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 Ltryptophan. 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 Headache Syndromes and Neuropathic Pain There is altered melatonin secretion in migraine and other headache syndromes [1]. Melatonin levels were found to be decreased in migraine and cluster headaches. Melatonin has potential therapeutic role in these headache disorders because of its antioxidant, anti-inflammatory, and antinociceptive properties. The exact mechanism of the protective effect of melatonin in headache occurrence is not clear. It might be due to its effect on beta-endorphins, nitric oxide, GABAergic, glutamatergic and opiate pathways [2, 3]. Its chemical structure is similar to indomethacin [4]. It showed its efficacy in patients with migraine, cluster headaches, hemicrania continua, idiopathic stabbing headache, nocturnal headaches and delayed sleep phase syndrome [5-10]. It also has potential role in migraine prevention and status migrainosus [5]. See Table 1 for details of these studies. Seizure Disorders Role of melatonin in seizure disorders is controversial. It has unpredictable effects in patients with epilepsy. It has been shown to have anticonvulsant [11-17] and proconvulsant properties [18-20] without any demonstrable influence on seizure control [21]. It has also been shown to potentiate the efficacy of other antiepileptic drugs [22]. Its anti-convulsant effects might be due to the enhancement of inhibitory neurotransmitters like GABA, inhibition of excitatory neurotransmitters like glutamate and its potential antioxidant effects as well. The anticonvulsant effects of melatonin have been reported in children with some learning disabilities and mental retardation. These children are also prone to have seizure disorder as a group. Melatonin has been used in these children, especially with
*Address correspondence to this author at the Department of Neurology and Ophthalmology, A-217 Clinical Center, Michigan State University, East Lansing, MI 48824, USA; Tel: 517-353-8122; Fax: 517-432-9414; E-mail: archit.bhatt@ht.msu.edu 1872-2148/09 $100.00+.00

co-existing sleep disorders. Melatonin has shown to reduce seizure frequency in few reported cases. This effect is more pronounced in children with myoclonic and nocturnal seizure. The frequency of seizure decreased from 3.6 per day (base line) to 1.5 per day while on melatonin (3mg/day) from three to six month treatment period in a study conducted by Pedel et al. [16]. Melatonin has also been used (2-10mg) at bed time to treat sleep disturbance in children with epilepsy. This effect might be responsible for the improved seizure control. Jones et al. did a study on 13 people (11 children and 2 adults) with seizure disorders, learning disabilities and behavioral problems [21]. The dose of melatonin ranged from 2-6mg. Three out of 11 patients with seizure disorder had an increase in their seizure rate, seven had a decreased seizure rate and one person did not have any observable difference. The beneficial effect of melatonin in this study was not statistically significant [21]. Cerebrovascular Disorders Melatonin has been shown neuroprotective in experimental models of focal permanent and temporary cerebral ischemia [23-27]. It has potential as add on therapy to tissue plasminogen activator for acute ischemic stroke cases as intravenous administration of melatonin reduces the intracerebral cellular inflammatory response after transient focal ischemia [28]. Its neuroprotective role might be related with its ability to scavenge and neutralize reactive oxygen species, stimulate antioxidative enzymes, increase levels of phosphorylated mitogen-activated protein kinase/extracellular-regulated kinase-1/-2 and Jun kinase-1/-2, inhibit endothelin converting enzyme (ECE-1) and some unknown mechanisms [29-32]. Inhibition of ECE-1 improves vasodilation after cerebral ischemia. Endogenous melatonin has protective effect during ischemia/reperfusion and its deficiency is associated with an increase infarct size [33-35]. Melatonin may also be suitable as a prophylactic agent against stroke and maintaining higher blood melatonin levels
2009 Bentham Science Publishers Ltd.

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

Type of Study Disorder Therapeutic Intervention Results

Author (Year) Headache syndromes Peres (2004) [5] Spears (2006) [6] Rozen (2006) [7]

Open label trial

Migraine

3 mg of melatonin 30mins before bed time was started in 34 migraine patients with and without aura

32/34 pts completed the study. 25/32 patients had at least 50% reduction. 100% response in 8 , >75% in 7, 5075% in 10 patients. Attacks were successfully eliminated

Case report

Hemicrania Continua (HC)

Melatonin 7 mg at bed time

Case reports

Hemicrania Continua (HC)

1st case-9 mg melatonin 2nd case-9 mg melatonin + 6 mg extra at times 3rd case-15 mg of melatonin with 75 mg of indomethacin

All three patients did well after starting melatonin and as far as they remained on melatonin.

