This study examined the ability of the nicotinic receptor agonist cytisine and two halogenated derivatives (3-bromocytisine and 5-bromocytisine) to stimulate dopamine release in vivo and protect against dopamine depletion in a rat model of Parkinson's disease. Microdialysis experiments showed that cytisine, 5-bromocytisine, and nicotine were more effective than 3-bromocytisine at inducing striatal dopamine release. Administration of cytisine and 5-bromocytisine before and after an intranigral injection of 6-hydroxydopamine significantly prevented the decrease in striatal dopamine levels, but 3-bromocytisine did not provide protection. These results suggest that the efficacy
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.
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.
Personalized nanomedicine for the treatment of vascular hypertensionSusanta Kumar Rout
This study includes designing a nanomedical device for the treatment of vascular hypertension in polycystic kidney diseases (PKD) model through cilia targeting.
They generated and compared two different metal and polymer cilia-targeted nanoparticle drug delivery systems (DDS), i.e. gold (Au) and poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs)
The target is Dopamine-receptor type-5 (DRS) on primary cilia.
The drug-loaded is Fenoldopam (FD).
Subacute dermal toxicity investigation of nanosilver on serum chemical biomar...Nanomedicine Journal (NMJ)
Abstract
Objective(s):
Nanosilver is one of the most widely used nanomaterials due to its strong antimicrobial activity. Thus, because of increasing potential for exposure of human to nanosilver, there is an increasing concern about possible side effects of these nanoparticles. In this study, we tested the potential dermal toxicity of nanosilver bandage on serum chemical biomarkers in mice.
Materials and Methods:
In this study, 20 male BALB/c mice were randomly allocated into the treatment and control groups (n=10). After general anesthesia and shaving the back of all animals in near the vertebral column, in the nanosilver group, a volume of 50μl of 10 μg/ml of nanosilver solution (40 nm), and in the control group the same amount of distilled water was added to the sterile bandage of mice, then the bandages were fixed on the skin surface with cloth glue. After 3 and 7 days, the bandages were opened and serum levels of blood urea
nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by using standard kits for two groups of mice.
Results:
In treatment group, a significant increase in ALT, AST and BUN levels were observed compared with control group during experiment periods (p<0.05),>0.05).
Conclusion:
The present results indicated that the dermal absorption of 10 μg/ml nanosilver (40 nm) can lead to hepatotoxicity and renal toxicity in mice.
Inter Simple Sequence Repeats (ISSR) markers were utilized to identify the levels of heritable varieties and patterns of the populace structure among the five populaces of Pteris biaurita, a natural fern in India. A comprehensive examination was directed in three replicates at 2013-14 seasons in the Western Ghats, South India. Five wild P. biaurita, accessions (maiden hair) were assessed for genotyping studies. Results demonstrated a pivotal discrepancy among genotypes for they were characterized in view of this uniqueness in four groups by the genetic cluster examination. In this trial, ISSR primers amplified 63 polymorphic groups. In view of the genetic identity data, genotypes were figured and differed from 0.5714 to 0.6984. The percentage of polymorphism indicated predominant genotype that may be utilized for the conservation of species. ISSR appeared to be an obliging marker for prediction of genotype inside a closed group of inter specific populace in the investigation territory
Personalized nanomedicine for the treatment of vascular hypertensionSusanta Kumar Rout
This study includes designing a nanomedical device for the treatment of vascular hypertension in polycystic kidney diseases (PKD) model through cilia targeting.
They generated and compared two different metal and polymer cilia-targeted nanoparticle drug delivery systems (DDS), i.e. gold (Au) and poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs)
The target is Dopamine-receptor type-5 (DRS) on primary cilia.
The drug-loaded is Fenoldopam (FD).
