60                                 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, 3, 60-64


The The...
Melatonin & Neurological Disorders                               Recent Patents on Endocrine, Metabolic & Immune Drug Disc...
62 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1                                     ...
Melatonin & Neurological Disorders                             Recent Patents on Endocrine, Metabolic & Immune Drug Discov...
64 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1                                     ...
Upcoming SlideShare
Loading in...5
×

The Therapeutic Potential of Melatonin in Neurological Disorders

4,608

Published on

0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
4,608
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
19
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

The Therapeutic Potential of Melatonin in Neurological Disorders

  1. 1. 60 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, 3, 60-64 The Therapeutic Potential of Melatonin in Neurological Disorders Bhavini Bhavsar1, Muhammad U. Farooq2 and Archit Bhatt2,* 1 Department of Internal Medicine, Michigan State University, East Lansing, MI48824, USA 2Department of Neurology and Ophthalmology, Michigan State University, East Lansing, MI 48824, USA Received: October 14, 2008; Accepted: November 6, 2008; Revised: November 11, 2008 Abstract: Melatonin (N-acetyl-5- methoxytryptamine) is a pineal gland hormone, synthesized from amino acid L- tryptophan. Other tissues including retina, skin, and gastrointestinal tract also synthesize it. It is secreted into the cerebrospinal fluid and circulatory system in a circadian pattern. Its production is light:dark dependent and its levels are low during the day and maximal during the hours of darkness. It plays an important role in different physiological and pathophysiological processes in the brain, which includes regulation of biological rhythms and seasonal reproduction. Its biological activity is associated with its action on melatonin receptors - ML-1 and ML-2. It has antioxidant and neuroprotective propertities and potential therapeutic role in different neurological disorders. Melatonin has been used as a sleep-promoting agent; more recently it has also been used in headache, movement disorders, neuropathic pain, and seizure disorders. In this review, some recent patents also discussed. Keywords: Melatonin, neurological disorders. INTRODUCTION co-existing sleep disorders. Melatonin has shown to reduce seizure frequency in few reported cases. This effect is more Headache Syndromes and Neuropathic Pain pronounced in children with myoclonic and nocturnal There is altered melatonin secretion in migraine and seizure. The frequency of seizure decreased from 3.6 per day other headache syndromes [1]. Melatonin levels were found (base line) to 1.5 per day while on melatonin (3mg/day) from to be decreased in migraine and cluster headaches. Melatonin three to six month treatment period in a study conducted by has potential therapeutic role in these headache disorders Pedel et al. [16]. because of its antioxidant, anti-inflammatory, and antino- Melatonin has also been used (2-10mg) at bed time to ciceptive properties. The exact mechanism of the protective treat sleep disturbance in children with epilepsy. This effect effect of melatonin in headache occurrence is not clear. It might be responsible for the improved seizure control. might be due to its effect on beta-endorphins, nitric oxide, GABAergic, glutamatergic and opiate pathways [2, 3]. Its Jones et al. did a study on 13 people (11 children and 2 chemical structure is similar to indomethacin [4]. It showed adults) with seizure disorders, learning disabilities and its efficacy in patients with migraine, cluster headaches, behavioral problems [21]. The dose of melatonin ranged hemicrania continua, idiopathic stabbing headache, nocturnal from 2-6mg. Three out of 11 patients with seizure disorder headaches and delayed sleep phase syndrome [5-10]. It also had an increase in their seizure rate, seven had a decreased has potential role in migraine prevention and status seizure rate and one person did not have any observable migrainosus [5]. See Table 1 for details of these studies. difference. The beneficial effect of melatonin in this study was not statistically significant [21]. Seizure Disorders Cerebrovascular Disorders Role of melatonin in seizure disorders is controversial. It has unpredictable effects in patients with epilepsy. It has Melatonin has been shown neuroprotective in experi- been shown to have anticonvulsant [11-17] and procon- mental models of focal permanent and temporary cerebral vulsant properties [18-20] without any demonstrable infl- ischemia [23-27]. It has potential as add on therapy to tissue uence on seizure control [21]. It has also been shown to plasminogen activator for acute ischemic stroke cases as potentiate the efficacy of other antiepileptic drugs [22]. intravenous administration of melatonin reduces the intracerebral cellular inflammatory response after transient Its anti-convulsant effects might be due to the enhan- focal ischemia [28]. Its neuroprotective role might be related cement of inhibitory neurotransmitters like GABA, with its ability to scavenge and neutralize reactive oxygen inhibition of excitatory neurotransmitters like glutamate and species, stimulate antioxidative enzymes, increase levels of its potential antioxidant effects as well. The anticonvulsant phosphorylated mitogen-activated protein kinase/extra- effects of melatonin have been reported in children with cellular-regulated kinase-1/-2 and Jun kinase-1/-2, inhibit some learning disabilities and mental retardation. These endothelin converting enzyme (ECE-1) and some unknown children are also prone to have seizure disorder as a group. mechanisms [29-32]. Inhibition of ECE-1 improves vaso- Melatonin has been used in these children, especially with dilation after cerebral ischemia. Endogenous melatonin has protective effect during ischemia/reperfusion and its *Address correspondence to this author at the Department of Neurology and deficiency is associated with an increase infarct size [33-35]. Ophthalmology, A-217 Clinical Center, Michigan State University, East Melatonin may also be suitable as a prophylactic agent Lansing, MI 48824, USA; Tel: 517-353-8122; Fax: 517-432-9414; against stroke and maintaining higher blood melatonin levels E-mail: archit.bhatt@ht.msu.edu 1872-2148/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd.