Rozen (2003) [8] Movement Disorders Shamir (2000) [60] Shamir (2001) [61]

Case reports

Idiopathic stabbing headache (ISH)

1st case-12 mg melatonin 2 case- 6 mg melatonin, increased to 9 mg 3rd case-3 mg melatonin

nd

All patients remained headache free on the dose of melatonin as mentioned before.

Double-blind, placebocontrolled, crossover trial Double-blind, placebo controlled, crossover study

Tardive dyskinesia(TD)

2 mg/day of slow release melatonin, or placebo for 4 weeks in 19 patients with schizophrenia and TD. with 2-week washout period 10 mg/d of melatonin for 6 weeks in 22 patients with schizophrenia and TD

Mean AIMS* scores did not change significantly from baseline in either treatment arm. All patients completed the study withoutany side effects. The decrease (mean +/- SD) in AIMS* score was 2.45 +/- 1.92 for the melatonin and 0.77 +/- 1.11 for the placebo treatment groups (P<.001).

Tardive dyskinesia(TD)

*AIMS-Abnormal Involuntary Movement Scale.

may reduce the vulnerability of the brain to ischemic damage in old age [31, 36]. It has protective effect on the preservation of blood brain barrier permeability and decreasing the risk of hemorrhagic transformation after ischemic stroke [37]. Melatonin can also prevent vasospasm after subarachnoid hemorrhage due to its antioxidant properties [38]. Movement Disorders Melatonin has potential pharmacological role in different movement disorders including Parkinsons disease (PD) and tardive dyskinesia. It has neuroprotective effects and prevents neurodegeneration in the nigrostriatal dopaminergic system as shown by different experimental models [39-48]. This protective effect is most likely due to its potent antioxidant properties. Melatonin treatment has been showed to restore the rotenone-induced decrease in glutathione level and changes in antioxidant enzymes including superoxide dismutase and catalase in substantia nigra [49]. Sandyk for the first time proposed that the deregulation of the secretory activity of pineal melatonin may be associated with the pathophysiology and clinical manifestations of Parkinson's disease [50]. Further studies showed that it can inhibit the pro-oxidant effects of dopamine and levodopa and is more effective than trolox, a vitamin E analogue,

in preventing dopamine auto-oxidation [51, 52]. It can also prevent lipid peroxidation induced by MPTP(1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) and 6-OHDA(6hydroxydopamine) treatment in striatum, substantia nigra and hippocampus in animal studies [39, 46-48]. It also has direct anti-oxidant effects and the ability to reduce the MPTP-induced loss of TH-reactive dopaminergic neurons [42]. It has been shown that melatonin reduced free radical formation and preserved the glutathione concentrations in substantia nigra after MPTP treatment [44, 45, 53]. Melatonin also has protective role against apoptosis and can prevent cell death from necrosis and apoptosis [54, 55]. Tardive dyskinesia (TD) is a disabling problem associated with antipsychotic treatment. The pathophysiology of TD has been linked to the disturbances of melatonin secretion [56-59]. The production of neurotoxic free radicals as a result of antipsychotic treatment might be related to the development of TD. Melatonin as an antioxidant has been evaluated for the treatment of this serious neurological side effect of neuroleptic treatment [60, 61]. Alzheimers disease, Cognitive and Learning Disorders in Cytotoxic activity of free radicals plays an important role neurodegenerative disorders including dementia.

62 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1

Bhatt et al.