Subacute dermal toxicity investigation of nanosilver on serum chemical biomar...Nanomedicine Journal (NMJ)
Abstract
Objective(s):
Nanosilver is one of the most widely used nanomaterials due to its strong antimicrobial activity. Thus, because of increasing potential for exposure of human to nanosilver, there is an increasing concern about possible side effects of these nanoparticles. In this study, we tested the potential dermal toxicity of nanosilver bandage on serum chemical biomarkers in mice.
Materials and Methods:
In this study, 20 male BALB/c mice were randomly allocated into the treatment and control groups (n=10). After general anesthesia and shaving the back of all animals in near the vertebral column, in the nanosilver group, a volume of 50μl of 10 μg/ml of nanosilver solution (40 nm), and in the control group the same amount of distilled water was added to the sterile bandage of mice, then the bandages were fixed on the skin surface with cloth glue. After 3 and 7 days, the bandages were opened and serum levels of blood urea
nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by using standard kits for two groups of mice.
Results:
In treatment group, a significant increase in ALT, AST and BUN levels were observed compared with control group during experiment periods (p<0.05),>0.05).
Conclusion:
The present results indicated that the dermal absorption of 10 μg/ml nanosilver (40 nm) can lead to hepatotoxicity and renal toxicity in mice.
Inter Simple Sequence Repeats (ISSR) markers were utilized to identify the levels of heritable varieties and patterns of the populace structure among the five populaces of Pteris biaurita, a natural fern in India. A comprehensive examination was directed in three replicates at 2013-14 seasons in the Western Ghats, South India. Five wild P. biaurita, accessions (maiden hair) were assessed for genotyping studies. Results demonstrated a pivotal discrepancy among genotypes for they were characterized in view of this uniqueness in four groups by the genetic cluster examination. In this trial, ISSR primers amplified 63 polymorphic groups. In view of the genetic identity data, genotypes were figured and differed from 0.5714 to 0.6984. The percentage of polymorphism indicated predominant genotype that may be utilized for the conservation of species. ISSR appeared to be an obliging marker for prediction of genotype inside a closed group of inter specific populace in the investigation territory
Microanatomical and Hormonal Studies of the Effects of Aqueous Cannabis sativa Leaf Extract on the Testis of Adult Wistar Rats
http://dx.doi.org/10.21276/SSR-IIJLS.2020.6.4.1
Anti-Fertility Effects of Nicotiana tabacum Leaf Smoke on the Spermatogenic Cells of the Adult Male Wistar Rats Testis
http://dx.doi.org/10.21276/SSR-IIJLS.2020.6.3.7
2006 a space oddity – the great pluto debate science _ the guardianGeorgi Daskalov
Long known as the ninth planet, Pluto was downgraded in 2006, sparking a scientific spat that raises basic questions about how we understand the universe
Getting cytisine licensed for use world-wide: a call to actionGeorgi Daskalov
Most tobacco users live in low and middle income countries where stop smoking medicines are unavailable or unaffordable. There is an urgent need for action by key stakeholders to get cytisine licensed worldwide so that its life-saving potential can be realised.
Evaluation of the efficacy and safety of tribulus terrestris in male sexual d...Georgi Daskalov
Evaluation of the efficacy and safety of tribulus terrestris in male sexual dysfunction – a prospective, randomized, double blinded, placebo controlled clinical trial 2015 poster
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
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Title: Sense of Taste
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 structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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.
