Language: Spanish
References: 52
Page: 167-173
PDF size: 127.90 Kb.
ABSTRACT
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 photoperiod. 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 hypersomniaassociated 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 photosynthetic 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, α-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.
REFERENCES
Lamont EW, Legault-Coutu D, Cermakian N, Boivin DB. The role of circadian clock genes in mental disorders. Dialogues Clin Neurosci 2007;9:333-342.
Cardinali DP, Furio AM, Reyes MP. Clinical perspectives for the use of melatonin as a chronobiotic and cytoprotective agent. Ann N Y Acad Sci. 2005;1057:327- 336.
Whitehead DL, Davies AD, Playfer JR, Turnbull CJ. Circadian rest-activity rhythm is altered in Parkinson’s disease patients with hallucinations. Mov Disord 2008;23:1137-45.
Mahé V, Chevalier JF. Role of biological clock in human pathology. Presse Med 1995;24:1041-1046.
Pittendrigh CS. Circadian systems: General perspective. En: Aschoff J (ed). Handbook of behavioral neurobiology. Vol. 4. New York: Plenum Press USA; 1981.
Pittendrigh CS, Daan, S. A functional analysis of circadian pacemakers in nocturnal rodents IV, Entrainment: Pacemakers and clocks. J Comp Physiol 1976;106:291-331.
Alila-Johansson A. Daily and Seasonal rhythms of melatonin, cortisol, leptin, free acids and glycerol in goats. Helsinki: Department of Basic Veterinary Sciences, Faculty of Veterinary; 2008; p. 88.
Rusak B, Zucker I. Neural regulation of circadian rhythms. Physiol Rev 1979;59:449-526.
Kappers JA. Short history of pineal discovery and research. En: Kappers JE, Pévet P (eds). The pineal gland of vertebrates including man. Amsterdam: Elsevier; 1979.
Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 1991;12:151-180.
Pévet P, Bothorel B, Slotten H, Saboureau M. The chronobiotic properties of melatonin. Cell Tissue Res 2002;309:183-191.
Redman J, Armstrong S, Ng KT. Free-running activity rhythms in the rat: entrainment by melatonin. Science 1983;219:1089-1091.
American Academy of Sleep Medicine. The international classification of sleep disorders. Segunda edición. Diagnostic and Coding Manual. Westchester, Illinois (US): American Academy of Sleep Medicine; 2005.
Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. BMJ 1989;298:705-707.
Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biol Psychiatry 1993;33:526-530.
Nurnberger JI, Adkins S, Lahiri DK, Mayeda A et al. Melatonin suppression by light in euthymic bipolar and unipolar patients. Arch Gen Psychiatry 2000;57:572–579.
Nair NP, Hariharasubramanian N, Pilapil C. Circadian rhythm of plasma melatonin in endogenous depression. Prog Neuropsychopharmacol Biol Psychiatry 1984;8:715-718.
Robinson S, Rosca P, Durst R, Shai U et al. Serum melatonin levels in schizophrenic and schizoaffective hospitalized patients. Acta Psychiatr Scand 1991;84:221-224.
Barbini B, Bertelli S, Colombo C, Smeraldi E. Sleep loss, a possible factor in augmenting manic episode. Psychiatry Res 1996;65:121–125.
Detre T, Himmelhoch J, Swartzburg M, Anderson CM et al. Hypersomnia and manic-depressive disease. Am J Psychiatry 1972;128:1303–1305.
Tsujimoto T, Yamada N, Shimoda K, Hanada K et al. Circadian rhythms in depression. Part I: Monitoring of the circadian body temperature rhythm. J Affect Disord 1990;18:193-197.
Tandon R, Shipley JE, Taylor S, Greden JF et al. Electroencephalographic sleep abnormalities in schizophrenia: relationship to positive/negative symptoms and prior neuroleptic treatment. Arch Gen Psychiatry 1992;49:185-194.
