells, axons, dendrites, Purkinje cells, and microglia cells. In the trauma group, increased GFAP expression was observed in glial processes, neurons, and Purkinje cells. In the Trauma+Resveratrol group, GFAP was expressed in molecular layer and glial processes. In the control group, ADAMTS-4 activity was observed in granulosa layer, glial cells, and Purkinje cells. In the trauma group, ADAMTS-4 expression was positive in Purkinje cells and glial cells. In the Trauma+ Resveratrol group, ADAMTS-4 was expressed in Purkinje cells, granular cells, and glial cells.
Conclusion: GFAP and ADAMTS-4 proteins may be involved in regeneration of damaged astroglial cells and other glial cells, Purkinje cells, and synaptic extensions. We suggest that antioxidative drugs such as resveratrol may be alternative target agents in neurological disease.
Keywords: ADAMTS-4, brain, cerebellum, GFAP, rat, resveratrol, traumatic brain injury
ABSTRACT- The aim of this study was to evaluate the pharmacological effect of EGb761 on the dynamic alterations of the level of magnesium,
glucose, and lactate in the brain cortex of gerbils during focal cerebral ischemia. A single-dose of EGb761 (100 mg/kg, i.p.) was given 30 min prior to
cerebral ischemic surgery. Cerebral ischemia was induced by occlusion of the right middle cerebral artery (RMCA) for 180 minutes. Two
microdialysis probes were stereotaxically implanted bilaterally into the brain cortex for auto-sampling the extracellular fluid. Experimental result
showed that pretreatment gerbil with EGb761 could preserve the highest Mg and glucose level in the contralateral (non-ischemic) brain. Meanwhile,
the lowest lactate concentration was observed in the contralateral (non-ischemic) brain in gerbils pretreated with EGb761. Interestingly, an opposite
result concerning the level of Mg, glucose, and lactate was found in the ipsilateral (ischemic) brain in EGb761 pretreated subject. Based on our
present finding, it seems likely that due to the pharmacological and compensatory effect, EGb761 can exert its biological effects by preserving more
Mg and glucose level but not the lactate concentration in the contralateral brain. Also, this phenomenon, at least in part, may be helpful for the nonischemic
brain not only in preserving more Mg and glucose level, but also in preventing the non-ischemic brain from further serious cerebral
ischemic challenge.
Key words- Cerebral ischemia, Microdialysis, Magnesium, Glucose, Lactate; EGb761
Morphohistometric analysis of the effects of Coriandrum sativum on cortical a...Prof. Hesham N. Mustafa
Objective: Natural compounds can act as metal chelators and oxygen free radical scavengers, which allows them to be used as bioactive antagonists to heavy metals neurotoxicity. The aim of the study to analyze the morphometric effects of Coriandrum sativum (C. sativum) on lead-induced neurotoxicity.
Materials and Methods: Forty Sprague-Dawley albino rats were divided into four equal groups (ten in each group): control group; coriander group: received aqueous C. sativum extracts (600 mg/kg BW for 60 days orally); lead (Pb) group: received a daily dose of lead acetate (Pb) (10 mg/kg BW for 60 days orally); Pb+ coriandrum group: received: aqueous C. sativum extract (600 mg/kg BW) prior to 10 mg/kg BW of Pb. The following parameters malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured. Layers thickness and nuclei density were analyzed.
Results: Lead levels in blood and tissues were decreased significantly in the Pb group and those findings were corrected significantly (p=0.001) with C. sativum addition. Data exhibited an increase in oxidative stress marker MDA and a decrease in antioxidant enzymes activities (SOD, CAT, and GPx) significantly in the Pb group and those effects were reversed significantly (p=0.001) by C. sativum administration. The cerebellar cortex and all layers of the somatosensory cortex thickness and nuclei density were diminished significantly in the Pb group. The morphometrical measurements were corrected significantly (p=0.001) by C. sativum.
Conclusion: From the findings of the current study, Pb caused noticeable structural and functional variations in the cerebellar cortex and somatosensory cortex. C. sativum corrected these parameters as it possesses chelating and antioxidant potentials.
Phytochemicals are considered as natural bio-active compounds with extraordinary bio-activities like free radical scavenging, enhancing mitochondrial integrity. preventing severe inflammation, regulating apoptosis and inhibiting toxic protein aggregations. This presentation deals with how phytochemicals are promoting brain health against various molecular assaults and wide range of diseases and disorders.
Liver ischemia/reperfusion injury, a setting in which the functional mass is ...Prof. Hesham N. Mustafa
Liver ischemia reperfusion is induced during sur-gical procedures like liver transplantation and re-section. Multiple mechanisms have been postulat-ed to liver damage following liver ischemia reperfu-sion injury, such as oxidative stress and inflamma-tory reactions. The present study declares the pos-sible mechanism of tadalafil, toward modulating the inflammatory response. Forty-eight rats were divided into 4 groups as follows; Sham group sub-jected to midline laparotomy only. Tadalafil group administered Tadalafil 10 mg/kg intraperitoneal 45 min before sham operation. I/R (Ischemia-reperfusion) group, rats undergo 60 min of hepatic ischemia followed by 60 min of reperfusion. Tada-lafil + I/R group rats undergo a similar pattern of I/R after the treatment with Tadalafil 10 mg/kg, 45 min before ischemia. At the end of the reperfusion, the blood samples were collected for estimation of biochemical markers including liver enzymes using colorimetric assay method and serum: TNF-α (tumor necrosis factor-α), IL-6 (interleukin 6) le-vels, ICAM- 1 (Intercellular Adhesion Molecule-1) were measured. Tissues were evaluated by semi-quantitative and morphometrical approaches. Ta-dalafil succeeded in restoring normal levels of liverenzymes and ameliorating the oxidative stress as evidenced by decreasing MDA and restoring redu-ced glutathione levels in liver tissue homogenate. Also, Tadalafil exhibits anti-inflammatory effects, as it significantly decreased the levels of TNF-α, IL6 and ICAM-1. The findings are supported by BCL-2, TNF-α immunomarkers. It is concluded that modulation of the inflammatory response might be one of the mechanisms of Tadalafil-mediated he-patoprotection, so it is recommended as an adju-vant therapy in liver surgery.Keywords: Ischemia/reperfusion injury – Oxidative stress – Apoptosis – TNF-α – BCL-2
Event Details
This webinar will introduce the Advanced MethylDetox Profile, discuss the scientific underpinnings of methylation and detoxifications, and explain how this test can benefit your patients. Our speakers have a diverse range of backgrounds from research to clinical practice.
Key Learning Points
-Discover the critical genes in the methylation pathway
-Understand each gene’s role in patient methylation function
-See how the MethylDetox Profile can be used clinically
-Learn how to monitor treatment progress
Objective: A spinal cord injury (SCI) is damage to the spinal cord either from trauma, loss of its normal blood supply, or compression from tumor or infection. In this study we focused on alterations in the bladder tissue with angiogenic and apoptotic aspects after spinal cord injury.
Study Design: Twenty Wistar Albino rats were categorized as control and SCI groups. At T7-T9 vertebras, a steel rod was dropped from 10 cm to create a spinal cord injury under anesthesia. Rats were decapitated and spinal tissue was processed to measure malondialdehyde (MDA), glutathione (GSH), and myeloperoxidase (MPO).
Results: MDA, MPO, epithelial degeneration, vascular dilation, inflammation, VEGF, and APAF-1 expressions in the SCI group were statistically higher than those in the control group. GSH content of the SCI group was statistically lower than that in the control group. In the hematoxylin-eosin–stained sections of the control group, normal histology was observed in bladder tissue. In the SCI group, degeneration epithelial cells, thinned epithelium, increased fibrosis, dilated and congested blood vessels, and hyperplastic endothelial cells were observed. In the control group, VEGF expression was slightly observed in some epithelial cells and vascular cells. In the SCI group, VEGF expression was increased in inflammatory and vascular endothelial cells. For APAF-1 expression, the control group showed no expression. In the SCI group, APAF-1 expression was positive in degenerated epithelial cells and connective tissue cells.
Conclusion: It is thought that the urination reflex was affected due to increased inflammation in the bladder tissue, leading to alterations in the regulation and function of the muscles.
Objective: To investigate the protective effect of lo- sartan, an angiotensin II type 1 receptor blocker with antioxidative effect on intestinal ischemia-reperfusion (I/R) injury in rats, against inflammation and apoptotic development.