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
In vivo modulation of dopaminergic nigrostriatal pathways by cytisine derivatives Implications for Parkinson's Disease
1. In vivo modulation of dopaminergic nigrostriatal pathways by cytisine derivatives:
Implications for Parkinson's Disease
J. Andrés Abin-Carriquiry a,
⁎, Gustavo Costa a
, Jessika Urbanavicius a
, Bruce K. Cassels b
,
Marco Rebolledo-Fuentes b
, Susan Wonnacott c
, Federico Dajas a
a
Department of Neurochemistry, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay
b
Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile
c
Department of Biology and Biochemistry, University of Bath, Bath, UK
A B S T R A C T
Keywords:
Cytisine
Dopamine
Neuroprotection
Parkinson's Disease
Nicotinic acetylcholine receptor
6-Hydroxydopamine
Nicotinic acetylcholine receptor agonists are considered potential pharmacological agents for Parkinson's Disease
treatment, due to their ability to improve experimental Parkinson symptomatology, reduce 3,4-dihydroxy-L-
phenylalanine-induced dyskinesias and stop the neurodegenerative process at an experimental level. In the
present work, the ability of the nicotinic agonist cytisine and two halogenated derivatives (3-bromocytisine and
5-bromocytisine) to induce striatal dopamine release was characterized in vivo by microdialysis. Cytisine,
5-bromocytisine and nicotine were much more efficacious than 3-bromocytisine in eliciting dopamine
release in response to their local application through the microdialysis probe. Moreover, the agonists were
intermittently administered before and after an intranigral injection of 6-hydroxydopamine (6-OHDA), and
striatal dopamine tissue levels were assessed 8 days after the lesion. Both cytisine and its 5-bromo derivative
(but not the 3-bromo derivative) significantly prevented the decrease of striatal dopamine tissue levels induced
by 6-OHDA. These results suggest that the efficacy of nicotinic agonists to stimulate dopamine release in vivo
through presynaptic nicotinic receptors could be related to their potential to induce striatal protection.
1. Introduction
The motor symptoms that are at the core of Parkinson's Disease –
rigidity, bradykinesia and postural instability – are linked to the loss of
nigrostriatal dopaminergic neurons (Singh et al., 2007). However, the
administration of 3,4-dihydroxy-L-phenylalanine (L-DOPA) or dopa-
mine receptor agonists, the key therapeutic strategies in use today to
improve the dopaminergic functions in Parkinson's Disease, are
unable to stop the neurodegenerative process (Singh et al., 2007).
Acetylcholine modulates the function of the nigrostriatal dopa-
mine system through multiple subtypes of nicotinic acetylcholine
receptors located postsynaptically on the neuronal cell bodies of the
substantia nigra and presynaptically on terminals at the corpus
striatum. Because nicotinic receptor activation increases the fre-
quency of firing at the neuronal bodies (Lichtensteiger et al., 1982;
Clarke et al., 1985) or causes neurotransmitter release at the dopa-
minergic terminals (Lichtensteiger et al., 1982; Clarke et al., 1985;
Kaiser and Wonnacott, 2000; Wonnacott et al., 2000; Zhou et al.,
2001; Zoli et al., 2002), nicotinic receptors are considered to be po-
tential therapeutic targets for the treatment of Parkinson's Disease
symptoms (Quik et al., 2007a, b). In addition, epidemiological studies
have shown that smokers have a lower incidence of Parkinson's
Disease and nicotine, a non-selective nicotinic receptor agonist, has
been postulated to be responsible for this effect (Baron, 1986; 1996;
Gorell et al., 1999).
Previously, we have shown that systemic administration of nicotine
partially prevents the decrease of dopamine levels in the corpus
striatum following administration of 6-hydroxydopamine (6-OHDA)
(Costa et al., 2001; Abin-Carriquiry et al., 2002; Urbanavicius et al.,
2007). As Quik et al. recently reviewed, other studies have confirmed
these results in different experimental models of Parkinson's Disease
(Visanji et al., 2006; Quik et al., 2006a, b, 2007c; Khwaja et al., 2007;
Urbanavicius et al., 2007).
Depending on the experimental paradigm, both α7 and/or α4β2
subtypes of nicotinic receptors have been described as mediating
protection by nicotine against various toxic insults in cell cultures
(Kihara et al., 1997, 1998; Hejmadi et al., 2003; Stevens et al., 2003),
consistent with a requirement for stimulation of more than one
receptor subtype for protection (O'Neill et al., 2002; Dajas-Bailador
and Wonnacott, 2004; Wonnacott et al., 2006). In vivo, although
nicotine-induced protection against experimental parkinsonian
lesions has been shown to be mediated by nicotinic receptor (Costa
et al., 2001), identification of particular receptor subtypes has not
⁎ Corresponding author. Department of Neurochemistry, Instituto de Investigaciones
Biológicas Clemente Estable, Avenida Italia 3318, 11600 Montevideo, Uruguay. Tel./fax:
+598 2 4872603.