  2. 2. Melatonin & Neurological Disorders Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1 61 Table 1. Melatonin in Headache Syndromes and Movement Disorders Author (Year) Type of Study Disorder Therapeutic Intervention Results Headache syndromes Peres Open label trial Migraine 3 mg of melatonin 30mins before bed time was 32/34 pts completed the study. 25/32 (2004) started in 34 migraine patients with and patients had at least 50% reduction. without aura 100% response in 8 , >75% in 7, 50- [5] 75% in 10 patients. Spears Case report Hemicrania Melatonin 7 mg at bed time Attacks were successfully eliminated (2006) Continua [6] (HC) Rozen (2006) Case reports Hemicrania 1st case-9 mg melatonin All three patients did well after starting [7] Continua (HC) 2nd case-9 mg melatonin + 6 mg extra at times melatonin and as far as they remained on melatonin. 3rd case-15 mg of melatonin with 75 mg of indomethacin Rozen Case reports Idiopathic 1st case-12 mg melatonin All patients remained headache free on (2003) stabbing headache nd 2 case- 6 mg melatonin, increased to 9 mg the dose of melatonin as mentioned (ISH) before. [8] 3rd case-3 mg melatonin Movement Disorders Shamir Double-blind, Tardive 2 mg/day of slow release melatonin, or Mean AIMS* scores did not change (2000) placebo- dyskinesia(TD) placebo for 4 weeks in 19 patients with significantly from baseline in either controlled, schizophrenia and TD. with 2-week washout treatment arm. All patients completed [60] crossover trial period the study withoutany side effects. Shamir Double-blind, Tardive 10 mg/d of melatonin for 6 weeks in 22 The decrease (mean +/- SD) in AIMS* (2001) placebo dyskinesia(TD) patients with schizophrenia and TD score was 2.45 +/- 1.92 for the controlled, melatonin and 0.77 +/- 1.11 for the [61] crossover study placebo treatment groups (P<.001). *AIMS-Abnormal Involuntary Movement Scale. may reduce the vulnerability of the brain to ischemic damage in preventing dopamine auto-oxidation [51, 52]. It can also in old age [31, 36]. It has protective effect on the preser- prevent lipid peroxidation induced by MPTP(1-methyl-4- vation of blood brain barrier permeability and decreasing the phenyl-1,2,3,6-tetrahydropyridine) and 6-OHDA(6- risk of hemorrhagic transformation after ischemic stroke hydroxydopamine) treatment in striatum, substantia nigra [37]. Melatonin can also prevent vasospasm after subara- and hippocampus in animal studies [39, 46-48]. It also has chnoid hemorrhage due to its antioxidant properties [38]. direct anti-oxidant effects and the ability to reduce the MPTP-induced loss of TH-reactive dopaminergic neurons Movement Disorders [42]. It has been shown that melatonin reduced free radical formation and preserved the glutathione concentrations in Melatonin has potential pharmacological role in different substantia nigra after MPTP treatment [44, 45, 53]. movement disorders including Parkinson’s disease (PD) and Melatonin also has protective role against apoptosis and can tardive dyskinesia. It has neuroprotective effects and prevent cell death from necrosis and apoptosis [54, 55]. prevents neurodegeneration in the nigrostriatal dopaminergic system as shown by different experimental models [39-48]. Tardive dyskinesia (TD) is a disabling problem associa- This protective effect is most likely due to its potent ted with antipsychotic treatment. The pathophysiology of TD antioxidant properties. Melatonin treatment has been showed has been linked to the disturbances of melatonin secretion to restore the rotenone-induced decrease in glutathione level [56-59]. The production of neurotoxic free radicals as a and changes in antioxidant enzymes including superoxide result of antipsychotic treatment might be related to the dismutase and catalase in substantia nigra [49]. development of TD. Melatonin as an