Abstract

JIMENEZ-RUBIO, Graciela; SOLIS-CHAGOYAN, Héctor; DOMINGUEZ-ALONSO, Aline  and  BENITEZ-KING, Gloria. Circadian cycle alterations in psychiatric diseases: melatonin role as a synchronizer of sleep-awake cycle and the neuronal polarity. Salud Ment [online]. 2011, vol.34, n.2, pp.167-173. ISSN 0185-3325.

Circadian rhythms are oscillations of physiological functions. The period of their oscillation is about 24 h, and can be synchronized by environmental periodic signals as night-day cycle. The endogenous periodical changes depend on various structural elements of the circadian system which consists of the effectors, the secondary oscillators, the synchronizers and the circadian pacemaker. In mammalian species, the physiological function better understood respect their oscillation pattern are the synthesis and release of several hormones (i.e. cortisol and melatonin), the body temperature, the sleep-awake cycle, the locomotive activity, cell proliferation, neuronal activity among other rhythms. The Suprachiasmatic nucleus is the main circadian pacemarker in mammals; its oscillation keeps the circadian system synchronized particularly with respect to the environment photo period. When light reaches the pigment melanopsin in ganglionar neurons in the retina, the photoperiod signal is sent to Suprachiasmatic nucleus, and its postsinaptic neurons distributes the temporal signal to pheripheral oscillators by nervous or humoral pathways. Among the oscillators, the pineal gland is a peripheral one modulated by Suprachiasmatic nucleus. At night, the indolamine melatonin is synthesized and released from pinealocytes, and reaches other peripheral oscillators. Melatonin interacts with membrane receptors on Suprachiasmatic nucleus pacemarker neurons, reinforcing the signal of the photoperiod. In mammals, exogenous melatonin synchronizes several circadian rhythms including locomotive activity and melatonin release. When this indolamine is applied directly into the Suprachiasmatic nucleus, it produces a phase advance of the endogenous melatonin peak and increases the amplitude of the oscillation. In humans, melatonin effect on the circadian system is evident because it changes the circadian rhythms phase in subjects with advanced sleep-phase syndrome, night workers or blind people. Also it reduces jet lag symptoms enhancing sleep quality and reseting the circadian system to local time. Melatonin effects on circadian rhythms indicate their role as a chronobiotic, since decreased daily melatonin levels that occur with age and in neuropsychiatric disorders are associated with disturbances in the sleep-awake cycle. In particular, it has been described that Alzheimer's disease patients have disturbed sleep-awake cycle and have decreased serum melatonin levels. Sleep disorders in Alzheimer's disease patients decrease when they are treated with melatonin. Moreover, sleep disturbances have been observed in bipolar disorder patients and often precede relapses of insomnia-associated mania and hypersomnia-associated depression. These disturbances are linked to delayed- and advanced- phases of circadian rhythms or arrhythmia; therefore, it has been suggested that bipolar disorder patients could be treated with light and dark therapy. In depressed patients, the levels of melatonin are low throughout the 24 hour period and have a delayed onset of the indolamine concentration and showed an advance of its peak. Schizophrenic patients have decreased levels in the plasmatic melatonin in both phases of the light-dark cycle. Melatonin administration to these patients increases their sleep efficiency. In addition, melatonin acts as a neuroprotector because of its potent antioxidant action and through its cytoskeletal modulation properties. In neurodegenerative animal models, its protector effect has been observed using okadaic acid. This neurotoxin is employed for reproducing cytoskeletal damage in neurons and increased oxidative stress levels, which are molecular events similar to those that occur in Alzheimer's disease. In N1E-115 cell cultures incubated with okadaic acid, the administration of melatonin diminishes hyperphosphorylated tau and oxidative stress levels, and prevents the neurocytoskeletal damage caused by the neurotoxin. Although it is known that melatonin plays a key role in the circadian rhythms entrainment, little is known about its synchronizing effects at molecular and structural level. In algae, it has been observed a link between morphological changes and the light-dark cycle and it is known that shape is determinated by the cytoskeletal structure. In particular, the alga Euglena gracilis changes its shape two times per day under the effect of a daily light-dark cycle. This alga has a long shape when there is a higher photosynthetic capacity at the half period of the day; on the contrary, it showed a rounded shape at the end of 24 h cycle. Also, the influence of the cell shape changes on the photosynthetic reactions was investigated by altering them with drugs that disrupt the cytoskeletal structure as cytochalasin B and colchicine. Both inhibitors blocked the rhythmic shape changes and the photo-synthetic rhythm. Moreover, there are some reports about cytoskeletal changes in plants targeted by circadian rhythms. Guarda cells of Vicia faba L. showed a diurnal cycle on the alpha and beta tubulin levels. In addition, it has been proposed that melatonin synchronizes different body rhythms through cytoskeletal rearrangements. In culture cells, nanomolar melatonin concentrations cause an increase in both the polimerization rate and microtubule formation through calmodulin antagonism. A cyclic pattern produced by melatonin in the actin microfilament organization has been demonstrated in canine kidney cells. Cyclic incubation of MDCK cells with nanomolar concentrations of melatonin, resembling the cyclic pattern of secretion and release to plasma produces a microfilament reorganization and the formation of domes. Studies in animals are controvertial regarding if the amount of microtubules in different tissues varies cyclically. In rats and baboons, melatonin administration or exposure of rats to darkness induced an increased number of microtubules in the pineal gland. However, in the hypothalamus, the exposure of rats to light resulted in an increase in the microtubular protein content. Similarly, (X-tubulin mRNA was augmented during the light phase in the hypothalamus, hippocampus and cortex. By contrast, in rats maintained in constant darkness, a decreased level in the tubulin content was observed in the visual cortex. Additional information on cycle variations observed in cytoskeletal molecules indicated that beta actin mRNA levels are lower during the day in the hippocampus and cortex. But no change was observed in actin protein levels in the cerebral cortex. However, increased levels of actin and its mRNA were observed in the hypothalamus. Exogenous melatonin administration at onset of night decreased the amount of actin in the hypothalamus, while the actin mRNA levels decreased when the administration was realized in the morning. In this review we will describe the synchronizer role of melatonin in the sleep-awake cycle and in the organization of cytoskeletal proteins and their mRNAs. Also, we will describe alterations in the melatonin secretion rhythm associated with a neuronal cytoskeleton disorganization in the neuropsychiatric diseases such as Alzheimer, depression, bipolar disorder and schizophrenia.

Keywords : Melatonin; neuropsychiatric diseases; circadian rhythms; microtubules; microfilaments.

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