E-mail addresses: abin@adinet.com.uy, abin.ja@gmail.com (J.A. Abin-Carriquiry).
2. been reported yet. Visanji et al. recently demonstrated that in contrast
to the non-selective agonist nicotine, subtype-selective nicotinic ago-
nists did not protect striatal dopamine terminals from a 6-OHDA insult
in rats (Visanji et al., 2006), suggesting that interaction with multiple
nicotinic receptor subtypes may be necessary to afford neuroprotection.
Cytisine, an alkaloid present in many plants of the Leguminosae
familyand a broad-specific nicotinic receptoragonist, has been shown to
protect cells in culture against toxic agents (Kihara et al., 1998; Jonnala
and Buccafusco, 2001). In this context, we recently studied a series of
cytisine derivatives in striatal slices, showing that halogenation in
positions 3 and 5 could increase or reduce respectively their potency to
induce dopamine release without significant changes in their selectivity
for nicotinic receptors subtypes (Abin-Carriquiry et al., 2006).
Given the potential of nicotinic receptor agonists as therapeutic
agents in Parkinson's Disease it appeared meaningful to extend the
characterization of cytisine and its bromo derivatives, studying their
pharmacological profile in vivo. In the present study we explored
the ability of cytisine, 3-bromocytisine (3-BrCy) and 5-bromocytisine
(5-BrCy) to induce dopamine release in vivo by microdialysis, as well
as their capacity to prevent the decline in dopamine tissue levels in
experimental Parkinson's Disease.
2. Materials and methods
2.1. Animals
Experiments were carried out using male Sprague–Dawley rats
(230–260 g). Animals had access to food and water ad libitum, and
were housed in groups of six in a temperature-controlled environ-
ment on a 12-h light/dark cycle.
Experimental procedures were approved by the CommitteeonEthical
Care and Use of Laboratory Animals of the Instituto de Investigaciones
Biológicas Clemente Estable in accordance with the National Institutes of
Health guide for the care and use of laboratory animals.
2.2. Materials
Chemicals for high performance liquid chromatography (HPLC)
analysis, artificial cerebrospinal fluid and saline were purchased from
Baker (Phillipsburg, PA, USA). Dopamine (hydrochloride), 3,4-dihy-
droxyphenylacetic acid, 6-OHDA, (−)-nicotine tartrate, and L-ascorbic
acid were obtained from Sigma (St. Louis, MO, USA). Chlorisondamine
was donated by Novartis Pharmaceuticals (NJ, USA).
2.3. Cytisinoids
Cytisine and its derivatives were obtained as previously described
(Houlihan et al., 2001; Slater et al., 2003) and used as the hydrochloride
salts. Briefly, cytisine was purified from the seeds of the Mexican plant
Sophora secundiflora using standard methodology. Bromination of
cytisine with a slight excess of molecular bromine in acetic acid led
to the formation of a mixture of products containing a small amount of
3,5-dibromocytisineand mainly3-BrCyand5-BrCy.Thesewereseparated
by column chromatography on silica gel, crystallized to homogeneity, and
characterized by 1
H and 13
C NMR and HREIMS. Definitive structure as-
signments were based on 1
H–1
H COSY experiments.