Study Design: Forty male Wistar albino rats with a mean weight of 200–250 g each were divided into 4 groups: (1) Sham operation (laparotomy only, sham surgical preparation including isolation of the superior mesenteric artery [SMA] without occlusion), (2) Ischemia model with SMA closure for 2 hours, (3) I/R group (2 hours of ischemia followed by 3-hour reperfusion (SMA occlusion for 120 minutes followed by 240 minutes reperfusion), and (4) Losartan group (2 hours of ischemia, 40 mg/kg losartan was administered to the animals; losartan was dissolved in 1 mL distilled water and administered intraperitoneally after 2 hours of ischemia). Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were examined in jejunum tissue.
Results: Losartan treatment reduced the I/R-induced increase in MDA levels in the gut. Statistically, while SOD, CAT, and GSH activities decreased significantly in the I/R group, they increased in the I/R+Losartan group. Villus loss and increase in inflammation after ischemia persisted after reperfusion. Losartan treatment played a role in the reduction of inflammation and apoptosis and in the regulation of TNF-α and caspase-9 activity.
Conclusion: It has been thought that losartan in I/R may reduce mucosal damage and cell apoptosis in the direction of inflammation and may stabilize caspase-9 activity by inhibiting TNF-α stimulus.
Keywords: caspase-9, ischemia, ischemia/reperfusion, rat, reperfusion injury, TNF-α, tumor necrosis factor-alpha
Using Pathway Studio in Neurodegenerative diseaseAnn-Marie Roche
Dr. Gabor Juhasz of ELTE University in Budapest discusses use of Pathway Studio in the study of neurodegenerative diseases such as Alzheimer’s Disease.
ABSTRACT- The anticancer drug arsenic trioxide is effective for acute promyelocytic leukemia. But the clinical trials are
restricted due to its potential side effects. Since the major part of arsenic metabolism and detoxification occurs in liver,
this organ faces the major threat. The hepatic side effects include fatty liver, fibrosis, and inflammation and hepatocyte
degeneration. Our study aimed to evaluate the protective potential of the fatty acid, docosahexaenoic acid, against adversities
of arsenic trioxide in an in vitro model, the Chang liver cells. Two preliminary dose standardization assays, cell
viability and lactate dehydrogenase release assays, were employed. The assays were performed as Pre-treatment,
Co-treatment and Post treatment experiments for a period of 24 hours. Arsenic trioxide at various doses (2.5, 5, 7.5, 10,
12.5 and 15 μM) showed a significant (p≤0.05) dose dependant reduction in cell viability along with a dose dependant
enhancement of lactate dehydrogenase release. However when the cells were treated with a combination of docosahexaenoic
acid at varying concentrations (50, 75, 100, 125 and 150 μM), the above mentioned conditions were found to be
reversed in Pre-treatment and Co-treatment experiments, but not in Post treatment. The most effective combination was
found to be 10 μM arsenic trioxide with 100 μM of docosahexaenoic acid in both Pre-treatment and Co- treatment studies.
Thus the preliminary assays of our study showed that docosahexaenoic acid administration as Pre-treatment or
Co-treatment can aid in reducing arsenic trioxide induced hepatotoxicity. Further studies are required to elucidate the mechanisms
behind the protective effects.
Key Words– Arsenic trioxide, hepatotoxicity, docosahexaenoic acid, cell damage
Crocin, the main constituent of Crocus sativus L., protected against infl ammation-induced neurotoxicity and improved learning behavior. Also, crocin inhibited production of inducible nitric oxide synthase. Studies also indicated an interaction between NO and Formaldehyde (FA) -induced neurotoxicity. In this study, effect of crocin on memory and body weight changes in neurotoxicity induced by FA was evaluated in a rat model. Moreover, the possible involvement of NO on protective effects of crocin was investigated. FA (5 mg/kg) was administered intraperitoneally for 5 consecutive days. Effect of crocin post-treatment (25, 50 and 100 mg/kg, i.p.) on FA neurotoxicity was evaluated on passive avoidance memory.
La hipotermia moderada se ha estado estudiando y se ha demostrado que ayuda a prevenir el daño neuronal. El siguiente seminario se realiza en unos experimentos con unas neuronas y unas proteínas proapoptoticas (PARP1) y genes de apoptosis (AIF). Se demostró que la hipotermia tiene la capacidad de reducir el daño provocado por estas proteínas y estos genes, dando así una mayor posibilidad de estudio para en un futuro lograr hacer terapias y medicinas para la conservación cerebral.
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
we are teleologically cardioprotected. we are already cardioprotected. nature has given us everything we need to be unbreakable.we just have to push the right buttons.
please, pay heed to the turtles! they know best!
Objective: Ischemia-reperfusion (I/R) leads to reactive oxygen species formation and cell death in kidney tissue with injury and organ transplantation. Simvastatin (SIM) is an antioxidant, anti-inflammatory, and anticoagulant agent. Alterations in I/R-induced acute kidney injury model with SIM treatment were analyzed.
Study Design: Wistar rats (n=28) were grouped into Sham, Ischemia, I/R, and I/R+SIM treated. Left rat kidney renal vessels were clamped for 60 minutes for ischemia, and the I/R group had 6 hours of reperfusion. 10 mg/kg SIM was given orally for 28 days. MDA, GSH, and MPO were analyzed. Kidney tissues were paraffin embedded, and primary antibodies TNF-α and caspase-3 were applied for immunohistochemistry.
Results: In the I/R group, intense inflammatory cell infiltration around the vessels and necrosis in the glomerular structures were observed. In the treated group, proximal and distal tubular cells were found to be close to normal. Immunoexpression of caspase-3 in the ischemia group was positive in degenerative glomeruli. In the treated group, TNF-α expression was negative in the glomerular structures. MDA and MPO levels were significantly increased in ischemia and I/R.
Conclusion: We suggest that SIM treatment improved kidney tissue structure and function in a model of I/R injury.
Keywords: caspase-3; immunohistochemistry; ischemia/reperfusion; kidney; MPO; simvastatin
Targetting cancer with Ru(III/II)-phosphodiesterase inhibitor adducts: A nove...rkkoiri
Lack of specificity and normal tissue toxicity are the two major limitations faced with most of the anticancer
agents in current use. Due to effective biodistribution and multimodal cellular actions, during
recent past, ruthenium complexes have drawn much attention as next generation anticancer agents. This
is because metal center of ruthenium (Ru) effectively binds with the serum transferrin and due to higher
concentration of transferrin receptors on the tumor cells, much of the circulating Ru-transferrin complexes
are delivered preferentially to the tumor site. This enables Ru-complexes to become tumor cell
specific and to execute their anticancer activities in a somewhat targeted manner. Also, there are evidences
to suggest that inhibition of phosphodiesterases leads to increased cyclic guanosine monophosphate
(cGMP) level, which in turn can evoke cell cycle arrest and can induce apoptosis in the tumor
cells. In addition, phosphodiesterase inhibition led increased cGMP level may act as a potent vasodilator
and thus, it is likely to enhance blood flow to the growing tumors in vivo, and thereby it can further facilitate
delivery of the drugs/compounds to the tumor site.
Therefore, it is hypothesized that tagging PDE inhibitors (PDEis) with Ru-complexes could be a relevant
strategy to deliver Ru-complexes-PDEi adduct preferentially to the tumor site. The Ru-complex tagged
entry of PDEi is speculated to initially enable the tumor cells to become a preferential recipient of such
adducts followed by induction of antitumor activities shown by both, the Ru-complex & the PDEi, resulting
into enhanced antitumor activities with a possibility of minimum normal tissue toxicity due to
administration of such complexes.
An overview of the toxic effect of potential human carcinogen Microcystin-LR ...rkkoiri
The worldwide occurrence of cyanobacterial blooms due to water eutrophication evokes
extreme concerns. These blooms produce cyanotoxins which are hazardous to living organisms.
So far among these toxins, Microcystin-LR (MC-LR) is the most toxic and the most
frequently encountered toxin produced by the cyanobacteria in the contaminated aquatic
environment. Microcystin-LR is a potential carcinogen for animals and humans, and the
International Agency for Research on Cancer has classified Microcystin-LR as a possible
human carcinogen. After liver, testis has been considered as one of the most important target
organs of Microcystin-LR toxicity. Microcystin-LR crosses the blood–testis barrier and
interferes with DNA damage repair pathway and also increases expression of the protooncogenes,
genes involved in the response to DNA damage, cell cycle arrest, and apoptosis
in testis. Toxicity of MC-LR disrupts the motility and morphology of sperm and also affects
the hormone levels of male reproductive system. MC-LR treated mice exhibit oxidative
stress in testis through the alteration of antioxidant enzyme activity and also affect the
histopathology of male reproductive system. In the present review, an attempt has been
made to comprehensively address the impact of MC-LR toxicity on testis.