Dementia is associated with circadian rhythm disturbances resulting in alteration in body hormonal levels including melatonin [62, 63]. It is well documented that melatonin levels are lower in AD patients as compared to age-matched control subjects [64-69]. Wu et al described the distribution of the melatonin receptor MT1 in the human hypothalamus and pituitary [70]. Other studies have demonstrated the impairment of MT1-mediated effects of Melatonin on the hypothalamic suprachiasmatic nucleus in aging and AD patients [71]. Brunner et al showed the immunohistochemical evidence for alteration of melatonin receptors (MT1 and MT2) in the human pineal gland and occipital cortex in AD [72]. These changes might be related with neuropathology and clinical symptoms of AD. Melatonin therapy might have potential efficacy and neuroprotective role in some patients with Alzheimers disease (AD) due to its remarkable antioxidant properties. Jean-Louis et al. reported the effects of melatonin administration in two patients with AD [73,74] for example Wong et al. disclosed a pharmaceutical composition for treating pathological condition associated with a melatonin receptor such as neurodegenerative diseases (Parkinson's disease (PD), Alzheimer's disease (AD) [75]. Melatonin enhanced and stabilized the circadian rest-activity rhythm in one of the patients along with some reduction of day time sleepiness and mood improvement [73]. The results of this study are not statistically significant because of small sample size. Therefore, the supplementary use of melatonin in AD patients cannot be recommended base of the results of these small studies. Meningitis and Encephalomyelitis Bacterial meningitis may result in neuronal injury and neurological sequelae due to the direct toxic effects of bacterial components and different other oxidative mechanisms. Melatonin has potential beneficial role in meningitis and encephalitis due to its ability to act as free radical scavenger and to induce interleukin-1 beta production. Interleukin-1 beta is an important cytokine which can augment the expression of inducible nitric oxide synthase (NOS) in viral encephalitis. Gerber et al. demonstrated that melatonin reduced the cellular damage in experimental Streptococcus pneumoniae meningitis [76]. In this study, the activity of superoxide dismutase in hippocampal formation was higher and the density of apoptotic dentate granule cells was lower in melatonin treated animals [76]. Another animal study conducted by Spreer et al. did not show the reduction in neuronal injury in gram-positive Streptococcus pneumoniae or gram-negative Escherichia coli meningitis with melatonin therapy [77]. Valero et al. demonstrated that melatonin treatment decreased nitrite concentration and lipid peroxidation products in brain of mice with Venezuelan equine encephalomyelitis(VEE) indicating its potential role in human VEE viral infection [78]. Melatonin has also been studied in animal models of sepsis showing its efficacy to counteract inducible mitochondrial nitric oxide synthasedependent mitochondrial dysfunction [79]. Neurooncology Melatonin has significant anti-tumor effect against a variety of malignancies by its action on the expression of

some oncogenesis-related genes [80-82]. Yang et al. demonstrated that melatonin inhibits pituitary prolactin secreting tumor cell growth by inducing apoptosis [83]. Melatonin increased the activity of caspse-3 and the expression of Bax m RNA and cytochrome c protein. Bcl-2 m RNA expression and mitochondrial membrane potential were inhibited after melatonin treatment in this study [83]. There is alteration of melatonin level after radiation therapy in some patients [84]. Sleep Melatonin helps people with different neurological disorders to sleep in a better way [21]. For example Clement et al. disclosed the use of multi-layered solid dosage form for of Melatonin to promote and maintain a state of sleep in an individual [85]. It can be helpful in combination for example Bilodeau et al. disclosed the use of atypical antipsychotics, in combination with hypnotics, anxiolytics, melatonin etc. for treatment of neurological and psychiatric disorders [86]. In addition to the above-mentioned co-morbid conditions melatonin has been extensively studied especially in pediatric population. Circadian rhythm disorders are characterized by insomnia and excessive sleepiness. They are primarily due to poor or altered sleep hygiene. Melatonin is not an FDA-approved drug for the treatment of circadian rhythm disorders as. There have been studies ranging from small uncontrolled to large randomized controlled trials. Two meta-analysis have been carried out. One meta-analyses [87] concluded that it improved sleep in patients with insomnia. A second meta-analysis concluded that melatonin was safe in short term (<3 months), but was not effective in sleep disorders related to jet lag or shift work [88]. This finding underscores the utility of melatonin in patients who actually do respond, especially in delayed sleep phase syndrome. It was criticized, as it did not include all controlled trials. It was also concluded that successful use of melatonin for jet lag and shift work requires correct timing. Uncontrolled exposure to light, individual unscheduled sleep times contribute to incorrect timings. It is still a challenge to assess and predict the right circadian timing prior to melatonin treatment [89]. A recent trial concluded that melatonin was effective in patients who had low pretreatment melatonin levels in adults with developmental brain disorders [90]. Moreover, Exogenous melatonin a relatively safe substance when used in the short term, but the relative safety for long term use is unclear. The most commonly reported side effects of melatonin were nausea, headache, dizziness, and drowsiness; however, these effects were not significant compared to placebo [91]. Future of melatonin looks promising, although long term efficacy trials are needed. Also further research is needed for feasible pretreatment assessment of circadian rhythm. CURRENT & FUTURE DEVELOPMENTS Melatonin might have potential beneficial role in the neurological disorders mentioned. However, most of the current data lacks large sample sizes and long-term longitudinal efficacy and safety for these disorders. Thus, the role of melatonin in these conditions needs to be elucidated more comprehensively. Its exact place