antioxidant has been evaluated for the treatment of this serious neurological side Sandyk for the first time proposed that the deregulation effect of neuroleptic treatment [60, 61]. of the secretory activity of pineal melatonin may be asso- ciated with the pathophysiology and clinical manifestations Alzheimer’s disease, Cognitive and Learning Disorders of Parkinson's disease [50]. Further studies showed that it Cytotoxic activity of free radicals plays an important role can inhibit the pro-oxidant effects of dopamine and levo- in neurodegenerative disorders including dementia. dopa and is more effective than trolox, a vitamin E analogue,
  3. 3. 62 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1 Bhatt et al. Dementia is associated with circadian rhythm disturbances some oncogenesis-related genes [80-82]. Yang et al. resulting in alteration in body hormonal levels including demonstrated that melatonin inhibits pituitary prolactin melatonin [62, 63]. It is well documented that melatonin secreting tumor cell growth by inducing apoptosis [83]. levels are lower in AD patients as compared to age-matched Melatonin increased the activity of caspse-3 and the control subjects [64-69]. Wu et al described the distribution expression of Bax m RNA and cytochrome c protein. Bcl-2 of the melatonin receptor MT1 in the human hypothalamus m RNA expression and mitochondrial membrane potential and pituitary [70]. Other studies have demonstrated the were inhibited after melatonin treatment in this study [83]. impairment of MT1-mediated effects of Melatonin on the There is alteration of melatonin level after radiation therapy hypothalamic suprachiasmatic nucleus in aging and AD in some patients [84]. patients [71]. Brunner et al showed the immunohisto- chemical evidence for alteration of melatonin receptors Sleep (MT1 and MT2) in the human pineal gland and occipital Melatonin helps people with different neurological cortex in AD [72]. These changes might be related with disorders to sleep in a better way [21]. For example Clement neuropathology and clinical symptoms of AD. et al. disclosed the use of multi-layered solid dosage form Melatonin therapy might have potential efficacy and for of Melatonin to promote and maintain a state of sleep in neuroprotective role in some patients with Alzheimer’s an individual [85]. It can be helpful in combination for disease (AD) due to its remarkable antioxidant properties. example Bilodeau et al. disclosed the use of atypical Jean-Louis et al. reported the effects of melatonin antipsychotics, in combination with hypnotics, anxiolytics, administration in two patients with AD [73,74] for example melatonin etc. for treatment of neurological and psychiatric Wong et al. disclosed a pharmaceutical composition for disorders [86]. In addition to the above-mentioned co-morbid treating pathological condition associated with a melatonin conditions melatonin has been extensively studied especially receptor such as neurodegenerative diseases (Parkinson's in pediatric population. Circadian rhythm disorders are disease (PD), Alzheimer's disease (AD) [75]. Melatonin characterized by insomnia and excessive sleepiness. They enhanced and stabilized the circadian rest-activity rhythm in are primarily due to poor or altered sleep hygiene. Melatonin one of the patients along with some reduction of day time is not an FDA-approved drug for the treatment of circadian sleepiness and mood improvement [73]. The results of this rhythm disorders as. There have been studies ranging from study are not statistically significant because of small sample small uncontrolled to large randomized controlled trials. size. Therefore, the supplementary use of melatonin in AD Two meta-analysis have been carried out. One meta-analyses patients cannot be recommended base of the results of these [87] concluded that it improved sleep in patients with small studies. insomnia. A second meta-analysis concluded that melatonin was safe in short term (<3 months), but was not effective in Meningitis and Encephalomyelitis sleep disorders related to jet lag or shift work [88]. This finding underscores the utility of melatonin in patients who Bacterial meningitis may result in neuronal injury and actually do respond, especially in delayed sleep phase neurological sequelae due to the direct toxic effects of syndrome. It was criticized, as it did not include all bacterial components and different other oxidative mecha- nisms. Melatonin has potential beneficial role in meningitis controlled trials. It was also concluded that successful use of melatonin for jet lag and shift work requires correct timing. and encephalitis due to its ability to act as free radical Uncontrolled exposure to light, individual unscheduled sleep scavenger and to induce interleukin-1 beta production. times contribute to incorrect timings. It is still a challenge to Interleukin-1 beta is an important cytokine which can assess and predict the right circadian timing prior to augment the expression of inducible nitric oxide synthase melatonin treatment [89]. A recent trial concluded that (NOS) in viral encephalitis. Gerber et al. demonstrated that melatonin reduced the cellular damage in experimental melatonin was effective in patients who had low pretreat- ment melatonin levels in adults with developmental brain Streptococcus pneumoniae meningitis [76]. In this study, the disorders [90]. Moreover, Exogenous melatonin a relatively activity of superoxide dismutase in hippocampal formation safe substance when used in the short term, but the relative was higher and the density of apoptotic dentate granule cells safety for long term use is unclear. The most commonly was lower in melatonin treated animals [76]. Another animal reported side effects of melatonin were nausea, headache, study conducted by Spreer et al. did not show the reduction in neuronal injury in gram-positive Streptococcus pneu- dizziness, and drowsiness; however, these effects were not significant compared to placebo [91]. Future of melatonin moniae or gram-negative Escherichia coli meningitis with looks promising, although long term efficacy trials are melatonin therapy [77]. Valero et al. demonstrated that needed. Also further research is needed for feasible pretreat- melatonin treatment decreased nitrite concentration and lipid ment assessment of circadian rhythm. peroxidation products in brain of mice with Venezuelan equine encephalomyelitis(VEE) indicating its potential role CURRENT & FUTURE DEVELOPMENTS in human VEE viral infection [78]. Melatonin has also been studied in animal models of sepsis showing its efficacy to Melatonin might have potential beneficial role in the counteract inducible mitochondrial nitric oxide synthase- neurological disorders mentioned. dependent mitochondrial dysfunction [79]. However, most of the current data lacks large sample sizes and long-term longitudinal efficacy and safety for these Neurooncology disorders. Thus, the role of melatonin in these conditions Melatonin has significant anti-tumor effect against a needs to be elucidated more comprehensively. Its exact place variety of malignancies by its action on the expression of