Activation of p53 mediated glycolytic inhibition-oxidative stressapoptosis pa...rkkoiri
There is a general agreement that most of the cancer cells switch over to aerobic glycolysis (Warburg
effect) and upregulate antioxidant enzymes to prevent oxidative stress induced apoptosis. Thus, there is
an evolving view to target these metabolic alterations by novel anticancer agents to restrict tumor
progression in vivo. Previously we have reported that when a non toxic dose (10 mg/kg bw i.p.) of a novel
anticancer ruthenium(II)-complex containing 4-carboxy N-ethylbenzamide; Ru(II)-CNEB, was administered
to the Dalton's lymphoma (DL) bearing mice, it regressed DL growth by inducing apoptosis in the
DL cells. It also inactivated M4-LDH (M4-lactate dehydrogenase), an enzyme that drives anaerobic
glycolysis in the tumor cells. In the present study we have investigated whether this compound is able to
modulate regulation of glycolytic inhibition-apoptosis pathway in the DL cells in vivo. We observed that
Ru(II)-CNEB could decline expression of the inducible form of 6-phosphofructo-2-kinase (iPFK2:
PFKFB3), the master regulator of glycolysis in the DL cells. The complex also activated superoxide dismutase
(the H2O2 producing enzyme) but declined the levels of catalase and glutathione peroxidase (the
two H2O2 degrading enzymes) to impose oxidative stress in the DL cells. This was consistent with the
enhanced p53 level, decline in Bcl2/Bax ratio and activation of caspase 9 in those DL cells. The findings
suggest that Ru(II)-CNEB is able to activate oxidative stress-apoptosis pathway via p53 (a tumor
supressor protein) mediated repression of iPFK2, a key glycolytic regulator, in the DL cells in vivo.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Acute and chronic hyperammonemia modulate antioxidant
1. Neurochem Res (2008) 33:103–113
DOI 10.1007/s11064-007-9422-x
ORIGINAL PAPER
Acute and Chronic Hyperammonemia Modulate Antioxidant
Enzymes Differently in Cerebral Cortex and Cerebellum
Santosh Singh Æ Raj K. Koiri Æ Surendra Kumar Trigun
Accepted: 18 June 2007 / Published online: 4 August 2007
Ó Springer Science+Business Media, LLC 2007
Abstract Studies on acute hyperammonemic models stress. This is supported by ~ 2- and 3-times increases in the
suggest a role of oxidative stress in neuropathology of level of lipid peroxidation in cerebellum during chronic and
ammonia toxicity. Mostly, a low grade chronic type acute HA respectively, however, with no change in the
hyperammonemia (HA) prevails in patients with liver cortex due to chronic HA.
diseases and causes derangements mainly in cerebellum
associated functions. To understand whether cerebellum Keywords Hyperammonemia Á Ammonia neurotoxicity Á
responds differently than other brain regions to chronic type Antioxidant enzymes Á Oxidative stress Á Cerebral cortex Á
HA with respect to oxidative stress, this article compares Cerebellum
active levels of all the antioxidant enzymes vis a vis extent
of oxidative damage in cerebral cortex and cerebellum of
rats with acute and chronic HA induced by intra-peritoneal Introduction
injection of ammonium acetate (successive doses of
10 · 103 & 8 · 103 lmol/kg b.w. at 30 min interval for Hepatic encephalopathy (HE) is a serious nervous system
acute and 8 · 103 lmol/kg b.w. daily up to 3 days for disorder developed due to increased ammonia level in brain
chronic HA). As compared to the respective control sets, resulting from liver dysfunction. This is of great concern
cerebral cortex of acute HA rats showed significant decline because a number of liver disorders like viral hepatitis,
(P < 0.01–0.001) in the levels of superoxide dismutase liver intoxication, alcoholism and inborn errors of urea
(SOD), catalase and glutathione peroxidase (GPx) but with cycle are associated with different grades of hyperammo-
no change in glutathione reductase (GR). In cerebellum of nemic conditions in the patients [1]. It has been reported
acute HA rats, SOD, catalase and GR though declined that acute ammonia exposure of brain cells causes
significantly, GPx level was found to be stable. Contrary to dysfunction of multiple neurotransmitter system [1, 2] and
this, during chronic HA, levels of SOD, catalase and GPx glutamate & ammonia mediated excitotoxicity of neurons
increased significantly in cerebral cortex, however, with a [3]. At down stream level, defects in brain bioenergetics [4]
significant decline in the levels of SOD and GPx in cere- and mitochondrial dysfunction mediated oxidative stress
bellum. The results suggest that most of the antioxidant [5, 6] are considered to play important roles in patho-
enzymes decline during acute HA in both the brain regions. physiology of HE. Moreover, most of the evidences for a
However, chronic HA induces adaptive changes, with role of oxidative stress in ammonia neurotoxicity have
respect to the critical antioxidant enzymes, in cerebral cor- been derived either from cell culture studies [6, 7] and/or
tex and renders cerebellum susceptible to the oxidative from acute hyperammonemic animal models [8–10].
Nonetheless, low grade chronic hyperammonemic condi-
tion is more prevalent in the patients suffering from viral
hepatitis and liver dysfunction due to alcoholism and long
S. Singh Á R. K. Koiri Á S. K. Trigun (&)
term drug abuse. Therefore, it is important to understand
Biochemistry & Molecular Biology Laboratory, Department of
Zoology, Banaras Hindu University, Varanasi 221005, India how chronic HA affects cellular antioxidant defense
e-mail: sktrigun@sify.com; sktrigun@bhu.ac.in mechanisms in susceptible brain regions.
123
2. 104 Neurochem Res (2008) 33:103–113
There are some reports on the role of oxidative stress in Experimental procedure
chronic hyperammonemic models also; however, most of
them are focused to the hyperammonemia (HA) dependent Animal and chemicals
impairment of NMDA receptor activity [1] via alterations
in glutamate-NO-cGMP pathway [11, 12]. In addition, Male adult albino rats weighing 100–120 g were main-
chronic HA has been found to induce adaptive changes tained in an animal house as per the recommendations from
in brain energy and ammonia metabolites, which are institutional ethical committee for the care and use of
altered otherwise during acute ammonia intoxication [13]. laboratory animals.
Increases in the levels of ammonia, glutamate and mito- All chemicals used were of analytical grade or of the best
chondrial NAD/NADH ratio in chronic HA models [13] quality supplied by E-Merk, Glaxo and SRL (INDIA).
hint for a mitochiondrial dysfunction and implication of Acrylamide, N N-methylene bis acrylamide, Coomassie
oxygen free radicals in the pathophysiology of chronic type Brilliant Blue R-250 (CBB), TEMED (N N N N-tetrameth-
HE also. Nonetheless, information is scarce on implication ylethylene diamine) and Phenyl methyl sulphonyl fluoride
of antioxidant enzyme system during chronic HA in animal (PMSF) were purchased from Sigma Chemical Co., USA.
models.
Primary level neuropathology of HE, like motor Experimental design
disturbances, expressionless face, rigid muscle tone, tremor
etc, is common with the low-grade chronic type HE Acute and chronic HA in rats were induced by intraperi-
patients [14, 15] and these functions are mainly associated toneal injection of ammonium acetate prepared in physio-
with the derangements in motor activities of cerebellum. logical saline (0.9% NaCl). As described earlier [24], for
Thus, it is likely that cerebellum responds differently to acute HA, first 10 · 103 lmol/kg b.w. of ammonium
HA than the other brain regions. Differential susceptibility acetate was administered to the rats followed by a second
of cerebellum and cerebral cortex with respect to the injection of 8 · 103 lmol/kg b.w. after 30 min interval.
activation of guanylate cyclase by NO in mild HA animal Chronic HA group rats were injected daily up to 3 days
models has been reported [12] and importantly, similar with 8 · 103 lmol/kg b.w. ammonium acetate. Control
changes were also observed in these brain regions of group rats for each experimental set were simultaneously
chronic type HE patients [16]. Therefore, it is important to given with equivalent volume of physiological saline.
ascertain whether and how different brain regions respond About 80% of the rats with acute/ episodic treatment
to chronic HA with respect to O– based oxidative stress.
