Melatonin

Melatonin protects against neurobehavioral and mitochondrial deficits in a chronic mouse model of Parkinson’s disease.
Patki G, Lau YS.
Pharmacol Biochem Behav. 2011 Jul 1

 Neuronal oxidative stress and mitochondrial dysfunction have been implicated in Parkinson’s disease. Melatonin is a natural antioxidant and free radical scavenger that has been shown to effectively reduce cellular oxidative stress and protect mitochondrial functions in vitro. However, whether melatonin is capable of slowing down the neurodegenerative process in animal models of Parkinson’s disease remains controversial. In this research, we examined long-term melatonin treatment on striatal mitochondrial and dopaminergic functions and on animal locomotor performance in a chronic mouse model of Parkinson’s disease originally established in our laboratory by gradually treating C57BL/6 mice with 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (15mg/kg, s.c.) and probenecid (250mg/kg, i.p.) over five weeks. We report here that when the chronic Parkinsonian mice were pre-treated and continuously treated with melatonin (5mg/kg/day, i.p.) for 18weeks, the defects of mitochondrial respiration, ATP and antioxidant enzyme levels detected in the striatum of chronic Parkinson’s mice were fully preempted. Meanwhile, the striatal dopaminergic and locomotor deficits seen in the chronic Parkinson’s mice were partially and significantly forestalled. These results imply that long-term melatonin is not only mitochondrial protective but also moderately neuronal protective in the chronic Parkinson’s mice. Melatonin may potentially be effective for slowing down the progression of idiopathic Parkinson’s disease and for reducing oxidative stress and respiratory chain inhibition in other mitochondrial disorders. PMID: 21741988 Copyright © 2011 Elsevier Inc. All rights reserved.

  Chronobiological therapy for mood disorders.
Dallaspezia S, Benedetti F.
Expert Rev Neurother. 2011 Jul;11(7):961-70.

 Alteration of the sleep-wake cycle and of the sleep structure are core symptoms of a major depressive episode, and occur both in course of bipolar disorder and of major depressive disorder. Many other circadian rhythms, such as the daily profiles of body temperature, cortisol, thyrotropin, prolactin, growth hormone, melatonin and excretion of various metabolites in the urine, are disrupted in depressed patients, both unipolar and bipolar individuals. These disrupted rhythms seem to return to normality with patient recovery. Research on circadian rhythms and sleep have led to the definition of nonpharmacological therapies of mood disorder that can be used in everyday practice. These strategies, named chronotherapeutics, are based on controlled exposures to environmental stimuli that act on biological rhythms, and demonstrate good efficacy in the treatment of illness episodes. They include manipulations of the sleep-wake rhythm (such as partial and total sleep deprivation, and sleep phase advance) and of the exposure to the light-dark cycle (light therapy and dark therapy). In recent years, an increasing literature about the safety and efficacy of chronobiological treatments in everyday psychiatric settings has supported the inclusion of these techniques among the first-line antidepressant strategies for patients affected by mood disorders. PMID: 21721914

Day and Night GSH and MDA Levels in Healthy Adults and Effects of Different Doses of Melatonin on These Parameters.
Chakravarty S, Rizvi SI.
Int J Cell Biol. 2011;2011:404591

 The pineal secretory product melatonin (chemically, N-acetyl-5-methoxytryptamine) acts as an effective antioxidant and free-radical scavenger and plays an important role in several physiological functions such as sleep induction, immunomodulation, cardiovascular protection, thermoregulation, neuroprotection, tumor-suppression and oncostasis. Membrane lipid-peroxidation in terms of malondialdehyde (MDA) and intracellular glutathione (GSH) is considered to be a reliable marker of oxidative stress. The present work was undertaken to study the modulating effect of melatonin on MDA and GSH in human erythrocytes during day and night. Our observation shows the modulation of these two biomarkers by melatonin, and this may have important therapeutic implications. In vitro dose-dependent effect of melatonin also showed variation during day and night. We explain our observations on the basis of melatonin’s antioxidative function and its effect on the fluidity of plasma membrane of red blood cells. Rhythmic modulation of MDA and GSH contents emphasized the role of melatonin as an antioxidant and its function against oxidative stress. PMID: 21647290

  Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies.
Wilhelmsen M, Amirian I, Reiter RJ, Rosenberg J, Gögenur I.
J Pineal Res. 2011 Apr 18.