Melatonin & Neurological Disorders

Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1 [26]

63

in the treatment of individual disorders warrants further clarification. REFERENCES

[1] [2] Claustrat B, Loisy C, Brun J, Beorchia S, Arnaud JL, Chazot G. Nocturnal plasma melatonin levels in migraine: A preliminary report. Headache 1989; 29: 242-245. Shavali S, Ho B, Govitrapong P, et al. Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull 2005 30; 64: 471-479. Peres MF. Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia 2005; 25: 403-411. Peres MF, Stiles MA, Oshinsky M, Rozen TD. Remitting form of hemicrania continua with seasonal pattern. Headache 2001; 41: 592-594. Peres MF, Zukerman E, da Cunha TF, Moreira FR, Cipolla-Neto J. Melatonin, 3 mg, is effective for migraine prevention. Neurology 2004; 63: 757. Spears RC. Hemicrania continua: A case in which a patient experienced complete relief on melatonin. Headache 2006; 46: 524527. Rozen TD. Melatonin responsive hemicrania continua. Headache 2006; 46: 1203-1204. Rozen TD. Melatonin as treatment for idiopathic stabbing headache. Neurology 2003; 61: 865-866. Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996; 16: 494-496. Nagtegaal JE, Smits MG, Swart AC, Kerkhof GA, van der Meer YG. Melatonin-responsive headache in delayed sleep phase syndrome: Preliminary observations. Headache 1998; 38: 303-307. Reiter RJ, Morgan WW. Attempts to characterize the convulsive response of parathyroidectomized rats to pineal gland removal. Physiol Behav 1972; 9: 203-208. Mevissen M, Ebert U. Anticonvulsant effects of melatonin in amygdala-kindled rats. Neurosci Lett 1998; 257: 13-16. Costa-Lotufo LV, Fonteles MM, Lima IS, et al. Attenuating effects of melatonin on pilocarpine-induced seizures in rats. Comp Biochem Physiol C Toxicol Pharmacol 2002; 131: 521-529. Yildirim M, Marangoz C. Anticonvulsant effects of melatonin on penicillin-induced epileptiform activity in rats. Brain Res 2006; 1099: 183-188. Fauteck J, Schmidt H, Lerchl A, Kurlemann G, Wittkowski W. Melatonin in epilepsy: First results of replacement therapy and first clinical results. Biol Signals Recept 1999; 8: 105-110. Peled N, Shorer Z, Peled E, Pillar G. Melatonin effect on seizures in children with severe neurologic deficit disorders. Epilepsia 2001; 42: 1208-1210. Molina-Carballo A, Munoz-Hoyos A, Reiter RJ, et al. Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a child with severe myoclonic epilepsy: Two years experience. J Pineal Res 1997; 23: 97-105. Sandyk R, Tsagas N, Anninos PA. Melatonin as a proconvulsive hormone in humans. Int J Neurosci 1992; 63: 125-135. Stewart LS, Leung LS. Hippocampal melatonin receptors modulate seizure threshold. Epilepsia 2005; 46: 473-480. Sheldon SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998 25; 351: 1254. Jones C, Huyton M, Hindley D. Melatonin and epilepsy. Arch Dis Child 2005; 90: 1203-1204. Borowicz KK, Kaminski R, Gasior M, Kleinrok Z, Czuczwar SJ. Influence of melatonin upon the protective action of conventional anti-epileptic drugs against maximal electroshock in mice. Eur Neuropsychopharmacol 1999; 9: 185-190. MacLeod MR, O'Collins T, Horky LL, Howells DW, Donnan GA. Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. J Pineal Res 2005; 38: 35-41. Lee EJ, Lee MY, Chen HY, et al. Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. J Pineal Res 2005; 38: 42-52. Tutunculer F, Eskiocak S, Basaran UN, Ekuklu G, Ayvaz S, Vatansever U. The protective role of melatonin in experimental hypoxic brain damage. Pediatr Int 2005; 47: 434-439.

