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
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-
75% in 10 patients.
Spears Case report Hemicrania Melatonin 7 mg at bed time Attacks were successfully eliminated
Rozen (2006) Case reports Hemicrania 1st case-9 mg melatonin All three patients did well after starting
 Continua (HC) 2nd case-9 mg melatonin + 6 mg extra at times melatonin and as far as they remained
3rd case-15 mg of melatonin with 75 mg of
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
 3rd case-3 mg melatonin
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
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
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
. 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 . direct anti-oxidant effects and the ability to reduce the
MPTP-induced loss of TH-reactive dopaminergic neurons
Movement Disorders . 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 . 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 . 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,
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 .
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 . Other studies have demonstrated the were inhibited after melatonin treatment in this study .
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 .
patients . 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 . These changes might be related with disorders to sleep in a better way . 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 . 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 . 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) . 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 . 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  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 . 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 . 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 . In this study, the
disorders . 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 . 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 . Future of melatonin
moniae or gram-negative Escherichia coli meningitis with
looks promising, although long term efficacy trials are
melatonin therapy . 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 . 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 . 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
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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