2.4. Microdialysis
Animals were anaesthetized with ketamine (90 mg/kg)/xylazine
(5 mg/kg) and placed in a D. Kopf stereotaxic frame. Through a skull
hole, a guide cannula (BAS, MD-2250) was implanted into the dorsal
striatum (caudate–putamen) and secured to the skull with steel
screws and dental cement. The coordinates for cannula implantation
were A/P=+0.6, L/M=+3.2, D/V=−3.2 from Bregma according to the
atlas of Paxinos and Watson (Paxinos and Watson, 1986). After sur-
gery, the rats were housed individually into test cages and allowed to
recover for 24–48 h. On the experimental day, a microdialysis probe
(BAS MD-2204, membrane length=4.0 mm) was inserted into the
cannula. The location of the tip of the microdialysis probe was −7.2.
The probe was connected to a microperfusion pump and continuously
perfused with artificial cerebrospinal fluid (147 mM NaCl, 3.4 mM
CaCl2, 4.0 mM KCl) at a flow rate of 2.0 μl/min. The sample collection
(30 μl sample every 15 min) was started after a 2-h equilibration
period. Concentrations of dopamine were determined immediately
using an Epsilon Electrochemical Detector e5P with oxidation
potential set at +0.650 V (glassy carbon working electrode versus a
Ag/AgCl reference electrode). The column (Phenomenex Luna, 5 μm,
C18, 4.6×100 mm) was kept at room temperature. The mobile phase
consisted of citric acid (0.15 M), sodium octylsulphate (0.6 mM), 4%
acetonitrile and 1.6% tetrahydrofuran at pH 3.0; with a flow rate of
1.0 ml/min. The average concentration of the first three dialysis
samples was determined as baseline and defined as 100%. Nicotinic
receptor agonist solutions were prepared in artificial cerebrospinal
fluid adjusting the pH to 7.0 with HCl/NaOH and perfused through the
dialysis probe during 15 min. Doses of nicotine utilized were
according to the literature (Marshall et al., 1997; Quarta et al., 2007).
At the end of each experiment, the probe was removed and the animal
sacrificed. The brain was immediately removed, dissected and frozen
for confirmation of probe localization (Abin-Carriquiry et al., 2002).
The in vitro recovery of each nicotinic agonist was measured from a
standard 1-mM solution by HPLC-UV. Eluate concentrations of nico-
tine, cytisine, 3-BrCyand 5-BrCy were determined immediately using a
Gilson UV–Visible 118 Detector at 255 nm. The column (Phenomenex
Luna, 5 μm, C18, 4.6×100 mm) was kept at room temperature. The
mobile phase consisted of acetic acid (50 mM), sodium octylsulphate
(0.6 mM) and 15% methanol at pH 3.7; with a flow rate of 1.4 ml/min. A
similar recovery of 17% was found for the different nicotinic agonists.
2.5. Intranigral injection of 6-OHDA
6-OHDA lesions were provoked by the injection of 6-OHDA into the
substantia nigra as previously described (Costa et al., 2001). Briefly,
animals were anaesthetized with halothane (Halocarbon Laboratories,
River Edge, NJ, USA) and placed in a D. Kopf stereotaxic frame. Through
a skull hole, the needle (0.022 mm o.d., 0.013 mm i.d.) of a Hamilton
syringe (5 μl) was attached to a micro-injection unit (D. Kopf), and was
lowered to the right substantia nigra (H, −4.8; L, −2.2; V, −7.2 from
bregma, according to the atlas of Paxinos and Watson). A total of 2.0 μl
of a 6-OHDA solution (3 mg/ml) prepared immediately before use, was
injected over 1 min and the needle was slowly withdrawn, allowing
the drug to diffuse for another 4 min. Body temperature was main-
tained at 37 °C using a temperature control system (Costa et al., 2001).
Control rats for 6-OHDA lesions were injected with 2 μl vehicle
(artificial cerebrospinal fluid with 0.2% ascorbic acid).
