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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                                     ...
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The Therapeutic Potential of Melatonin in Neurological Disorders


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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: 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
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