[27]

[28]

[3] [4]

[29]

[30] [31]

[5] [6]

[32]

[7] [8] [9]

[33]

[34]

[10] [11]

[35] [36]

[12] [13] [14]

[37]

[38]

[15] [16]

[39] [40]

[17]

[41] [42]

[18] [19] [20] [21] [22]

[43]

[44]

[23] [24]

[45]

[46]

[25]

Duan Q, Wang Z, Lu T, Chen J, Wang X. Comparison of 6hydroxylmelatonin or melatonin in protecting neurons against ischemia/reperfusion-mediated injury. J Pineal Res 2006 ; 41: 351357. Letechipia-Vallejo G, Lopez-Loeza E, Espinoza-Gonzalez V, et al. Long-term morphological and functional evaluation of the neuroprotective effects of post-ischemic treatment with melatonin in rats. J Pineal Res 2007; 42: 138-146. Lee MY, Kuan YH, Chen HY, et al. Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats. J Pineal Res 2007; 42: 297-309. Li XJ, Zhang LM, Gu L, Zhang AZ, Sun FJ. Melatonin decreases production of the hydroxyl radical during cerebral ischemiareperfusion. Acta Pharmacol Sin 1997; 18: 394-396. Rodriguez C, Mayo JC, Sainz RM, et al. Regulation of antioxidant enzymes: A significant role for melatonin. J Pineal Res 2004; 36: 19. Kilic E, Kilic U, Reiter RJ, Bassetti CL, Hermann DM. Prophylactic use of melatonin protects against focal cerebral ischemia in mice: Role of endothelin converting enzyme-1. J Pineal Res 2004 ; 37: 247-251. Kilic U, Kilic E, Reiter RJ, Bassetti CL, Hermann DM. Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice. J Pineal Res 2005; 38: 67-71. Joo JY, Uz T, Manev H. Opposite effects of pinealectomy and melatonin administration on brain damage following cerebral focal ischemia in rat. Restor Neurol Neurosci 1998; 13: 185-191. Kilic E, Ozdemir YG, Bolay H, Kelestimur H, Dalkara T. Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia. J Cereb Blood Flow Metab 1999; 19: 511-516. Cho S, Joh TH, Baik HH, Dibinis C, Volpe BT. Melatonin administration protects CA1 hippocampal neurons after transient forebrain ischemia in rats. Brain Res 1997; 755: 335-338. Reiter RJ, Tan DX, Leon J, Kilic U, Kilic E. When melatonin gets on your nerves: its beneficial actions in experimental models of stroke. Exp Biol Med (Maywood) 2005; 23: 104-117. Chen TY, Lee MY, Chen HY, et al. Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice. J Pineal Res 2006 ; 40: 242-250. Aydin MV, Caner H, Sen O, et al. Effect of melatonin on cerebral vasospasm following experimental subarachnoid hemorrhage. Neurol Res 2005; 27: 77-82. Kim YS, Joo WS, Jin BK, Cho YH, Baik HH, Park CW. Melatonin protects 6-OHDA-induced neuronal death of nigrostriatal dopaminergic system. Neuroreport 1998 13; 9: 2387-2390. Sharma R, McMillan CR, Tenn CC, Niles LP. Physiological neuroprotection by melatonin in a 6-hydroxydopamine model of Parkinson's disease. Brain Res 2006; 12(1068): 230-236. Singh S, Ahmed R, Sagar RK, Krishana B. Neuroprotection of the nigrostriatal dopaminergic neurons by melatonin in hemiparkinsonium rat. Indian J Med Res 2006; 124: 419-426. Antolin I, Mayo JC, Sainz RM, et al. Protective effect of melatonin in a chronic experimental model of Parkinson's disease. Brain res 2002; 943: 163-173. Ortiz GG, Crespo-Lopez ME, Moran-Moguel C, Garcia JJ, Reiter RJ, Acuna-Castroviejo D. Protective role of melatonin against MPTP-induced mouse brain cell DNA fragmentation and apoptosis in vivo. Neuro Endocrinol Lett 2001; 22: 101-108. Khaldy H, Escames G, Leon J, Bikjdaouene L, Acuna-Castroviejo D. Synergistic effects of melatonin and deprenyl against MPTPinduced mitochondrial damage and DA depletion. Neurobiol Aging 2003; 24: 491-500. Chen ST, Chuang JI, Hong MH, Li EI. Melatonin attenuates MPP+induced neurodegeneration and glutathione impairment in the nigrostriatal dopaminergic pathway. J Pineal Res 2002; 32: 262269. Jin BK, Shin DY, Jeong MY, et al. Melatonin protects nigral dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity in rats. Neurosci Lett 1998; 245: 61-64.