2.6. Agonists administration schedule
Rats (groups of 6–8) that had been injected with 6-OHDA (6 μg) in
the right substantia nigra received nicotinic receptor agonist or saline
subcutaneously, according to the following protocols: (1) 4 h before,
and 20, 44 and 68 h after 6-OHDA; (2) the same administration
schedule following treatment with the long-lasting nicotinic antago-
nist chlorisondamine (10 mg/kg s.c.) given 30 min before the first
application of nicotinic receptor agonist or saline. After chlorisonda-
mine administration, the motor activity of the rats decreased
showing also bilateral palpebral ptosis. These effects lasted a few
hours, with complete recovery afterwards. No other symptoms were
observed.
The starting dose (1 mg/kg) for cytisine and 5-BrCy protection
studies was similar to the one shown to be effective for nicotine in vivo
(Costa et al., 2001). In the case of 3-BrCy, a dose of 1 mg/kg induced
3. tonic–clonic convulsions that lasted approximately 5 min. These ef-
fects limited the concentrations that could be evaluated in vivo.
Since even after receiving 0.3 mg/kg 3-BrCy, animals still showed a
strong depressed motor activity and ptosis for approximately 1 h, the
doses studied were lowered (0.01, 0.05 and 0.10 mg/kg).
2.7. Neurochemical analysis
To measure dopamine tissue levels, rats were decapitated 8 days
after 6-OHDA injection, the brains rapidly removed and the left and right
corpus striatum dissected and stored at −70 °C. On the next day tissue
samples were weighed, sonicated in 1000 μl of perchloric acid (0.1 M)
and centrifuged (15,000 g) for 15 min. Samples were then injected into
an HPLC system (PM-80 BAS, West Lafayette, IN, USA) equipped with a
C18 column (5 μm particles, 220 mm×34.6 mm; BAS, USA) and an
electrochemical detector (LC-4C BAS) with oxidation potential set at
+0.75 V (glassy carbon working electrode versus a Ag/AgCl reference
electrode). The mobile phase was composed of citric acid (0.15 M),
sodiumoctylsulphate (0.6 mM),4%acetonitrile and 1.6% tetrahydrofuran
at pH 3.0; with a flow rate of 1.0 ml/min (Costa et al., 2001).
2.8. Statistical analysis
2.8.1. Microdialysis
Dopamine levels were calculated from a standard solution and
values were expressed as a percentage of basal levels (individual means
of three pre-drug fractions). Statistical analysis was carried out using
one- or two-way analysis of variance (ANOVA) for repeated measures of
the dopamine values followed by post-hoc t-test when appropriate.
2.8.2. Tissue levels
Dopamine levels in the lesioned hemisphere of each animal were
expressed as percent of the level in the unlesioned side. Comparison of
the means was performed by ANOVA followed by Tukey–Kramer
Multiple Comparison test.
3. Results
3.1. Striatal dopamine release evoked by cytisine and bromocytisines
The nicotinic agonists were evaluated for their ability to evoke
dopamine release in the striatum by in vivo microdialysis following
local application via the dialysis probe. Basal striatal extracellular
dopamine levels of dialysate (1.91±0.34 nM) were similar to those
obtained in our previous studies (Abin-Carriquiry et al., 2002). Local
perfusion of nicotine, cytisine and 5-BrCy increased extracellular
levels of dopamine in a concentration-dependent way (Fig. 1). 3-BrCy
was the most potent and release was obtained already with 0.33 mM
concentrations, showing little concentration-dependence over an
extended concentration range.
The comparison of dopamine release induced by cytisine and its
derivatives at10 mM concentrations showed that 5-BrCy was significantly
Fig. 1. Extracellular dopamine assessed by microdialysis in awake rats 24 h after the implantation of a cannula in the corpus striatum. Drugs were applied locally through the probe
and dopamine release was monitored after the application of nicotine, cytisine, 5-BrCy and 3-BrCy at different doses after three stable basal samples. Data are expressed as percent
over the basal levels (mean±S.E.M.). For each dose n=4–6. ⁎ denotes significant difference against controls (artificial cerebrospinal fluid, aCSF) (⁎Pb0.05). Δ ⁎ denotes significant
difference against agonist+chlorisondamine (Chl) 1 mM (ΔPb0.05).