2 survived up to 30 min after the last injection. In case of
Brain consumes more O2 than any other tissues and thus, chronically treated rats, 90% of them could survive after
produces high level of reactive oxygen species (ROS) and the last injection. All animals were sacrificed by decapi-
operates efficient antioxidant enzyme systems to counteract tation after 30 min of the final injection and cerebral cortex
the deleterious effects of oxidative stress [17, 18]. Super- & cerebellum were dissected out, washed in ice cold saline
oxide dismutase (SOD) and catalase scavenge O– to pro-
2 (0.9% NaCl) and stored frozen at –70°C for further studies.
duce water & O2, whereas, interplay of SOD, glutathione Level of HA was ascertained by measuring ammonia
peroxidase (GPx) and glutathione reductase (GR) channels concentration in whole brain taking fresh tissues from 3
O– in a NADPH dependent pathway to maintain the ratio of
2 rats from each control as well as experimental groups.
GSH/GSSG and to prevent lipid peroxidation during
oxidative stress. It has been reported that though catalase is Preparation of tissue extracts
also found in brain cells, it is SOD-GPx-GR pathway that is
more important for antioxidant activities in brain [19, 20]. Whole brain, cerebral cortex and cerebellum extracts were
In view of a high degree of metabolic plasticity in brain prepared in 0.02 M Tris–Cl (pH 7.4) containing protease
cells in general [18] and with respect to antioxidant inhibitors as described from our lab [25]. Extracts were
enzymes in particular [21–23], it may be speculated that as centrifuged at 35,000 g for 45 min at 4°C. The superna-
compared to the acute conditions, chronic HA may produce tants collected were used for the studies on antioxidant
differential changes in the antioxidant enzyme system in enzymes and other biochemical assays. Protein content was
different brain regions. In the present report, we have determined by the method of Lowery et al. [26].
compared, in a concerted manner, the extent of oxidative
damage and levels of all the key antioxidant enzymes in rat Biochemical estimations
brain cortex (less affected due to mild HA) and cerebellum
(whose functions are affected the most in chronic HE Ammonia concentration was measured using a kit sup-
patients) in acute and chronic HA rat models. plied by Sigma–Aldrich, USA. The brain extracts were
123
3. Neurochem Res (2008) 33:103–113 105
deproteinized in 1/5 volumes of ice-cold 100 g/l trichlo- chromogen. Absorbance was measured at 560 nm using
roacetic acid, and kept on ice for 15 min. After centrifu- butanol as blank. Unit of the enzyme was defined as the
gation at 15,000 g for 15 min at 4°C, the supernatants were amount of enzyme that produced 50% inhibition of NBT
neutralized with 2.0 M KHCO3, centrifuged again and used reduction per min. and the activity was expressed as units/
for estimating ammonia. The method employed measuring mg protein.
the rate of conversion of a-ketoglutarate to glutamate cat- Catalase (EC: 1.11.1.6) was assayed following an earlier
alyzed by glutamate dehydrogenase in the presence of reported procedure [30] with some modifications. Briefly,
ammonia. The reaction mixture (1 ml) contained 50 ll of in a reaction mixture containing 0.01 M Potassium phos-
sample, 3.4 mM a-ketoglutarate and 0.23 mM reduced phate buffer (pH 7.0) and 0.1 ml of tissue extract, reaction
NADPH in 50 mM phosphate buffer (pH 7.4). The reaction was started by the addition of 0.8 M hydrogen peroxide
was started by the addition of suitably diluted glutamate (H2O2) and stopped after 60 s by 2.0 ml dichromate acetic
dehydrogenase. Initial and final (after 5 min) absorbance at acid reagent. All the tubes were heated in a boiling water
340 nm was used to calculate the concentration of bath for 10 min., cooled and absorbance was read at
ammonia in terms of lmol/g wet wt of tissue. 570 nm. After comparing with a standard plot constructed
Malondialdehyde (MDA), the product of lipid peroxi- using a range of 10–160 lmoles of H2O2, the activity of
dation, was measured by the method reported earlier [27]. catalase was expressed as lmoles of H2O2 consumed/min/
Briefly, 1 ml of Tris–Maleate buffer (0.2 M, pH 5.9) and mg protein.
0.5 ml of the extract was incubated at 37°C for 30 min.
Thereafter, 1.5 ml of thiobarbituric acid (TBA) was added Analysis of SOD and catalase by non-denaturing PAGE
and the mixture was incubated in boiling water bath for
10 min using tight condensers. After cooling, 3 ml of Non-denaturing PAGE of the tissue extracts were per-
pyridine: n-butanol mixture (3:1 v/v) and 1 ml of 1.0 N (w/ formed as reported from this laboratory [31]. For SOD, the
v) NaOH were added. The contents were thoroughly mixed extract containing 60 lg protein was loaded in each lane of
and allowed to stand for 10 min. The absorbance was read 12% non-denaturing PAGE. After electrophoresis, the gels
at 548 nm and the levels of lipid peroxidation were ex- were subjected to substrate specific staining of SOD bands
pressed as nmole MDA/g wet wt. as described earlier [32]. The staining mixture consisted of
Total thiol was estimated as described earlier [28]. 2.5 mM NBT, 28 lM riboflavin, and 28 mM TEMED.
Aliquots of 0.1 ml tissue extracts were mixed with 1.5 ml After 20 min incubation in the dark, gels were exposed to
of 0.2 M Tris buffer, pH 8.2 and 0.1 ml 0.01 M 5,5’-Di- a fluorescent light to develop achromatic bands against
thio-bis (2-nitrobenzoic acid) (DTNB) . The mixture was dark blue background corresponding to SOD protein in
made up to 10 ml with methanol and was incubated for the gel.
30 min. The mixture was then centrifuged at 3,000 rpm for For catalase, tissue extracts containing 60 lg proteins
15 min. and absorbance of the supernatant was read at were electrophoressed on 8% non-denaturing PAGE.
412 nm. The molar extinction coefficient of 13,100 was Catalase specific bands were developed according to Sun
used to calculate GSH (reduced glutathione) and values et al. [33]. Briefly, gels were soaked for 10 min in 0.003%
were presented as nmol/mg protein. H2O2 and then incubated in a staining mixture consisted of 2%
potassium ferricyanide and 2% ferric chloride. Achromatic
Studies on antioxidant enzymes catalase bands appeared against a blue–green background.
The intensity of bands was quantitated by gel densitometry
Assay of SOD and catalase using alphaimager 2200 gel documentation software.
The activity of superoxide dismutase (SOD; EC: 1.15.1.1) Active level of glutathione peroxidase
was measured following an earlier described method [29].
The reaction mixture consisted of 0.02 M sodium Glutathione peroxidase (GPx; EC:1.11.1.9) level was
pyrophosphate buffer (pH 8.3), 6.2 lM phenazine metho- determined by in gel detection method as described earlier
sulphate (PMS), 30 lM nitroblue tetrazolium (NBT), and [34]. After 10% non-denaturing PAGE of the extracts
0.1 ml suitably diluted tissue extracts. The reaction was containing 30 lg protein in each lane, the gels were
started by the addition of 50 lM NADH at 30°C and incubated in a GPx specific staining mixture composed of
stopped after 90 s by the addition of 2.0 ml glacial acetic 50 mM Tris–Cl buffer (pH 7.9), 3 mM GSH, 0.004%
acid. A control set without tissue extract was run simul- H2O2, 1.2 mM NBT and 1.6 mM PMS. Achromatic bands
taneously. The reaction mixture was stirred, shaken with corresponding to GPx activity appeared against a violet–
4 ml of n-butanol, allowed to stand for 10 min and blue background. The level of GPx was quantified by gel
centrifuged to separate butanol layer containing the densitometry as described earlier.
123
4. 106 Neurochem Res (2008) 33:103–113
During PAGE based detection of all the three antioxi- as a measure of reducing equivalents in the brain cells,
dant enzymes, SOD, catalase and GPx, development of was observed to be unaltered in both cerebral cortex and
enzyme specific bands were confirmed by comparing the cerebellum under acute and chronic HA.
results of similarly run gels stained in the presence and
absence of the enzyme specific substrates. In each case, Degree of HA & the level of antioxidant enzymes
PAGE was performed 3–4 times and mean ± SD of
densitometric values of the bands as % of control lane from In general, activity of the enzymes measured in cell free
all the gels run were presented with a representative gel extracts is correlated with the metabolic efficiency of the
photograph. cells under a variety of pathophysiological conditions.