  4. 4. Melatonin & Neurological Disorders Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1 63 in the treatment of individual disorders warrants further [26] Duan Q, Wang Z, Lu T, Chen J, Wang X. Comparison of 6- clarification. hydroxylmelatonin or melatonin in protecting neurons against ischemia/reperfusion-mediated injury. J Pineal Res 2006 ; 41: 351- REFERENCES 357. [27] Letechipia-Vallejo G, Lopez-Loeza E, Espinoza-Gonzalez V, et al. [1] Claustrat B, Loisy C, Brun J, Beorchia S, Arnaud JL, Chazot G. Long-term morphological and functional evaluation of the Nocturnal plasma melatonin levels in migraine: A preliminary neuroprotective effects of post-ischemic treatment with melatonin report. Headache 1989; 29: 242-245. in rats. J Pineal Res 2007; 42: 138-146. [2] Shavali S, Ho B, Govitrapong P, et al. Melatonin exerts its [28] Lee MY, Kuan YH, Chen HY, et al. Intravenous administration of analgesic actions not by binding to opioid receptor subtypes but by melatonin reduces the intracerebral cellular inflammatory response increasing the release of beta-endorphin an endogenous opioid. following transient focal cerebral ischemia in rats. J Pineal Res Brain Res Bull 2005 30; 64: 471-479. 2007; 42: 297-309. [3] Peres MF. Melatonin, the pineal gland and their implications for [29] Li XJ, Zhang LM, Gu L, Zhang AZ, Sun FJ. Melatonin decreases headache disorders. Cephalalgia 2005; 25: 403-411. production of the hydroxyl radical during cerebral ischemia- [4] Peres MF, Stiles MA, Oshinsky M, Rozen TD. Remitting form of reperfusion. Acta Pharmacol Sin 1997; 18: 394-396. hemicrania continua with seasonal pattern. Headache 2001; 41: [30] Rodriguez C, Mayo JC, Sainz RM, et al. Regulation of antioxidant 592-594. enzymes: A significant role for melatonin. J Pineal Res 2004; 36: 1- [5] Peres MF, Zukerman E, da Cunha TF, Moreira FR, Cipolla-Neto J. 9. Melatonin, 3 mg, is effective for migraine prevention. Neurology [31] Kilic E, Kilic U, Reiter RJ, Bassetti CL, Hermann DM. 2004; 63: 757. Prophylactic use of melatonin protects against focal cerebral [6] Spears RC. Hemicrania continua: A case in which a patient ischemia in mice: Role of endothelin converting enzyme-1. J Pineal experienced complete relief on melatonin. Headache 2006; 46: 524- Res 2004 ; 37: 247-251. 527. [32] Kilic U, Kilic E, Reiter RJ, Bassetti CL, Hermann DM. Signal [7] Rozen TD. Melatonin responsive hemicrania continua. Headache transduction pathways involved in melatonin-induced neuro- 2006; 46: 1203-1204. protection after focal cerebral ischemia in mice. J Pineal Res 2005; [8] Rozen TD. Melatonin as treatment for idiopathic stabbing 38: 67-71. headache. Neurology 2003; 61: 865-866. [33] Joo JY, Uz T, Manev H. Opposite effects of pinealectomy and [9] Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. melatonin administration on brain damage following cerebral focal Melatonin versus placebo in the prophylaxis of cluster headache: a ischemia in rat. Restor Neurol Neurosci 1998; 13: 185-191. double-blind pilot study with parallel groups. Cephalalgia 1996; 16: [34] Kilic E, Ozdemir YG, Bolay H, Kelestimur H, Dalkara T. 494-496. Pinealectomy aggravates and melatonin administration attenuates [10] Nagtegaal JE, Smits MG, Swart AC, Kerkhof GA, van der Meer brain damage in focal ischemia. J Cereb Blood Flow Metab 1999; YG. Melatonin-responsive headache in delayed sleep phase 19: 511-516. syndrome: Preliminary observations. Headache 1998; 38: 303-307. [35] Cho S, Joh TH, Baik HH, Dibinis C, Volpe BT. Melatonin [11] Reiter RJ, Morgan WW. Attempts to characterize the convulsive administration protects CA1 hippocampal neurons after transient response of parathyroidectomized rats to pineal gland removal. forebrain ischemia in rats. Brain Res 1997; 755: 335-338. Physiol Behav 1972; 9: 203-208. [36] Reiter RJ, Tan DX, Leon J, Kilic U, Kilic E. When melatonin gets [12] Mevissen M, Ebert U. Anticonvulsant effects of melatonin in on your nerves: its beneficial actions in experimental models of amygdala-kindled rats. Neurosci Lett 1998; 257: 13-16. stroke. Exp Biol Med (Maywood) 2005; 23: 104-117. [13] Costa-Lotufo LV, Fonteles MM, Lima IS, et al. Attenuating effects [37] Chen TY, Lee MY, Chen HY, et al. Melatonin attenuates the of melatonin on pilocarpine-induced seizures in rats. Comp postischemic increase in blood-brain barrier permeability and Biochem Physiol C Toxicol Pharmacol 2002; 131: 521-529. decreases hemorrhagic transformation of tissue-plasminogen [14] Yildirim M, Marangoz C. Anticonvulsant effects of melatonin on activator therapy following ischemic stroke in mice. J Pineal Res penicillin-induced epileptiform activity in rats. Brain Res 2006; 2006 ; 40: 242-250. 