4. more efficacious than cytisine and 3-BrCy, being 3-BrCy the less effi-
cacious (Fig. 1).
Perfusion of chlorisondamine (1 mM), a non-specific nicotinic
receptor antagonist, prevented the increase in dopamine release
induced by every agonist (Fig.1). Chlorisondamine alone did not affect
significantly the basal levels of dopamine (1.61±0.60 nM).
3.2. Prevention of striatal dopamine decrease after 6-OHDA injection
Eight days after intranigral injection of 6 μg of 6-OHDA, there was a
significant decrease in dopamine tissue levels in the ipsilateral stria-
tum (lesioned side) when compared with the contralateral (non-
lesioned side), (Fig. 2). Control rats injected in the substantia nigra
with 2 μl vehicle did not show any difference in dopamine levels
between ipsilateral and contralateral striatum (17.5±1.7 and 17.6±
2.8 ng/mg of wet tissue weight, respectively).
As reported previously (Costa et al., 2001), intermittent nicotine
administration (1 mg/kg, nicotine tartrate salt); significantly attenu-
ated the 6-OHDA-induced decrease in striatal dopamine tissue levels
(Fig. 2). Cytisine (2 mg/kg) and 5-BrCy (1 mg/kg), administered ac-
cording to the same schedule, prevented similarly the decrease of
striatal dopamine levels. In contrast, 3-BrCy (0.10 mg/kg) was unable
to prevent the decrease of striatal dopamine tissue levels induced by
6-OHDA (Fig. 2). Lower doses of 3-BrCy (0.01, 0.05 mg/kg) did not
prevent the dopamine decrease either (data not shown).
The protection afforded by cytisine and 5-BrCy was prevented
by the prior administration of the long-acting non-specific nicotinic
receptor antagonist chlorisondamine (10 mg/kg). Dopamine levels
(expressed as percent of lesioned versus intact corpus striatum) were
19.0±3.9%, 28.3±8.7% and 20.5±8.0% for saline, cytisine and 5-BrCy
treatments, respectively.
4. Discussion
Our data showed that local application of cytisine and its bromo
derivatives induced dopamine release in the corpus striatum, being
cytisine and 5-BrCy, as well as nicotine significantly more efficacious
than 3-BrCy.
Besides, cytisine and 5-BrCy prevented the decrease of striatal
dopamine tissue levels 8 days after the intranigral injection of 6-OHDA
in rats. To the extent of our knowledge, this is the first experimental
evidence of in vivo protection by nicotinic receptor agonists other than
nicotine. This protection was mediated by nicotinic receptor, since it
was blocked by chlorisondamine administration. However, pharma-
cological equivalent doses of 3-BrCy (taking into account that its
potency to induce dopamine release is more than one order of mag-
nitude higher than cytisine and 5-BrCy) did not have protective effect
against the 6-OHDA lesion.
In a previous work we compared the effects of cytisine halogena-
tion at C3 and C5 on α4β2 and α7 nicotinic receptor binding, showing
that both 3-BrCy and 5-BrCy presented higher affinity for heteromeric
α4β2 than for homomeric α7 nicotinic receptors. Additionally we
evaluated their ability to evoke [3
H]dopamine and [3
H]noradrenaline
release in striatal and hippocampal slices, respectively, showing that
both agonists presented greater potency as releasers of [3
H]dopamine
than of [3
H]noradrenaline. Nevertheless, both derivatives do not differ
significantly in subtype specificity between themselves or with
cytisine or nicotine (Cassels et al., 2005; Abin-Carriquiry et al., 2006).