However, measuring enzyme activity in cell free extracts
Glutathione reductase assay may not reflect actual levels of the enzymatic proteins in
the cells. Therefore, to monitor active levels of the anti-
Activity of glutathione reductase (GR; EC: 1.6.4.2) was oxidant enzymes, in the present study, cell extracts were
determined following the method of Carlberg and subjected to non-denaturing PAGE followed by activity
Mannervik [35]. In brief, the reaction mixture (1 ml) staining based detection of enzymatic proteins in the gel.
consisted of 0.2 M sodium phosphate buffer (pH 7.0), This method is relatively less sensitive than to detecting
0.2 mM EDTA, 1 mM oxidized glutathione (GSSG) and proteins by Western blotting. However, it is more relevant
0.2 mM NADPH. The reaction was initiated by the for physiological interpretations, as in this method detec-
addition of the tissue extract and oxidation of NADPH was tion is based on specificity of the enzyme for its substrate
recorded as decrease in absorbance at 340 nm for 5 min. and thus, activity based intensity of bands in gel reflects
Nonspecific oxidation of NADPH was corrected by the only active level of the enzyme (native protein). In com-
absorbance obtained in the absence of GSSG. Unit of the parison, antibody based detection can not differentiate
enzyme was defined as lmole NADP/min/ at 30°C and between the active and inactive structures of the proteins.
the enzyme activity was expressed as units/mg protein. A difference between Western blot detected enzymatic
Statistical analysis of the data was done as reported protein level and that with the intensity of activity bands in
earlier [25] and the student ‘t’ test was performed to find gel has been reported in case of most of the antioxidant
the level of significance between control and experimental enzymes in a tumor cell line [36]. Thus, in the present
groups. article, results from spectrophotometric measurements
have been interpreted as activity level of the enzyme and
PAGE bands as the level of active fraction of the enzymatic
Results protein in brain tissues.
As compared to the respective control groups, ~ 5–7 fold Effect of acute HA on antioxidant enzymes
increases in brain ammonia level was observed in rats with
episodic treatment of ammonium acetate and ~1.5–1.8 fold The first step of neutralization of O– is completed by
2
increase with those treated once daily up to 3 days. As synchronized activities of SOD & catalse and/or by SOD &
reported earlier [24], these groups were referred to as acute GPx in mammalian cells. As compared to the control group
and chronic HA groups respectively. rats, activities of SOD and catalase were observed to be
declined significantly (P < 0.01–0.001) in both, cerebral
Comparison of oxidative damage due to acute and cortex and cerebellum of rats with acute HA (Figs. 1A,
chronic HA 2A). The intensity of SOD band in gel also followed the
declining pattern in the cortex, however, with a significant
Measuring MDA level, as a stable product of lipid peroxi- (P < 0.05) increase in cerebellum of acute HA rats
dation, is a reliable tool to assess the extent of oxidative (Fig. 1B, C). And in case of catalase, intensity of PAGE
damage at cellular level. According to Table 1, as compared bands were found unchanged in both the brain regions
to the control rats, there was a significant increase (1.3 fold) during acute HA (Fig. 2B, C). Such a non-correlative
in MDA level in cerebral cortex of the rats with acute HA, pattern between the activity data and PAGE results of SOD
but with no change during chronic HA. In cerebellum, and catalase could be attributed to some inhibitory mech-
however, MDA level was 3- and 2-fold higher in acute and anisms for these enzymes in brain during acute HA.
chronic HA rats respectively than the corresponding control Four isoforms of GPx have been reported in mammalian
groups. When compared between cortex and cerebellum, tissues [20]. Though, brain contains pre-dominantly phos-
there was ~ 2 times higher MDA level in cerebellum than pholipids hydrogen peroxide GPx (pHGPx), the other three
the cortex in both the HA group rats. The level of total GSH, isoforms have also been reported in brain but in less
123
5. Neurochem Res (2008) 33:103–113 107
Table 1 Effect of acute and chronic hyperammonemia on the level of lipid peroxidation and total thiol (GSH) in cerebral cortex and cerebellum
Tissues Biochemical parameter Control Acute Control Chronic
Cerebral cortex Lipid peroxidation (MDA nmol/g wet wt) 58.65 ± 6.85 78.30 ± 5.8* 55.4 ± 5.41 55.09 ± 4.0
Total thiol (GSH) (nmol/mg protein) 1.35 ± 0.075 1.26 ± 0.125 1.37 ± 0.193 1.28 ± 0.13
Cerebellum Lipid peroxidation (MDA nmol/g wet wt) 54.50 ± 5.36 163.07 ± 7.12*** 54.72 ± 5.82 108.02 ± 8.48**
Total thiol (GSH) (nmol/mg protein) 1.28 ± 0.166 1.04 ± 0.080 1.06 ± 0.114 1.17 ± 0.075
Values are mean ± SD where n = 4 and each experiment done in duplicates
* ** ***
P < 0.05, P < 0.01, P < 0. 001 (Control versus experimental group)
amount [20]. In the absence of a literature on classification ammonia toxicity in brain, pure hyperammonemic animal
of GPx isoforms based on their migration in non-denatur- models, induced by administration of ammonium salt, with
ing PAGE, in this article, GPx bands have been referred to normal liver function is recommended over other HA
as GPx1–GPx 4 based on their relative migration in non- models with acute liver failure [37]. This is because the
denaturing PAGE starting from top to bottom (Figs. 3, 7). findings from pure HA models are assumed to be devoid of
According to Fig. 3A and B, as compared to the control the interferences from other pathological factors associated
lanes, all the four GPx isoforms though declined slightly to liver dysfunction. Additionally, ammonia diffuses in
(P < 0.05) in the cerebral cortex, but with an insignificant brain with a faster rate during HE than the normal condi-
change in cerebellum of rats with acute HA. A similar tion [38] and thus, brain ammonia level, than the concen-
pattern was also observed when GPx activity was measured tration of ammonia in blood, is considered more relevant
in vitro in the cell extracts from the respective brain re- for interpreting the data obtained using HA animal models
gions (unpublished results). Contrary to this, in comparison [24]. In the present report, we have used hyperammonemic
to the samples from control rats, though there was a small rats induced by administration of ammonium acetate
decline (P < 0.05) in the activity of GR in the cerebellum, wherein, as reported earlier [24], ~5–7 and 1.5–1.8 fold
GR activity in the cerebral cortex remained unchanged increases in brain ammonia level was considered as acute
during acute HA. and chronic HA groups respectively.