64 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 1 [47] Joo WS, Jin BK, Park CW, Maeng SH, Kim YS. Melatonin increases striatal dopaminergic function in 6-OHDA-lesioned rats. Neuroreport 1998; 9: 4123-4126. Acuna-Castroviejo D, Coto-Montes A, Gaia Monti M, Ortiz GG, Reiter RJ. Melatonin is protective against MPTP-induced striatal and hippocampal lesions. Life Sci 1997; 60: PL23-29. Saravanan KS, Sindhu KM, Mohanakumar KP. Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model. J Pineal Res 2007; 42: 247-253. Sandyk R. Pineal melatonin functions: Possible relevance to Parkinson's disease. Int J Neurosci 1990; 50: 37-53. Miller JW, Selhub J, Joseph JA. Oxidative damage caused by free radicals produced during catecholamine autoxidation: protective effects of O-methylation and melatonin. Free Radic Biol Med 1996; 21: 241-249. Khaldy H, Escames G, Leon J, Vives F, Luna JD, AcunaCastroviejo D. Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate in the suppression of hydroxyl radical formation during dopamine autoxidation in vitro. J Pineal Res 2000; 29: 100-107. Thomas B, Mohanakumar KP. Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the mouse nigrostriatum. J Pineal Res 2004; 36: 25-32. Iacovitti L, Stull ND, Johnston K. Melatonin rescues dopamine neurons from cell death in tissue culture models of oxidative stress. Brain Res 1997; 768: 317-326. Mayo JC, Sainz RM, Antolin I, Rodriguez C. Ultrastructural confirmation of neuronal protection by melatonin against the neurotoxin 6-hydroxydopamine cell damage. Brain Res 1999; 818: 221-227. Sandyk R, Kay SR. The relationship of pineal calcification and melatonin secretion to the pathophysiology of tardive dyskinesia and Tourette's syndrome. Int J Neurosci 1991; 58: 215-247. Sandyk R. The relationship of pineal calcification to subtypes of tardive dyskinesia in bipolar patients. Int J Neurosci 1990; 54: 307313. Sandyk R. The association of pineal calcification with drug-induced dystonic movements. Int J Neurosci 1990; 53: 217-222. Sandyk R, Fisher H. Increased incidence and severity of neuroleptic-induced movement disorder in pinealectomized rats. Int J Neurosci 1989; 48: 303-308. Shamir E, Barak Y, Plopsky I, Zisapel N, Elizur A, Weizman A. Is melatonin treatment effective for tardive dyskinesia? J Clin Psychiatry 2000; 61: 556-558. Shamir E, Barak Y, Shalman I, et al. Melatonin treatment for tardive dyskinesia: A double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 2001; 58: 1049-1052. Minors DS, Rabbitt PM, Worthington H, Waterhouse JM. Variation in meals and sleep-activity patterns in aged subjects; its relevance to circadian rhythm studies. Chronobiol Int 1989; 6: 139-146. Van Gool WA, Mirmiran M. Aging and circadian rhythms. Prog Brain Res 1986; 70: 255-277. Skene DJ, Vivien-Roels B, Sparks DL, et al. Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer's disease. Brain Res 1990; 528: 170-174. Uchida K, Okamoto N, Ohara K, Morita Y. Daily rhythm of serum melatonin in patients with dementia of the degenerate type. Brain Res 1996; 717(1-2): 154-159. Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF. Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein Eepsilon4/4 genotype. J Clin Endocrinol Metab 1999; 84: 323-327. Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, Okawa M. Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer's type with disturbed sleep-waking. Biol Psychiatry 1999; 45: 417-421. Ohashi Y, Okamoto N, Uchida K, Iyo M, Mori N, Morita Y. Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer's type. Biol Psychiatry 1999; 45: 1646-1652. Ferrari E, Arcaini A, Gornati R, et al. Pineal and pituitaryadrenocortical function in physiological aging and in senile dementia. Exp Gerontol 2000; 35: 1239-1250. Wu YH, Zhou JN, Balesar R, et al. Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary

Bhatt et al.