1099: 183-188. [38] Aydin MV, Caner H, Sen O, et al. Effect of melatonin on cerebral [15] Fauteck J, Schmidt H, Lerchl A, Kurlemann G, Wittkowski W. vasospasm following experimental subarachnoid hemorrhage. Melatonin in epilepsy: First results of replacement therapy and first Neurol Res 2005; 27: 77-82. clinical results. Biol Signals Recept 1999; 8: 105-110. [39] Kim YS, Joo WS, Jin BK, Cho YH, Baik HH, Park CW. Melatonin [16] Peled N, Shorer Z, Peled E, Pillar G. Melatonin effect on seizures in protects 6-OHDA-induced neuronal death of nigrostriatal children with severe neurologic deficit disorders. Epilepsia 2001; dopaminergic system. Neuroreport 1998 13; 9: 2387-2390. 42: 1208-1210. [40] Sharma R, McMillan CR, Tenn CC, Niles LP. Physiological [17] Molina-Carballo A, Munoz-Hoyos A, Reiter RJ, et al. Utility of neuroprotection by melatonin in a 6-hydroxydopamine model of high doses of melatonin as adjunctive anticonvulsant therapy in a Parkinson's disease. Brain Res 2006; 12(1068): 230-236. child with severe myoclonic epilepsy: Two years experience. J [41] Singh S, Ahmed R, Sagar RK, Krishana B. Neuroprotection of the Pineal Res 1997; 23: 97-105. nigrostriatal dopaminergic neurons by melatonin in [18] Sandyk R, Tsagas N, Anninos PA. Melatonin as a proconvulsive hemiparkinsonium rat. Indian J Med Res 2006; 124: 419-426. hormone in humans. Int J Neurosci 1992; 63: 125-135. [42] Antolin I, Mayo JC, Sainz RM, et al. Protective effect of melatonin [19] Stewart LS, Leung LS. Hippocampal melatonin receptors modulate in a chronic experimental model of Parkinson's disease. Brain res seizure threshold. Epilepsia 2005; 46: 473-480. 2002; 943: 163-173. [20] Sheldon SH. Pro-convulsant effects of oral melatonin in [43] Ortiz GG, Crespo-Lopez ME, Moran-Moguel C, Garcia JJ, Reiter neurologically disabled children. Lancet 1998 25; 351: 1254. RJ, Acuna-Castroviejo D. Protective role of melatonin against [21] Jones C, Huyton M, Hindley D. Melatonin and epilepsy. Arch Dis MPTP-induced mouse brain cell DNA fragmentation and apoptosis Child 2005; 90: 1203-1204. in vivo. Neuro Endocrinol Lett 2001; 22: 101-108. [22] Borowicz KK, Kaminski R, Gasior M, Kleinrok Z, Czuczwar SJ. [44] Khaldy H, Escames G, Leon J, Bikjdaouene L, Acuna-Castroviejo Influence of melatonin upon the protective action of conventional D. Synergistic effects of melatonin and deprenyl against MPTP- anti-epileptic drugs against maximal electroshock in mice. Eur induced mitochondrial damage and DA depletion. Neurobiol Aging Neuropsychopharmacol 1999; 9: 185-190. 2003; 24: 491-500. [23] MacLeod MR, O'Collins T, Horky LL, Howells DW, Donnan GA. [45] Chen ST, Chuang JI, Hong MH, Li EI. Melatonin attenuates MPP+- Systematic review and meta-analysis of the efficacy of melatonin in induced neurodegeneration and glutathione impairment in the experimental stroke. J Pineal Res 2005; 38: 35-41. nigrostriatal dopaminergic pathway. J Pineal Res 2002; 32: 262- [24] Lee EJ, Lee MY, Chen HY, et al. Melatonin attenuates gray and 269. white matter damage in a mouse model of transient focal cerebral [46] Jin BK, Shin DY, Jeong MY, et al. Melatonin protects nigral ischemia. J Pineal Res 2005; 38: 42-52. dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+) [25] Tutunculer F, Eskiocak S, Basaran UN, Ekuklu G, Ayvaz S, neurotoxicity in rats. Neurosci Lett 1998; 245: 61-64. Vatansever U. The protective role of melatonin in experimental hypoxic brain damage. Pediatr Int 2005; 47: 434-439.
