Article

Melatonin and mitochondrial dysfunction in the central nervous system

Pontificia Universidad Católica Argentina, Facultad de Ciencias Médicas, 1107 Buenos Aires, Argentina
Hormones and Behavior (Impact Factor: 4.51). 02/2012; 63(2). DOI: 10.1016/j.yhbeh.2012.02.020
Source: PubMed

ABSTRACT Cell death and survival are critical events for neurodegeneration, mitochondria being increasingly seen as important determinants of both. Mitochondrial dysfunction is considered a major causative factor in Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity and NO production, and disrupted electron transport system and mitochondrial permeability transition, have all been involved in impaired mitochondrial function. Melatonin, the major secretory product of the pineal gland, is an antioxidant and an effective protector of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective to prevent oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of AD, PD and HD. These effects are seen at doses 2-3 orders of magnitude higher than those required to affect sleep and circadian rhythms, both conspicuous targets of melatonin action. Melatonin is selectively taken up by mitochondria, a function not shared by other antioxidants. A limited number of clinical studies indicate that melatonin can improve sleep and circadian rhythm disruption in PD and AD patients. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50-100mg/day are needed to assess its therapeutic validity in neurodegenerative disorders.

Download full-text

Full-text

Available from: Pablo Antonio Scacchi Bernasconi, Jul 14, 2014
3 Followers
 · 
156 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Huntington's disease is a progressive neurological disorder that starts insidiously with motor, cognitive or psychiatric disturbance, and progresses through a distressing range of symptoms to end with a devastating loss of function, both motor and executive. There is a growing awareness that, in addition to cognitive and psychiatric symptoms, there are other important non-motor symptoms in HD, including sleep and circadian abnormalities. It is not clear if sleep-wake changes are caused directly by HD gene-related pathology, or if they are simply a consequence of having a neurodegenerative disease. From a patient point of view, the answer is irrelevant, since sleep and circadian disturbances are deleterious to good daily living in neurologically normal people. The assumption should be that, at the very least, sleep and/or circadian disturbance in HD patients will contribute to their symptoms. At worst, they may contribute to the progressive decline in HD. Here I review the state of our understanding of sleep and circadian abnormalities in HD. I also outline a set of simple rules that can be followed to improve the chances of a good night's sleep, since preventing any 'preventable' symptoms is the a logical first step in treating disease. The long-term impact of sleep disruption in HD is unknown. There have been no large-scale systematic studies of in sleep in HD. Furthermore, there has never been a study of the efficacy of pharmaceuticals that are typically used to treat sleep deficits in HD patients. Thus treatment of sleep disturbance in HD is necessarily empirical. A better understanding of the relationship between sleep/circadian abnormalities and HD pathology is needed, if treatment of this aspect of HD is to be optimized.
    Experimental Neurology 10/2012; 243. DOI:10.1016/j.expneurol.2012.10.014 · 4.62 Impact Factor
  • Journal of Comparative Pathology 01/2013; 148(1):57. DOI:10.1016/j.jcpa.2012.11.048 · 1.10 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Compromised pregnancies such as those associated with gestational diabetes mellitus, intrauterine growth retardation, preeclampsia, maternal undernutrition, and maternal stress may negatively affect fetal development. Such pregnancies may induce oxidative stress to the fetus and alter fetal development through the epigenetic process that may affect development at a later stage. Melatonin is an oxidant scavenger that reverses oxidative stress during the prenatal period. Moreover, the role of melatonin in epigenetic modifications in the field of developmental programming has been studied extensively. Here, we describe the physiological function of melatonin in pregnancy and discuss the roles of melatonin in fetal programming in compromised pregnancies, focusing on its involvement in redox and epigenetic mechanisms.
    International Journal of Molecular Sciences 03/2013; 14(3):5380-401. DOI:10.3390/ijms14035380 · 2.34 Impact Factor
Show more