Brain processes ~20% of O2 consumed by the whole
Effect of chronic HA on antioxidant enzymes body for generating ATP via oxidative phosphorylation in
mitochondria and therefore, brain cells are consistently
Figures 5–7 illustrate that in cerebral cortex of chronic HA exposed to high ROS. Abundance of myelinated nerve
rats, as compared to the control group, activities as well as fibers makes brain enriched with phospholipids containing
levels of active fractions of SOD, catalase and all isoforms poly unsaturated fatty acids, and thus, brain cells become
of GPx increased significantly (P < 0.05–0.001). However, highly prone to ROS dependent derangements in mem-
in cerebellum, though the activity and active levels of SOD brane structure and functions [39]. The level of lipid
(P < 0.001) & all the GPx bands including GPx 2 (pHGPx) peroxidation is a good indicator to assess the extent of
declined significantly (P < 0.05), there were no significant oxidative damage produced by ROS in the brain. The over
change observed in the activity and the level of catalase activation of NMDA receptors [1] and ammonia induced
during chronic HA. Moreover, as compared to the control mitochondrial dysfunction [4, 5] could be the main source
group rats, rats with chronic HA showed significant decline of excess of ROS in brain during HA. The rate of free
(P < 0.01) in the activity of GR in cerebral cortex but with radical production and the level of lipid peroxidation have
no change in cerebellum (Fig. 8). been reported to be significantly high in the whole brain of
acute HE rats [40]. According to Table 1, however, when
compared between the cerebral cortex and the cerebellum
Discussion in pure HA rats, significantly increased level of lipid per-
oxidation (~ 2 times higher) in cerebellum than the cortex
In the present article, we intended to address two aspects of under both acute and chronic conditions clearly suggest
ammonia neurotoxicity, one the relationship between the that cerebellum is more susceptible for oxidative damage
degree of HA and oxidative stress in brain & secondly, due to ammonia toxicity than the cortex. Furthermore, ~ 3
since cerebellum associated functions are affected the most and 2 fold increases in the MDA level in cerebellum of
during chronic HA, is it that cerebellum is more susceptible acute and chronic HA rats respectively suggest for a cause
to ammonia toxicity than other brain regions with respect and effect relationship between the degree of HA in brain
to oxidative stress. For such comparative studies on and the oxidative damage in cerebellum. Nonetheless,
123
6. 108 Neurochem Res (2008) 33:103–113
A control
A C ontrol
12 4
HA
Catalase (U/mg protein)
HA 3.5
10
3
SOD (U/mg protein)
** 2.5
8
2
6 1.5 ***
***
1 ***
4
0.5
2 0
Cerebral c ortex Cerebellum
0
Cerebral cortex Cerebellum B C o n t ro l HA Control HA
B C o nt r ol HA Control HA Catalase
SOD
C 120
100
C
% of control
140 80
Control
*
120 60
HA
100 40
% of control
80 ** 20
60 0
40 Cerebral c ortex Cerebellum
20 Fig. 2 Effect of acute hyperammonemia on activity (A) and level of
active catalase protein (B & C) in cerebral cortex and cerebellum of
0
Cerebral cortex Cerebellum
rats. The values in A represent mean ± SD where n = 4 and each
experiment done in duplicates. In case of B, pooled tissue extracts
Fig. 1 Effect of acute hyperammonemia on activity (A) and level of from 4 rats containing 60 lg protein in each lane was electropho-
active SOD protein (B & C) in cerebral cortex and cerebellum of rats. ressed on 8% non- denaturing PAGE followed by substrate specific
The values in A represent mean ± SD where n = 4 and each development of catalase bands. The gel photograph in B is a
experiment done in duplicate. In case of B, pooled tissue extracts representative out of the 3 PAGE repeats. In panel C, relative
from 4 rats containing 60 lg protein in each lane was electropho- densitometric values of catalase bands from experimental group as %
ressed on 12% non- denaturing PAGE followed by substrate specific of the control lane have been presented as mean ± SD from the 3
development of SOD bands. The gel photograph in B is a PAGE repeat experiments. ***P < 0.001 (control versus experimental
representative out of the 4 PAGE repeats. In panel C, relative groups)
densitometric values of SOD bands from experimental group as % of
the control lane have been presented as mean ± SD from the 4 PAGE
repeat experiments *P < 0.05, **P < 0.01, ***P < 0.001 (control
brain regions under acute as well as chronic HA conditions
versus experimental groups)
(Table 1). In the cellular antioxidant pathway, the turnover
of GSH/GSSG is regulated by synchronized activities of
cortex showed resistance to HA dependent oxidative stress, GPx and GR in mammalian cells. Both these enzymes did
as there was no change in MDA level in the cortex of not show much alternation, except a moderate decrease in
chronic but with a mild (1.3 fold) increase in that from GPx and GR in cortex and cerebellum respectively
acute HA rats. (Figs. 3, 4), due to acute HA, and thus, could be correlated
The level of reduced glutathione (GSH), a tripeptide with the unchanged level of GSH in both the brain regions
responsible to maintain reducing equivalents under oxida- during acute HA. However, significantly opposite trends of
tive stress, is another critical factor to assess the level of GPx and GR in the cerebral cortex of chronic HA rats
oxidative stress in mammalian cells. Interestingly, there (Figs. 7, 8) did not correlate with the unchanged level of
was no significant change in the level of GSH in both the GSH in the cortex of rats with chronic HA. It is suggested
123
7. Neurochem Res (2008) 33:103–113 109
A 40
Control HA Control HA Control
35
GPx 1 HA
30
GR (U/mg protein)
GPx 2 25
GPx 3 *
20
GPx 4
15
10
B
140 5
120 0
Cerebral cortex Cerebellum
100
% of control
*
Fig. 4 Effect of acute hyperammonemia on activity of GR in cerebral
80
cortex and cerebellum of rats. The values represent mean ± SD where
60 n = 4 and each experiment done in duplicates. *P < 0.05 (control
versus experimental groups)
40
20
mitochondria, is converted to H2O2 by SOD. Simultaneous
0
removal of H2O2 by either catalse and/or by GPx is crucial
Cerebral c ortex Cerebellum for preventing membrane damage due to oxidative stress.
Fig. 3 Effect of acute hyperammonemia on level of active GPx In brain, SOD-GPx-GR pathway is considered to play
protein in cerebral cortex and cerebellum of rats. In case of A, pooled major role of antioxidant activities [19, 20]. With the
tissue extracts from 4 rats containing 30 lg protein in each lane was increased production of ROS, most of these enzymes were
electrophoressed on 10% non-denaturing PAGE followed by substrate found to be declined in whole brain of rat with acute HE
specific development of GPx bands. The gel photograph in A is a
representative out of the 4 PAGE repeats. In panel B, relative [8]. However, according to the results presented here, when
densitometric values of GPx bands from experimental group as % of the levels of all these enzymes were compared in concerted
the control lane have been presented as mean ± SD from the 4 PAGE manner in two different brain regions (cerebral cortex and
repeat experiments. *P < 0.05 (control versus experimental group) cerebellum) under acute and chronic HA, changes in all
these enzymes were found to differ as a function of degree
that a highly adaptive metabolic coupling operates between of HA but with a regional specificity. In cerebellum,
astrocytes and neurons to maintain the normal level of this though GPx showed resistance against acute HA, there was
tripeptide under unphysiological conditions in brain [41, a significant decline in the levels of SOD, catalase and GR
42]. When neuron’s GSH gets depleted due to acute under acute HA and thus, suggested for acute HA depen-
ammonia intoxication, the precursors for GSH synthesis dent oxidative stress in rat cerebellum. It was also corre-
are supplied from astrocytes which are supposed to be less lated well with a significant increase in the level of lipid
susceptible to ROS insult [41]. Furthermore, gamma glut- peroxidation in cerebellum of acute HA rats (Table 1).
amyl-cystein synthetase is also responsible to produce GSH Cerebral cortex also showed significant decline in SOD and
in the cells, and this enzyme has been reported to be in- catalase, however, with a moderate decrease in GPx and no
creased in the astrocytes under acute HA condition [43]. change in the level of GR under acute HA (Figs. 3, 4). In
Thus, it is likely that these additional routes could con- view of relatively less increase in the level of lipid
tribute for maintaining GSH level in the cortex of chronic peroxidation due to acute HA in the cortex (~ 2 times less
HA rats even when GR activity declined significantly than cerebellum), it may be assumed that resistance of GPx
(P < 0.01). Similar argument may be given for the unal- and GR to acute HA might be accountable to prevent
tered level of GSH in cerebellum of chronic HA rats where, oxidative damage in cerebral cortex even at the face of
GPx showed significant decline (P < 0.05) but with a little significant decline in SOD and catalase.
change in GR activity (Figs. 7, 8). During chronic HA, a significant decline in the level of
The changes in the levels of antioxidant enzymes during SOD (both by activity and PAGE results) and GPx (Figs. 5,
oxidative stress are the most critical factors in determining 7) coincided with the significant increase in the level of
the extent of oxidative damage produced by ROS during lipid peroxidation in cerebellum (Table 1), however, with
neuropathology [17, 44]. All parts of brain contain SOD, no change in the level of catalase and GR (Figs. 6, 8).
catalase, GPx and GR in high concentration to counter This suggests that decline in the level of SOD and GPx
balance the deleterious effects of ROS [44, 45]. Excess are mainly accountable to allow oxidative damage in
of superoxide anion (O–), the major ROS produced in
2
cerebellum and unaffected GR plays a permissive role in
123
8. 110 Neurochem Res (2008) 33:103–113
A 16 A 7
**
Control *** Control
14 6
Catalase (U/mg protein)
SOD (U/mg protein)
HA HA
12 5
10
4
8
*** 3
6
4 2
2 1
0 0
Cerebral c ortex Cerebellum
Cerebral cortex Cerebellum
B Control HA Control HA
B C o n t ro l HA Control HA
Catalase
SOD
C 140
*
C 120
180
100
% of control
160 **
80
140
60
% of control
120
100 40
80 ** 20
60 0
40 Cerebral cortex Cerebellum
20
0 Fig. 6 Effect of chronic hyperammonemia on activity (A) and level
Cerebral c ortex Cerebellum of active catalase protein (B & C) in cerebral cortex and cerebellum
of rats. The values in A represent mean ± SD where n = 4 and each
Fig. 5 Effect of chronic hyperammonemia on activity (A) and level experiment done in duplicates. In case of B, pooled tissue extracts
of active SOD protein (B & C) in cerebral cortex and cerebellum of from 4 rats containing 60 lg protein in each lane was electropho-
rats. The values in A represent mean ± SD where n = 4 and each ressed on 8% non-denaturing PAGE followed by substrate specific
experiment done in duplicate. In case of B, pooled tissue extracts development of catalase bands. The gel photograph in B is a
from 4 rats containing 60 lg protein in each lane was electropho- representative out of the 3 PAGE repeats. In panel C, relative
ressed on 12% non-denaturing PAGE followed by substrate specific densitometric values of catalase bands from experimental group as %
development of SOD bands. The gel photograph in B is a of the control lane have been presented as mean ± SD from the 3
representative out of the 4 PAGE repeats. In panel C, relative PAGE repeat experiments. *P < 0.05, ***P < 0.001 (control versus
densitometric values of SOD bands from experimental group as % of experimental groups)
the control lane have been presented as mean ± SD from the 4 PAGE
repeat experiments. **P < 0.01, ***P < 0.001 (control versus exper-
imental groups) [18]. The whole brain of rats pre-exposed to chronic HA
have been found to resist the changes in the level of crucial
maintaining the normal level of GSH (Table 1) during metabolites which are normally produced otherwise during
chronic HA in this brain region. This again supports the acute HA [8]. At the face of significant decline in the
view that SOD and GPx are the most critical antioxidant activity of most of the antioxidant enzymes, SOD activity
enzymes in brain [19, 20]. Nonetheless, since, both these was reported to be increased significantly in all the brain
enzymes declined specifically in cerebellum (as compared regions of rats with fulminate liver type acute HE [10]. As
to the cortex) and that cerebellum associated functions are per the results presented here, however, it is evident that
affected the most in HE patients [14, 15], it may be argued chronic HA produces adaptive changes only in cerebral
that relatively greater susceptibility of cerebellum for cortex with respect to the SOD-GPx pathway in particular.