  5. 5. 64 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1 Bhatt et al. [47] Joo WS, Jin BK, Park CW, Maeng SH, Kim YS. Melatonin gland: Colocalization of MT1 with vasopressin, oxytocin, and increases striatal dopaminergic function in 6-OHDA-lesioned rats. corticotropin-releasing hormone. J Comp Neurol 2006; 499: 897- Neuroreport 1998; 9: 4123-4126. 910. [48] Acuna-Castroviejo D, Coto-Montes A, Gaia Monti M, Ortiz GG, [71] Wu YH, Zhou JN, Van Heerikhuize J, Jockers R, Swaab DF. Reiter RJ. Melatonin is protective against MPTP-induced striatal Decreased MT1 melatonin receptor expression in the and hippocampal lesions. Life Sci 1997; 60: PL23-29. suprachiasmatic nucleus in aging and Alzheimer's disease. [49] Saravanan KS, Sindhu KM, Mohanakumar KP. Melatonin protects Neurobiol Aging 2007; 28: 1239-1247. against rotenone-induced oxidative stress in a hemiparkinsonian rat [72] Brunner P, Sozer-Topcular N, Jockers R, et al. Pineal and cortical model. J Pineal Res 2007; 42: 247-253. melatonin receptors MT1 and MT2 are decreased in Alzheimer's [50] Sandyk R. Pineal melatonin functions: Possible relevance to disease. Eur J Histochem 2006; 50: 311-316. Parkinson's disease. Int J Neurosci 1990; 50: 37-53. [73] Jean-Louis G, Zizi F, von Gizycki H, Taub H. Effects of melatonin [51] Miller JW, Selhub J, Joseph JA. Oxidative damage caused by free in two individuals with Alzheimer's disease. Perceptual and motor radicals produced during catecholamine autoxidation: protective skills. 1998; 87: 331-339. effects of O-methylation and melatonin. Free Radic Biol Med 1996; [74] [74] Lopez BD, Debeljuk L. Prenatal melatonin and its interaction 21: 241-249. with tachykinins in the hypothalamic-pituitary-gonadal axis. [52] Khaldy H, Escames G, Leon J, Vives F, Luna JD, Acuna- Reprod Fertil Dev 2007; 19: 443-451. Castroviejo D. Comparative effects of melatonin, L-deprenyl, [75] Wong, Y. H., Ho, M. K. C., Hu, Y., New, D. C., He, X., Pang, H.: Trolox and ascorbate in the suppression of hydroxyl radical WO08092292A1 (2008). formation during dopamine autoxidation in vitro. J Pineal Res 2000; [76] Gerber J, Lotz M, Ebert S, et al. Melatonin is neuroprotective in 29: 100-107. experimental Streptococcus pneumoniae meningitis. J Infect Dis. [53] Thomas B, Mohanakumar KP. Melatonin protects against oxidative 2005; 191: 783-790. stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in [77] Spreer A, Gerber J, Baake D, Hanssen M, Huether G, Nau R. the mouse nigrostriatum. J Pineal Res 2004; 36: 25-32. Antiinflammatory but no neuroprotective effects of melatonin under [54] Iacovitti L, Stull ND, Johnston K. Melatonin rescues dopamine clinical treatment conditions in rabbit models of bacterial neurons from cell death in tissue culture models of oxidative stress. meningitis. J Neurosci Res 2006; 84: 1575-1579. Brain Res 1997; 768: 317-326. [78] Valero N, MarinaEspina L, Bonilla E, Mosquera J. Melatonin [55] Mayo JC, Sainz RM, Antolin I, Rodriguez C. Ultrastructural decreases nitric oxide production and lipid peroxidation and confirmation of neuronal protection by melatonin against the increases interleukin-1 beta in the brain of mice infected by the neurotoxin 6-hydroxydopamine cell damage. Brain Res 1999; 818: Venezuelan equine encephalomyelitis virus. J Pineal Res 2007; 42: 221-227. 107-112. [56] Sandyk R, Kay SR. The relationship of pineal calcification and [79] Escames G, Lopez LC, Tapias V, et al. Melatonin counteracts melatonin secretion to the pathophysiology of tardive dyskinesia inducible mitochondrial nitric oxide synthase-dependent mito- and Tourette's syndrome. Int J Neurosci 1991; 58: 215-247. chondrial dysfunction in skeletal muscle of septic mice. J Pineal [57] Sandyk R. The relationship of pineal calcification to subtypes of Res 2006; 40: 71-78. tardive dyskinesia in bipolar patients. Int J Neurosci 1990; 54: 307- [80] Vijayalaxmi TCR Jr, Reiter RJ, Herman TS. Melatonin: From basic 313. research to cancer treatment clinics. J Clin Oncol 2002; 20: 2575- [58] Sandyk R. The association of pineal calcification with drug-induced 