 Melatonin is an endogenous indoleamine, produced mainly by the pineal gland. Melatonin has been proven to have chronobiotic, antioxidant, antihypertensive, anxiolytic and sedative properties. There are also experimental and clinical data supporting an analgesic role of melatonin. In experimental studies, melatonin shows potent analgesic effects in a dose-dependent manner. In clinical studies, melatonin has been shown to have analgesic benefits in patients with chronic pain (fibromyalgia, irritable bowel syndrome, migraine). The physiologic mechanism underlying the analgesic actions of melatonin has not been clarified. The effects may be linked to G(i) -coupled melatonin receptors, to G(i) -coupled opioid μ-receptors or GABA-B receptors with unknown downstream changes with a consequential reduction in anxiety and pain. Also, the repeated administration of melatonin improves sleep and thereby may reduce anxiety, which leads to lower levels of pain. In this paper, we review the current evidence regarding the analgesic properties of melatonin in animals and humans with chronic pain. PMID: 21615490
Copyright © 2011 John Wiley & Sons A/S.

  Drug-mediated ototoxicity and tinnitus: alleviation with melatonin.
Reiter RJ, Tan DX, Korkmaz A, Fuentes-Broto L.
J Physiol Pharmacol. 2011 Apr;62(2):151-7

 This review evaluates the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear. A thorough search of the literature was performed using available databases for the purpose of uncovering articles applicable to the current review. Cochlear function was most frequently evaluated by measuring otoacoustic emissions and their distortion products after animals were treated with cytotoxic drugs alone or in combination with melatonin. Vestibular damage due to aminoglycosides was evaluated by estimating hair cell loss in explanted utricles of newborn rats. Tinnitus was assessed in patients who received melatonin using a visual analogue scale or the Tinnitus Handicap Inventory. Compared to a mixture of antioxidants which included tocopherol, ascorbate, glutathione and N-acetyl-cysteine, melatonin, also a documented antioxidant, was estimated to be up to 150 times more effective in limiting the cochlear side effects, evaluated using otoacoustic emission distortion products, of gentamicin, tobramycin and cisplatin. In a dose-response manner, melatonin also reduced vestibular hair cell loss due to gentamicin treatment in explanted utricles of newborn rats. Finally, melatonin (3 mg daily) limited subjective tinnitus in patients. These findings suggest the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin’s low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage. PMID: 21673362

  Melatonin in mitochondrial dysfunction and related disorders.
Srinivasan V, Spence DW, Pandi-Perumal SR, Brown GM, Cardinali DP.
Int J Alzheimers Dis. 2011;2011:326320

 Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R), septic shock, and neurodegenerative disorders like Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R. PMID: 21629741

 Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males.
Ochoa JJ, Díaz-Castro J, Kajarabille N, García C, Guisado IM, De Teresa C, Guisado R.
J Pineal Res. 2011 Apr 21

 Strenuous exercise induces inflammatory reactions together with high production of free radicals and subsequent muscle damage. This study was designed to investigate for the first time and simultaneously whether over-expression of inflammatory mediators, oxidative stress, and alterations in biochemical parameters induced by acute exercise could be prevented by melatonin. This indoleamine is a potent, endogenously produced free radical scavenger and a broad-spectrum antioxidant; consequently, it might have positive effects on the recovery following an exercise session. The participants were classified into two groups: melatonin-treated men (MG) and placebo-treated individuals (controls group, CG). The physical test consisted in a constant run that combined several degrees of high effort (mountain run and ultra-endurance). The total distance of the run was 50 km with almost 2800 m of ramp in permanent climbing and very changeable climatic conditions. Exercise was associated with a significant increase in TNF-α, IL-6, IL-1ra (in blood), and also an increase in 8-hydroxy-2′-deoxyguanosine (8-OHdG) and isoprostane levels (in urine), and indicated the degree of oxidative stress and inflammation induced. Oral supplementation of melatonin during high-intensity exercise proved efficient in reducing the degree of oxidative stress (lower levels of lipid peroxidation, with a significant increase in antioxidative enzyme activities); this would lead to the maintenance of the cellular integrity and reduce secondary tissue damage. Data obtained also indicate that melatonin has potent protective effects, by preventing over-expression of pro-inflammatory mediators and inhibiting the effects of several pro-inflammatory cytokines. In summary, melatonin supplementation before strenuous exercise reduced muscle damage through modulation of oxidative stress and inflammation signaling associated with this physical challenge. PMID: 21615492
Copyright © 2011 John Wiley & Sons A/S.