ammonia toxicity dependent antioxidant defense could be This could contribute for relatively less effect of chronic
accountable for pathogenesis of low grade chronic HA. HA on the cortex associated function than the cerebellum
In case of cortex, contrary to the effect of acute (Fig. 8).
ammonia exposure, chronic HA produced significant in- It has been suggested that each antioxidant enzyme
creases in the levels of SOD, catalase and GPx (Figs. 5–7) has a functionally distinct role, or cooperates with other
and thus, suggested positive adaptation in brain cortex enzymes to protect the cell under a variety of pathophysi-
against a low grade chronic HA with respect to these ological conditions [46] and thus, HA dependent differen-
antioxidant enzymes. Brain is considered to be a highly tial changes in the set of antioxidant enzymes e.g. up
plastic tissue so far metabolic adaptations are concerned regulation of SOD-GPx in cortex and their down regulation
123
9. Neurochem Res (2008) 33:103–113 111
A 35
Control HA Control HA Control
30 HA
GPx 1
GR (U/mg protein)
25
**
20
GPx 2
15
GPx 3
GPx 4 10
5
B 140.00 0
Cerebral cortex Cerebellum
120.00 *
100.00 Fig. 8 Effect of chronic hyperammonemia on activity of GR in
% of control
cerebral cortex and cerebellum of rats. The values represent
80.00 * mean ± SD where n = 4 and each experiment done in duplicates.
**
P < 0.01 (control versus experimental groups)
60.00
40.00
resulted due to SOD and catalase inhibitory conditions
20.00 induced in brain during acute HA. H2O2 is a known
0.00 physiological inhibitor of SOD [47, 48] and has been
Cerebral c ortex Cerebellum demonstrated recently to inhibit specific isoforms of this
enzyme in brain [49]. Increased accumulation of Mn2+ in
Fig. 7 Effect of chronic hyperammonemia on level of active GPx brain is associated with Alzheimers type II astrocytosis
protein in cerebral cortex and cerebellum of rats. In case of A, pooled
tissue extracts from 4 rats containing 30 lg protein in each lane was [50], a hall mark of acute HA [1] and as reviewed by
electrophoressed on 10% non-denaturing PAGE followed by substrate Takeda [51], increased level of Mn2+ inhibits catalase and
specific development of GPx bands. The gel photograph in A is a also induces a burst of H2O2 in brain cells. Also, as per the
representative out of the 4 PAGE repeats. In panel B, relative results presented here (Fig. 2A), a drastic decrease in the
densitometric values of GPx bands from experimental group as % of
the control lane have been presented as mean ± SD from the 4 PAGE activity of catalase in cerebellum of acute HA rats may also
repeat experiments. *P < 0.05 (control versus experimental group) contribute for an unusual increase in H2O2 and thus, can
further potentiate inhibition of SOD in this brain region
during acute HA. A two times higher level of MDA in
in cerebellum during chronic HA could be the result of cerebellum than the cortex of acute HA rats (Table 1)
differential sensitivity of cortex and cerebellum to chronic provide additional support to this argument. Furthermore, it
HA. Opposite responses of cortex and cerebellum to NO has been demonstrated that inhibition of SOD at cellular
dependent signaling pathway during HA in rats [12] and level induces increase in the mRNA level of this enzyme
also in HE patients [16] provide support to this argument. [52], and SOD proteins are highly resistant to denaturation
Such a pattern has been shown in other neurological & oxidative damage even at a high concentration of H2O2
disorders also. Different antioxidant enzymes showed [48]. Therefore, it is likely that inactivation of SOD
differential alterations in the brain of patients with observed in cell free extracts due to increased oxidative
Alzheimers type dementia [21] and also in D-amphitamine burst in cerebellum of acute HA rats might not be reflected
induced neurotoxicity [22]. Increase in the level of SOD at protein level (Fig. 1). Accordingly, since inactivation
and catalase in different brain regions of rats with mala- of SOD would be expected to be minimal during mild
thion-induced oxidative stress is another example of oxidative stress, in vitro activity data and level of SOD
adaptive changes in antioxidant enzymes [23]. protein should be mutually correlative. And indeed, a
With a view to have a molecular rationale behind similar pattern of SOD profile was observed in the cerebral
significant changes in the activities of SOD, catalase and cortex of acute HA rats (Fig. 1) with ~ 2 times less
GPx during HA, these enzymes were further analyzed on oxidative stress than cerebellum (Table 1, MDA data). As
PAGE. It was interesting to note that while level of SOD Mn2+ also inhibits catalase in the brain [51] and such
protein increased in cerebellum of rats with acute HA transitory metal-protein interaction is likely to get disso-
(Figs. 1B, C), activity of this enzyme (when measured ciated during electrophoresis, a similar argument may be
in vitro) showed significant decline (Fig. 1A). Similar given for significant decreases in the activity of catalase
pattern was observed with catalase in both the brain regions in vitro but with insignificant change in its level on PAGE
of acute HA rats (Fig. 2A–C). Such a mismatch could be analysis in both the brain regions of acute HA rats. These
123
10. 112 Neurochem Res (2008) 33:103–113
arguments get further support from a uniform correlative 11. Hermenegildo C, Montoliu C, Llansola M et al (1998) Chronic
pattern observed between in vitro data and PAGE patterns hyperammonemia impairs the glutamate-nitric oxide-cyclicGMP
pathway in cerebellar neurons in culture and in the rat in vivo.
of SOD and catalase in both the brain regions of chronic Eur J Neurosci 10:3201–3209
HA rats (Figs. 5, 6) showing significantly less oxidative 12. Rodrigo R, Felipo V (2006) Brain regional alternations in the
stress as compared to the acute HA rats (Table 1, MDA modulation of the glutamate-nitric oxide-cGMP pathway in liver
data). Thus, it is evident that the extent of oxidative stress cirrhosis: role of hyperammonemia and cell types involved.
Neorochem Int 48:472–477
induced during acute HA acts as an additional factor in 13. Kosenko E, Kaminsky YG, Felipo V et al (1993) Chronic
modulating the activities of SOD and catalase irrespective hyperammonemia prevents changes in brain energy and ammonia
of the actual levels of these proteins in both the brain metabolism induced by acute ammonia intoxication. Biochim
regions. Biophys Acta 1180:321–326
14. Gilberstadt SJ, Gilberstadt H, Zieve L et al (1980) Psychomotor
In conclusion, active levels of all the antioxidant enzymes performance defects in cirrhotic patients without overt encepha-
were found altered differently in cerebral cortex and cere- lopathy. Arch Int Med 140:519–521
bellum as a function of degree of HA. As compared to a 15. Tarter RE, Hegedus AM, Van Thiel DH et al (1984) Non-
uniform decline in the activities of most of the antioxidant alcoholic cirrhosis associated with neuropsychological dysfunc-
tion in the absence of overt evidence of hepatic encephalopathy.