2601. dystonic movements. Int J Neurosci 1990; 53: 217-222. [81] Martin V, Herrera F, Carrera-Gonzalez P, et al. Intracellular [59] Sandyk R, Fisher H. Increased incidence and severity of signaling pathways involved in the cell growth inhibition of glioma neuroleptic-induced movement disorder in pinealectomized rats. Int cells by melatonin. Cancer Res 2006; 66: 1081-1088. J Neurosci 1989; 48: 303-308. [82] Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, [60] Shamir E, Barak Y, Plopsky I, Zisapel N, Elizur A, Weizman A. Is Vesnushkin GM, Vinogradova IA. Melatonin as antioxidant, melatonin treatment effective for tardive dyskinesia? J Clin geroprotector and anticarcinogen. Biochim Biophys Acta 2006; Psychiatry 2000; 61: 556-558. 1757: 573-589. [61] Shamir E, Barak Y, Shalman I, et al. Melatonin treatment for [83] Yang QH, Xu JN, Xu RK, Pang SF. Antiproliferative effects of tardive dyskinesia: A double-blind, placebo-controlled, crossover melatonin on the growth of rat pituitary prolactin-secreting tumor study. Arch Gen Psychiatry 2001; 58: 1049-1052. cells in vitro. J Pineal Res 2007; 42: 172-179. [62] Minors DS, Rabbitt PM, Worthington H, Waterhouse JM. Variation [84] Wion-Barbot N, Berger F, Wion D. Should we control the pineal in meals and sleep-activity patterns in aged subjects; its relevance to status of patients following brain radiotherapy? J Neurooncol 2005 ; circadian rhythm studies. Chronobiol Int 1989; 6: 139-146. 74: 335. [63] Van Gool WA, Mirmiran M. Aging and circadian rhythms. Prog [85] Clement, K., Chaudhur, S.: US20080254121 (2008). Brain Res 1986; 70: 255-277. [86] Bilodeau, M. T., Nanda, K.K., Trotter, B.W.: WO2008124030A1 [64] Skene DJ, Vivien-Roels B, Sparks DL, et al. Daily variation in the (2008). concentration of melatonin and 5-methoxytryptophol in the human [87] Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous pineal gland: effect of age and Alzheimer's disease. Brain Res 1990; melatonin on sleep: A meta-analysis. Sleep Med Rev 2005; 9: 41- 528: 170-174. 50. [65] Uchida K, Okamoto N, Ohara K, Morita Y. Daily rhythm of serum [88] Buscemi N, VandermeerB, Hooton N, et al. Efficacy and safety of melatonin in patients with dementia of the degenerate type. Brain exogenous melatonin for secondary sleep disorders and sleep Res 1996; 717(1-2): 154-159. disorders accompanying sleep restriction: Meta-analysis. Br Med J [66] Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF. 2006; 332: 385-393. Decreased melatonin levels in postmortem cerebrospinal fluid in [89] Arendt J. Does melatonin improve sleep? Efficacy of melatonin. Br relation to aging, Alzheimer's disease, and apolipoprotein E- Med J 2006; 332: 550. epsilon4/4 genotype. J Clin Endocrinol Metab 1999; 84: 323-327. [90] Laakso ML, Lindblom N, Leinonen L, Kaski M. Endogenous [67] Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, melatonin predicts efficacy of exogenous melatonin in con- Okawa M. Melatonin secretion rhythm disorders in patients with solidation of fragmented wrist-activity rhythm of adult patients with senile dementia of Alzheimer's type with disturbed sleep-waking. developmental brain disorders: A double blind, placebo-controlled, Biol Psychiatry 1999; 45: 417-421. crossover study. Sleep Med 2007; 8(2): 222-239. [68] Ohashi Y, Okamoto N, Uchida K, Iyo M, Mori N, Morita Y. Daily [91] Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for rhythm of serum melatonin levels and effect of light exposure in Treatment of Sleep Disorders. Summary, Evidence Report/ patients with dementia of the Alzheimer's type. Biol Psychiatry Technology Assessment: Number 108. AHRQ Publication Number 1999; 45: 1646-1652. 05-E002-1, November 2004. Agency for Healthcare Research and [69] Ferrari E, Arcaini A, Gornati R, et al. Pineal and pituitary- Quality, Rockville, MD. http: //www.ahrq.gov/clinic/ adrenocortical function in physiological aging and in senile epcsums/melatsum.htm dementia. Exp Gerontol 2000; 35: 1239-1250. [70] Wu YH, Zhou JN, Balesar R, et al. Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary

×