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Sleep Science Abstracts

1. Pharmacol Biochem Behav. 2011 Oct;99(4):704-11. Epub 2011 Jul 1.

Melatonin protects against neurobehavioral and mitochondrial deficits in a chronic mouse model of Parkinson’s disease.

Patki G, Lau YS.
Source
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
Abstract
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 (15 mg/kg, s.c.) and probenecid (250 mg/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 18 weeks, 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.
2. Int J Dev Neurosci. 2008 Oct;26(6):585-91. Epub 2008 May 9.

Protective role of melatonin on PCB (Aroclor 1,254) induced oxidative stress and changes in acetylcholine esterase and membrane bound ATPases in cerebellum, cerebral cortex and hippocampus of adult rat brain.

Venkataraman P, Krishnamoorthy G, Vengatesh G, Srinivasan N, Aruldhas MM, Arunakaran J.
Source
Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600113, India.
Abstract
Polychlorinated biphenyls (PCBs) are one of the environmental toxicants and neurotoxic compounds which induce the production of free radicals leading to oxidative stress. Membrane proteins that control ion gradients across organellar and plasma membranes appear to be particularly susceptible to oxidation induced changes. Melatonin plays an important role in neurodegenerative diseases as an antioxidant and neuroprotector. The aim of this study was to determine the protective role of melatonin on PCB (Aroclor 1254) induced changes in activities of membrane bound ATPases and acetylcholine esterase in selected brain regions of adult rats. Group I: rats intraperitoneally (i.p.) administered corn oil (vehicle) for 30 days. Group II: rats injected i.p. with Aroclor 1,254 (PCB) at 2mg/kg bw/day for 30 days. Groups III and IV: rats intraperitoneally received melatonin (5 or 10mg/kg bw/day) simultaneously with Aroclor 1,254 for 30 days. Groups V and VI: rats intraperitoneally received melatonin (5 or 10mg/kg bw/day) alone for 30 days. After 30 days, rats were sacrificed and the brain regions were dissected to cerebral cortex (Cc), cerebellum (C) and hippocampus (H). Lipid peroxidation (LPO), hydrogen peroxide (H(2)O(2)), hydroxyl radical (OH) and the activities of Na(+)K(+) ATPase, Ca(2+) ATPase, Mg(2+) ATPase and acetyl cholinesterase were determined. Reduced glutathione (GSH) level was also determined. Melatonin levels in serum was measured by enzyme labeled immunosorbent assay (ELISA). Activities of all the enzymes and GSH level were decreased while an increase in H(2)O(2), OH and LPO were observed in brain regions of PCB treated animals. Melatonin levels in serum was decreased in PCB exposed animals. Exogenous melatonin supplementation retrieved all the parameters, significantly. These results suggest that PCB alters membrane bound ATPases and cholinergic function by inducing oxidative stress in brain regions, which can be protected by melatonin.
3. Prog Neurobiol. 1998 Oct;56(3):359-84.

Oxidative damage in the central nervous system: protection by melatonin.

Reiter RJ.
Source
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio 78284-7762, USA. reiter@uthscsa.edu
Abstract
Melatonin was recently reported to be an effective free radical scavenger and antioxidant. Melatonin is believed to scavenge the highly toxic hydroxyl radical, the peroxynitrite anion, and possibly the peroxyl radical. Also, secondarily, it reportedly scavenges the superoxide anion radical and it quenches singlet oxygen. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase (all of which are antioxidative enzymes), thereby increasing its antioxidative capacity. Also, melatonin, at least at some sites, inhibits nitric oxide synthase, a pro-oxidative enzyme. In both in vivo and in vitro experiments melatonin has been shown to reduce lipid peroxidation and oxidative damage to nuclear DNA. While these effects have been observed primarily using pharmacological doses of melatonin, in a small number of experiments melatonin has been found to be physiologically relevant as an antioxidant as well. The efficacy of melatonin in inhibiting oxidative damage has been tested in a variety of neurological disease models where free radicals have been implicated as being in part causative of the condition. Thus, melatonin has been shown prophylactically to reduce amyloid beta protein toxicity of Alzheimer’s disease, to reduce oxidative damage in several models of Parkinson’s disease (dopamine auto-oxidation, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), to protect against glutamate excitotoxicity, to reduce ischemia-reperfusion injury, to lower neural damage due to gamma-aminolevulinic acid (phorphyria), hyperbaric hyperoxia and a variety of neural toxins. Since endogenous melatonin levels fal 1 markedly in advanced age, the implication of these findings is that the loss of this antioxidant may contribute to the incidence or severity of some age-associated neurodegenerative diseases.
4. J Neurosci. 1997 Mar 1;17(5):1683-90.

Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide.

Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK.
Source
Department of Pathology and Laboratory Medicine, University of South Alabama, Mobile, Alabama 36617, USA.
Abstract
Studies from several laboratories have generated evidence suggesting that oxidative stress is involved in the pathogenesis of Alzheimer’s disease (AD). The finding that the amyloid beta protein (Abeta) has neurotoxic properties and that such effects are, in part, mediated by free radicals has provided insights into mechanisms of cell death in AD and an avenue to explore new therapeutic approaches. In this study we demonstrate that melatonin, a pineal hormone with recently established antioxidant properties, is remarkably effective in preventing death of cultured neuroblastoma cells as well as oxidative damage and intracellular Ca2+ increases induced by a cytotoxic fragment of Abeta. The effects of melatonin were extremely reproducible and corroborated by multiple quantitative methods, including cell viability studies by confocal laser microscopy, electron microscopy, and measurements of intracellular calcium levels. The importance of this finding is that, in contrast to conventional antioxidants, melatonin has a proposed physiological role in the aging process. Secretion levels of this hormone are decreased in aging and more severely reduced in AD. The reported phenomenon may be of therapeutic relevance in AD.
5. Life Sci. 1997;60(2):PL23-9.

Melatonin is protective against MPTP-induced striatal and hippocampal lesions.

Acuña-Castroviejo D, Coto-Montes A, Gaia Monti M, Ortiz GG, Reiter RJ.
Source
Instituto de Biotecnologia, Universidad de Granada, Spain.
Abstract
The in vivo effect of melatonin on MPTP-induced neurotoxicity in mouse brain was studied. Melatonin (10 mg/kg) or saline was administered intraperitoneally (i.p.) to mice 30 min prior to a s.c. injection of MPTP (20 mg/kg). After MPTP treatment, the animals received melatonin or saline injections every hour for three hours. Mice were killed 4 hours after the MPTP injection. Regionally-specific increases in lipid peroxidation were observed in corpus striatum and hippocampus (71% and 58%, respectively), but not in cerebral cortex, cerebellum or midbrain. Treatment with melatonin completely reversed the rises in lipid peroxidation products. MPTP-treated mice showed a significant decrease in the striatal tyrosine hydroxylase immunoreactive nerve terminals, an effect that was also prevented by melatonin. These data show that melatonin is neuroprotective in this MPTP model of Parkinson’s disease and suggest that melatonin, an endogenous antioxidant and nontoxic compound, may have potential beneficial effects for this neurodegenerative disorder.
6. Exp Gerontol. 1995 May-Aug;30(3-4):199-212.

The pineal gland and melatonin in relation to aging: a summary of the theories and of the data.

Reiter RJ.

Source

Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio 78284-7762, USA.

Abstract

Within recent years, many investigators have implicated the pineal gland and melatonin in the processes of both aging and age-related diseases. These theories stem from the importance of melatonin in a number of biological functions and the fact that melatonin production in the organism is gradually lost throughout life, such that in very old individuals of any species the circadian melatonin rhythm is bearly discernible. In most species, from algae to humans, where it has been investigated, melatonin has been shown to exhibit a strong circadian rhythm in production and secretion, with high levels of the indole always being associated with the dark period of the light:dark cycle. One theory states that when the melatonin rhythm deteriorates during aging, other circadian rhythms are likewise weakened and rhythms become dysynchronized. This dysynchronization is believed to contribute significantly to aging and to render animals more susceptible to age-related diseases. Another theory assumes that the waning melatonin cycle provides an important switch for genetically programmed aging at the cellular level; furthermore, because all cells in the organism are exposed to the same gradually dampening melatonin signal throughout life, all cells age more or less at the same rate. In this theory, it is presumed to be the duration of the nocturnally elevated melatonin (which, like the amplitude, is reduced during aging), which, when coupled to a time-gating signal, is consequential in determining the rate of aging. Another compelling argument that the reduction in melatonin with age may be contributory to aging and the onset of age-related diseases is based on the recent observation that melatonin is the most potent hydroxyl radical scavenger thus far discovered. A prominent theory of aging attributes the rate of aging to accumulated free radical damage. Inasmuch as melatonin can markedly protect macromolecules, especially DNA, against free radical attack, it could, indeed, be a major factor in determining the rate at which organisms age. Besides its ability to directly scavenge the highly toxic hydroxyl radical, melatonin also promotes the activity of the antioxidative enzyme glutathione peroxidase, thereby further reducing oxidative damage. These actions may be manifested more obviously in the central nervous system, which is highly susceptible to damage by oxygen-based radicals and, because of its inability to regenerate and its high vulnerability to oxidative attack, its deterioration may be especially important in aging. (ABSTRACT TRUNCATED AT 400 WORDS)