  The effect of melatonin, magnesium, and zinc on primary insomnia in long-term care facility residents in Italy: a double-blind, placebo-controlled clinical trial.
Rondanelli M, Opizzi A, Monteferrario F, Antoniello N, Manni R, Klersy C.
J Am Geriatr Soc. 2011 Jan;59(1):82-90

 To determine whether nightly administration of melatonin, magnesium, and zinc improves primary insomnia in long-term care facility residents. Double-blind, placebo-controlled clinical trial. One long-term care facility in Pavia, Italy. Forty-three participants with primary insomnia (22 in the supplemented group, 21 in the placebo group) aged 78.3 ± 3.9. Participants took a food supplement (5 mg melatonin, 225 mg magnesium, and 11.25 mg zinc, mixed with 100 g of pear pulp) or placebo (100 g pear pulp) every day for 8 weeks, 1 hour before bedtime. The primary goal was to evaluate sleep quality using the Pittsburgh Sleep Quality Index. The Epworth Sleepiness Scale, the Leeds Sleep Evaluation Questionnaire (LSEQ), the Short Insomnia Questionnaire (SDQ), and a validated quality-of-life instrument (Medical Outcomes Study 36-item Short Form Survey (SF-36)) were administered as secondary end points. Total sleep time was evaluated using a wearable armband-shaped sensor. All measures were performed at baseline and after 60 days. The food supplement resulted in considerably better overall PSQI scores than placebo (difference between groups in change from baseline PSQI score=6.8; 95% confidence interval=5.4-8.3, P<.001). Moreover, the significant improvements in all four domains of the LSEQ (ease of getting to sleep, P<.001; quality of sleep, P<.001; hangover on awakening from sleep, P=.005; alertness and behavioral integrity the following morning, P=.001), in SDQ score (P<.001), in total sleep time (P<.001), and in SF-36 physical score (P=.006) suggest that treatment had a beneficial effect on the restorative value of sleep. The administration of nightly melatonin, magnesium, and zinc appears to improve the quality of sleep and the quality of life in long-term care facility residents with primary insomnia. PMID: 21226679
Copyright © 2011, Copyright the Authors. Journal compilation © 2011, The American Geriatrics Society.

Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome.
Koziróg M, Poliwczak AR, Duchnowicz P, Koter-Michalak M, Sikora J, Broncel M.
J Pineal Res. 2011 Apr;50(3):261-6

 Experimental studies have proven that melatonin has many beneficial pleiotropic actions. The aim of this study was to assess melatonin efficacy in patients with metabolic syndrome (MS). The study included 33 healthy volunteers (who were not treated with melatonin) and 30 patients with MS, who did not respond to 3-month lifestyle modification. Patients with MS were treated with melatonin (5 mg/day, 2 hr before bedtime) for 2 months. The following parameters were studied: systolic and diastolic blood pressure (SBP, DBP), levels of glucose, serum lipids, C-reactive protein, fibrinogen, activities of antioxidative enzymes: catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), thiobarbituric acid reactive substrates (TBARS). After 2-month therapy in comparison with baseline, the following significant changes were measured: systolic blood pressure (132.8±9.8 versus 120.5±11.0 mmHg, P<0.001), DBP (81.7±8.8 versus 75±7.4 mmHg, P<0.01), low-density lipoprotein cholesterol (LDL-C) (149.7±26.4 versus 139.9±30.2 mg/dL, P<0.05), TBARS (0.5±0.2 versus 0.4±0.1 μm/gHb, P<0.01), and CAT (245.9±46.9 versus 276.8±39.4 U/gHb). Melatonin administered for 2 months significantly improved antioxidative defense (increase in CAT activity, decrease in TBARS level) and lipid profile (decrease in LDL-C), and lowered blood pressure. We conclude that melatonin therapy may be of benefit for patients with MS, particularly with arterial hypertension. Further studies with higher doses of melatonin or prolonged supplementation are awaited. PMID: 21138476
© 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S.