enzymes due to acute HA, chronic HA was found to induce Gastroenterology 86:1421–1427
brain region specific changes which are likely to render 16. Corbalan R, Chaturet N, Behrends S et al (2002) Region selective
cerebellum susceptible and cerebral cortex resistant to the alternation of soluble guanylate cyclase content and modulation
oxidative stress during chronic HA. Since, cerebellum asso- in brain of cirrhotic patients. Hepatology 6:1155–1162
17. Mates JM (2000) Effects of antioxidant enzymes in the molecular
ciated functions are mainly affected during low grade chronic control of reactive oxygen species toxicology. Toxicology
HA, such changes in antioxidant enzymes might be impli- 153:83–104
cated in the encephalopathy of chronic HA. 18. Magistretti PJ (2003) Brain energy metabolism. In: Fundamental
neuroscience, 2nd edn. Elsevier Science, New York, pp339–360
Acknowledgments This work was financially supported by a DAE: 19. Tureen JF (2003) Mitochondrial formation of reactive oxygen
BRNS grant (P-29/64) to SKT. The instrumental facilities provided species. J Physiol 552:335–344
by the DST FIST and UGC-CAS Program to the department of 20. Flohe RB (1999) Tissue-specific function of individual glutathi-
Zoology are also acknowledged. one peroxidases. Free Radical Biol Med 27:951–965
21. Gsell W, Conrad R, Hickethier M et al (1995) Decreased catalase
activity but unchanged superoxide dismutase activity in brain of
patients of Alzheimer type. J Neurochem 64:1216–1233
References 22. Frey BN, Valvassori SS, Reus GS et al (2006) Changes in antioxidant
defense enzymes after D-amphetamine exposure: implications as
1. Felipo V, Butterworth RF (2002) Neurobiology of ammonia. an animal model of mania. Neurochem Res 31:699–703
Prog Neurobiol 67:259–279 23. Furtunato JJ, Feier G, Vitali AM (2006) Malathione-induced
2. Butterworth RF (2000) Hepatic encephalopathy: a neuropsychi- oxidative stress in rat brain regions. Neurochem Res 31:671–678
atric disorder involving multiple neurotransmitter systems. Curr 24. Hilgier W, Albrecht J, Lisy V et al (1990) The effect of acute and
Opin Neurol 13:721–727 chronic hyperammonemia on y-glutamyl transpeptidase in vari-
3. Marcaida G, Felipo V, Hermengildo C et al (1992) Acute ous brain regions of young and adult rats. Mol Chem Neuropathol
ammonia toxicity is mediated by the NMDA type of glutamate 13:47–56
receptor. FEBS Lett 296:67–68 25. Pandey P, Singh SK, Trigun SK (2005) Developing brain of
4. Rama Rao KV, Norenberg MD (2001) Cerebral energy metabo- moderately hypothyroid mice shows adaptive changes in the key
lism in hepatic encephalopathy and hyperammonemia. Metab enzymes of glucose metabolism. Neurol Psych Brain Res 12:159–164
Brain Dis 16:67–78 26. Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein mea-
5. Kosenko E, Felipo V, Montoliu C et al (1996) Effects of acute surement with the Folin phenol reagent. J Biol Chem 193:
hyperammonemia in vivo on oxidative metabolism in nonsy- 265–275
naptic rat brain mitochondria. Metab Brain Dis 12:69–82 27. Placer ZA, Cushman LL, Johnson BC (1966) Estimation of
6. Rama Rao KV, Jayakumar AR, Norenberg MD (2005) Role of product of lipid peroxidation (malonyl dialdehyde) in biochemi-
oxidative stress in the ammonia-induced mitochondrial perme- cal systems. Anal Biochem 16: 359–364
ability transition in cultered astrocytes. Neurochem Int 47:31–38 28. Sedlak J, Raymond HL (1968) Estimation of total thiol, protein
7. Murthy CRK, Rama Rao KV, Bai G et al (2001) Ammonia in- bound, and non protein sulfhydryl groups in tissue with Ellman’s
duced production of free radicals in primary culture of rat as- reagent. Anal Biochem 25:192–205
trocytes. J Neurosci Res 66:282–288 29. Kakkar P, Das B, Viswanathan PN (1984) A modified spectro-
8. Kosenko E, Kaminski Y, Lopata O et al (1999) Blocking of photometric assay of superoxide dismutase ( SOD). Ind J
NMDA receptors prevents the oxidative stress induced by acute Biochem Biophys 21:130–132
ammonia intoxication. Free Radical Res 26:1369–1374 30. Sinha KA (1972) Colorimetric assay of catalase. Anal Biochem
9. Norenberg MD, Jayakumar AR, Rama Rao KV (2004) Oxidative 47:389–394
stress in the pathogenesis of hepatic encephalopathy. Metab Brain 31. Trigun SK, Singh AP, Asthana RK et al (2006) Assessment of
Dis 19:313–329 bioactivity of a Fischerella species colonizing Azadirachta Indica
10. Sathyasaikumar KV, Swapna I, Reddy PVB et al (2007) (neem) Bark. Appl Ecol Environ Res 4:119–128
Fulminant hepatic failure in rats induces oxidative stress differ- 32. Beauchamp C, Fridovich I (1971) Superoxide dismu-
entially in cerebral cortex, cerebellum and pons medula. Neuro- tase:improved assays and an assay applicable to acrylamide gels.
chem Res 32:517–524 Anal Biochem 44:276–287
123
11. Neurochem Res (2008) 33:103–113 113
33. Sun Y, Elwell JH, Oberley LW (1988) A simultaneous visuali- 43. Murthy Ch RK, Bender AS, Dombro RS et al (2000) Elevation of
zation of the antioxidant enzymes glutathione peroxidase and glutathione level by ammonium ions in primary cultures of rat
catalase on polyacrylamide gels. Free Radical Res Commun astrocytes. Neurochem Int 37:255–268
5:67–75 44. Halliwell B (2001) Role of free radicals in the neurodegenerative
34. Lin CL, Chen HJ, Hou WC (2002) Activity staining of gluta- diseases: therapeutic implications for antioxidant treatment. Drug
thione peroxidase after electrophoresis on native and sodium Aging 18:685–716
dodecylsulfate polyacrylamide gels. Electrophoresis 23:513–516 45. Patenaude A, Murthy MR, Mirault ME (2005) Emerging roles of
35. Carlberg I, Mannervik B (1975) Purification and characterization thioredoxin cycle enzymes in the central nervous system. Cell
of the flavoenzyme glutathione reductase from rat liver. J Biol Mol Life Sci 62:1063–1080
Chem 250:5475–5480 46. Imai H, Nakagawa Y (2003) Biological significance of phos-
36. Wang H (2000) Over expression of L-PhGPx in MCF-7 cells. pholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4)
In: The role of mitochondrial phospholipids hydroperoxide glu- in mammalian cells. Free Radical Biol Med 34:145–169
tathione peroxide in cancer therapy. Ph.D. thesis. The University 47. Bray RC, Cockel SA, Fielden EM et al (1974) Reduction and
of Iowa, Iowa, pp16–56 inactivation of superoxide dismutase by hydrogen peroxide.
37. Kanamori K, Ross BD, Chung JC et al (1996) Severity of hy- Biochem J 139:43–48
perammonemic encephalopathy correlates with brain ammonia 48. Salo DC, Pacifici RE, Lin SW (1990) Superoxide dismutase
level and saturation of glutmine synthetase in vivo. J Neurochem undergoes proteolysis and fragmentation following oxidative
67:1584–1594 modification and inactivation. J Biol Chem 265:11919–11927
38. Lockwood AH (2004) Blood ammonia levels and hepatic 49. Mokni M, Elkahoui S, Limam F et al (2007) Effect of resveratrol
encephalopathy. Metab Brain Dis 19:345–349 on antioxidant enzyme activities in the brain of healthy rat.
39. Halliwell B, Gutteridge JMC (1985) Oxygen radicals and nervous Neurochem Res 32:981–987
system. Trends Neurosci 8:22–26 50. Hazell AS, Normandin L, Norenberg MD et al (2006) Alzheimer
40. Kosenko E, Venediktova N, Kamanisky Y et al (2003) Sources of type II astrocytic changes following sub-acute exposure to
oxygen radical in brain in acute ammonia intoxication in vivo. manganese and its prevention by antioxidant treatment. Neurosci
Brain Res 981:193–200 Lett 396:167–171
41. Dringen R, Pawlowski PG, Hirrlinger J (2005) Peroxide detoxi- 51. Takeda A (2003) Manganese action in brain function. Brain Res
fication by brain cells. J Neurosci Res 79:157–165 Rev 41:79–87
42. Hovatta I, Tennant RS, Helton R et al (2005) Glyoxalase 1 and 52. Maitre B, Jornot L, Jonod AF (1993) Effects of inhibition of
glutathione reductase 1 regulate anxiety in mice. Nature 438: catalase and superoxide dismutase activity on antioxidant enzyme
662–666 mRNA levels. Am J Physiol 265:636–643
123