Abstract

REITER, Russel J.  and  BENITEZ-KING, Gloria. Melatonin reduces neuronal loss and cytoskeletal deterioration: implications for Psychiatry. Salud Ment [online]. 2009, vol.32, n.1, pp.3-11. ISSN 0185-3325.

This review article summarizes the potential role of circadian rhythmicity and melatonin in psychiatric disorders. The melatonin rhythm, with high blood levels at night and low values during the day, is a reflection of the biological clock, i.e., the suprachiasmatic nucleus (SCN). The SCN receive information about the prevailing light: dark conditions from specialized ganglion cells (only 1-2% of the total ganglion cells) in the retina. These unique cells contain a newly-discovered photopigment, melanopsin, which responds to a rather narrow band width of light that peaks at roughly 480 nm. The axons of these ganglion cells project via the retinohypothalamic tract through the optic nerve to the SCN, located just above the optic chiasm in the anterior hypothalamus. Via this pathway, light detected by the retina synchronizes the circadian clock to precisely 24 hours. In the absence of light, i.e., darkness, the SCN signals the pineal gland to produce melatonin via a complex neural pathway that involves fibers that project from the hypothalamus to the preganglionic sympathetic neurons in the intermediolateral cell column of the upper thoracic cord. Axons of these neurons exit the spinal cord to eventually synapse on neurons in the superior cervical ganglia. Then, postganglionic fibers convey the information to the pineal gland mediating the nighttime rise in melatonin synthesis. Because melatonin is only elevated at night, it is referred to as the <<chemical expression of darkness>>. Disturbances in the rhythmicity of the biological clock and/or the melatonin rhythm likely contribute to psychophysiological disturbances and mood disorders. Major disturbances occur in circadian rhythmicity when light, which activates the SCN and inhibits melatonin production, is imposed during the normal dark period. Thus, even brief periods of light at night are readily detected by the specialized ganglion cells mentioned above; this sets off a chain of events that alter biological clock physiology and depresses nighttime melatonin levels when they should be elevated. Depressed circulating melatonin levels at night provide misinformation to all cells that can <<read>> the message. This misinformation contributes to alterations in mood and negative psychological feelings of well-being. Melatonin has several major functions which probably assist in protecting humans from psychiatric illnesses. This indoleamine is widely known as a sleep-promoting factor. As such, it reduces the latency to sleep onset and improves sleep hygiene. Melatonin has been tested for its beneficial effects on sleep in children with neurodevelopmental disabilities, in individuals with delayed sleep phase syndrome and in elderly patients with insomnia. In each of these situations, melatonin has proven to be beneficial. Sleep disturbances are often associated with and probably contribute to psychiatric illness. Melatonin is also a potent free radical scavenger and antioxidant. It, as well as several of its metabolites, are powerful protectors against oxidative stress and free radical-mediated, mitochondrial-dependent cellular apoptosis. Melatonin seems to be particularly effective in protecting the brain from oxidative mutilation and loss of cells resulting from apoptosis. Given that a variety of neurodegenerative diseases, e.g., Alzheimer disease, parkinsonism, amyotrophic lateral sclerosis, have a free radical component, it is assumed that melatonin may be useful in fores talling the consequences of these debilitating conditions and improving the psychological makeup of these patients. Preliminary clinical trials suggest melatonin will be useful in this regard. A major action of melatonin in the Central Nervous System is protection of the neuronal cytoskeleton from oxidative damage. Structural damage to the cytoskeleton is consequential in the function of neurons and is not uncommonly associated with psychological illness and with neurodegenerative diseases. For example, tauopathies (tau is an important cytoskeletal protein) contribute to neuropsychiatric disorders. Damage to the tau protein, resulting from the hyperphos-phorylation of this important molecule, disrupts intraneuronal microtubules and alters synaptic physiology. The destruction of normal cytoskeletal function is often a result of excessive free radial generation. The free radical-mediated changes result in loss of neuronal polarization and cells die of apoptosis leading to neurobehavioral disorders and dementia. Given that melatonin is an antioxidant, it has been tested for its efficacy in reducing damage to the cytoskeleton as well as limiting the behavioral effects. In this capacity melatonin has been found highly effective in reducing damage to essential cytoskeletal elements and improving neurobehavioral outcomes. Overall, melatonin may well find utility in reducing neural deterioration with age as well as improving the psychological well-being of individuals. Melatonin is an inexpensive non-toxic molecule which should be considered for use in a number of psychiatric diseases and circadian rhythm disorders.

Keywords : Melatonin; mood disorders; neuronal apoptosis; cytoskeleton; cognitive impairment; psychopathology.

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