[48] [49]

[71]

[72] [73]

[50] [51]

[74] [75] [76]

[52]

[53]

[77]

[54] [55]

[78]

[56]

[79]

[57] [58] [59]

[80]

[81] [82]

[60] [61]

[83]

[62] [63] [64]

[84] [85] [86] [87] [88]

[65]

[66]

[89] [90]

[67]

[68]

[91]

[69] [70]

gland: Colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone. J Comp Neurol 2006; 499: 897910. Wu YH, Zhou JN, Van Heerikhuize J, Jockers R, Swaab DF. Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer's disease. Neurobiol Aging 2007; 28: 1239-1247. Brunner P, Sozer-Topcular N, Jockers R, et al. Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer's disease. Eur J Histochem 2006; 50: 311-316. Jean-Louis G, Zizi F, von Gizycki H, Taub H. Effects of melatonin in two individuals with Alzheimer's disease. Perceptual and motor skills. 1998; 87: 331-339. [74] Lopez BD, Debeljuk L. Prenatal melatonin and its interaction with tachykinins in the hypothalamic-pituitary-gonadal axis. Reprod Fertil Dev 2007; 19: 443-451. Wong, Y. H., Ho, M. K. C., Hu, Y., New, D. C., He, X., Pang, H.: WO08092292A1 (2008). Gerber J, Lotz M, Ebert S, et al. Melatonin is neuroprotective in experimental Streptococcus pneumoniae meningitis. J Infect Dis. 2005; 191: 783-790. Spreer A, Gerber J, Baake D, Hanssen M, Huether G, Nau R. Antiinflammatory but no neuroprotective effects of melatonin under clinical treatment conditions in rabbit models of bacterial meningitis. J Neurosci Res 2006; 84: 1575-1579. Valero N, MarinaEspina L, Bonilla E, Mosquera J. Melatonin decreases nitric oxide production and lipid peroxidation and increases interleukin-1 beta in the brain of mice infected by the Venezuelan equine encephalomyelitis virus. J Pineal Res 2007; 42: 107-112. Escames G, Lopez LC, Tapias V, et al. Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. J Pineal Res 2006; 40: 71-78. Vijayalaxmi TCR Jr, Reiter RJ, Herman TS. Melatonin: From basic research to cancer treatment clinics. J Clin Oncol 2002; 20: 25752601. Martin V, Herrera F, Carrera-Gonzalez P, et al. Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res 2006; 66: 1081-1088. Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA. Melatonin as antioxidant, geroprotector and anticarcinogen. Biochim Biophys Acta 2006; 1757: 573-589. Yang QH, Xu JN, Xu RK, Pang SF. Antiproliferative effects of melatonin on the growth of rat pituitary prolactin-secreting tumor cells in vitro. J Pineal Res 2007; 42: 172-179. Wion-Barbot N, Berger F, Wion D. Should we control the pineal status of patients following brain radiotherapy? J Neurooncol 2005 ; 74: 335. Clement, K., Chaudhur, S.: US20080254121 (2008). Bilodeau, M. T., Nanda, K.K., Trotter, B.W.: WO2008124030A1 (2008). Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev 2005; 9: 4150. Buscemi N, VandermeerB, Hooton N, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: Meta-analysis. Br Med J 2006; 332: 385-393. Arendt J. Does melatonin improve sleep? Efficacy of melatonin. Br Med J 2006; 332: 550. Laakso ML, Lindblom N, Leinonen L, Kaski M. Endogenous melatonin predicts efficacy of exogenous melatonin in consolidation of fragmented wrist-activity rhythm of adult patients with developmental brain disorders: A double blind, placebo-controlled, crossover study. Sleep Med 2007; 8(2): 222-239. Buscemi N, Vandermeer B, Pandya R, et al. Melatonin for Treatment of Sleep Disorders. Summary, Evidence Report/ Technology Assessment: Number 108. AHRQ Publication Number 05-E002-1, November 2004. Agency for Healthcare Research and Quality, Rockville, MD. http: //www.ahrq.gov/clinic/ epcsums/melatsum.htm