In recent years an important line of experimental evidence has
shown the protective capacity of nicotine in in vivo experimental
models of Parkinson's Disease, an effect mediated by nicotinic
receptor agonism (Costa et al., 2001; Visanji et al., 2006; Quik et al.,
2006b, 2007a,c). Our results suggest that the prevention of striatal
dopamine decrease is not an exclusive property of nicotine but also of
other non-subtype specific nicotinic receptor agonists. Moreover we
showed that protection afforded by nicotinic agonists is blocked by
chlorisondamine, a non-specific nicotinic receptor blocker (Costa
et al., 2001). In this sense Visanji et al. showed that neither the
modulation of α4β2 nor α7 subtypes alone appears to provide
protection in vivo (Visanji et al., 2006). Taken together these results
would suggest that broad nicotinic receptor subtype specificity would
be necessary for prevention of dopaminergic terminal degeneration.
Nicotine, cytisine and 5-BrCy, which attenuated dopamine loss
after 6-OHDA were also the most efficacious in evoking dopamine
release. This latter effect was clearly dose-dependent and was blocked
by chlorisondamine. 3-BrCy, which failed to induce protective effects
in a wide concentration range, was also the least efficacious inducer of
dopamine release. In this sense, the agonist dopamine releasing
efficacy (reflecting efficacy at nicotinic receptors) appears to be more
relevant than potency itself to induce the plastic changes on the
dopaminergic pathway.
As an explanatory hypothesis, the experimental evidence suggests
that activation of nicotinic receptor leads to Ca2+
entry into the
terminal (Rapier et al., 1990; Grady et al., 1992; Puttfarcken et al.,
2000). The greater efficacy shown by cytisine and 5-BrCy inducing
dopamine release, could be associated to a major Ca2+
entry to the cell,
leading to activation of several steps in the synaptic vesicle cycle
(Smith et al., 1998; Stevens and Wesseling, 1998; Turner, 2004) and
triggering specific intracellular signalling cascades related to plastic
changes in dopamine metabolism and other key protective pathways
(Dajas-Bailador and Wonnacott, 2004).
However an indirect pathway, involving the activation of dopami-
nergic autoreceptors (Bozzi and Borrelli, 2006; Scheller et al., 2007)
could also explain the relationship between efficacy and protection.
Evidence based largely on experimental in vitro and in vivo rodent
studies is showing that dopamine agonists may have neuroprotective
properties in addition to their symptomatic effects (Le and Jankovic,
2001; Schapira, 2002). In this sense, ropinirole has been shown to
protect mouse striatal neurons against 6-OHDA toxicity, by stimulat-
ing the increase of glutathione, catalase and superoxide dismutase
antioxidant activities in the striatum, and this effect was mediated
through dopamine D2 receptor (Iida et al., 1999). Nevertheless, further
experiments are required in order to discriminate between both
mechanisms.
The results obtained in the present work show for the first time in
vivo, that efficacious non-selective nicotinic receptor agonists, other
than nicotine, are able to reduce striatal dopamine depletion induced
by 6-OHDA injection in the substantia nigra and efficaciously evoke
dopamine release in vivo.
Fig. 2. Striatal dopamine assessed 8 days after the injection of 6-OHDA (6 μg) in the
substantia nigra. Agonists (nicotine, cytisine, 5-BrCy and 3-BrCy) were subcutaneously
administered 4 h before, and 20, 44 and 68 h after 6-OHDA injection. Data are expressed
as percent (mean±S.E.M.) of lesioned versus intact corpus striatum. For each treatment
n=6–8. ⁎ denotes significant difference against the control group (⁎Pb0.05). Δ denotes
significant difference against the saline group (ΔPb0.05).
5. The protective effect of cytisine and 5-BrCy is a challenging result
that provides a new lead for understanding the central nervous sys-
tem plasticity mediated by nicotinic receptors, suggesting their po-
tential for Parkinson's Disease treatment.
Acknowledgements
This work was supported by the Wellcome Trust Collaborative
Research Initiative Grant 073295/Z/03/Z and FONDECYT Grant 1040776.
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