Brusco LI, Márquez M, Cardinali DP. Monozygotic twins with Alzheimer’s disease treated with melatonin: Case report. J Pineal Res 1998;25:260-263.
Robertson JM, Tanguay PE. Case study: the use of melatonin in a boy with refractory bipolar disorder. J Am Acad Child Adolesc Psychiatry 1997;36:822-825.
Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. Am J Psychiatry 1998;155:1119-1121.
Shamir E, Laudon M, Barak Y, Anis Y et al. Melatonin improves sleep quality of patients with chronic schizophrenia. J Clin Psychiatry 2000;61:373-377.
Benítez-King G, Ramírez-Rodríguez G, Ortíz L, Meza I. The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. Curr Drug Targets CNS Neurol Disord 2004;3(6):515-533.
Stockmeier AC, Mahajan JG, Konick CL, Overholser CJ et al. Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry 2004;56:640-650.
Soares JC, Mann JJ. The anatomy of mood disorders - review of structural neuroimaging studies. Biol Psychiatry 1997;41:86-106.
Chana G, Landau S, Beasley C, Everall IP et al. Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density. Biol Psychiatry 2003;53:1086–1098.
Rosoklija G, Toomayan G, Ellis SP, Keilp J et al. Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders. Arch Gen Psychiatry 2000;57:349-356.
Senitz D, Winkelmann E. Morphology of the orbitofrontal cortex in persons schizophrenic psychotics. A Golgi and electron microscopy. Psychiatr Neurol Med Psychol 1981;33:1-9.
Broadbelt K, Byne W, Jones LB. Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex. Schizophr Res 2002;58:75-81.
Benítez-King G, Domínguez-Alonso A, Ramírez-Rodríguez G. Neurocytoskeletal protective effect of melatonin: Importance for morpho-functional neuronal polarization. Open Neuroendocrinol J 2010;3:105-111.
Eidenmuller J, Fath T, Hellwing A, Reed J et al. Structural and functional implications of tau hyperphophorylation: information from phosphorylation- mimicking mutated tau proteins. Biochemistry 2000;39: 13166-13175.
Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA 1994;91:5562-5566.
Iqbal K, Grundke-Iqbal I, Zaidi T, Merz PA et al. Defective brain microtubule assembly in Alzheimer’s disease. Lancet 1986;2:421-426.
Arnold SE, Lee VM, Gur RE, Trojanowski JQ. Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia. Proc Natl Acad Sci USA 1991;88:10850-1854.
Benítez-King G. Melatonin as a cytoskeletal modulator: implications for cell physiology and disease. J Pineal Res 2006;40(1):1-9.
Reiter RJ, Tan DX, Mayo JC, Sainz RM et al. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol 2003;50(4):1129-1146.
Bellon A, Ortíz-López L, Ramírez-Rodríguez G, Antón-Tay F et al. Melatonin induces neuritogenesis at early stages in N1E-115 cells through actin rearrangements via activation of protein kinase C and Rho-associated kinase. J Pineal Res 2007;42:214-221.
Arendt T, Holzer M, Brückner MK, Janke C et al. The use of okadaic acid in vivo and the induction of molecular changes typical for Alzheimer’s disease. Neuroscience 1998;85:1337-1340.
Benítez-King G, Túnez I, Bellon A, Ortíz GG et al. Melatonin prevents cytoskeletal alterations and oxidative stress induced by okadaic acid in N1E-115 cells. Exp Neurol 2003;182:151-159.
Jiménez-Rubio G, Benítez-King G, Ortiz-López L. Melatonin elicits neuritogenesis and reverses Tau hyperphosphorylation in NIE-115 neuroblastoma cells treated with okadaic Acid. En: Fernández AJ (ed). Focus on neuroblastoma research. Hauppauge, New York: Nova Science Publisher; 2007.
Benítez-King G, Ortíz-López L, Jiménez-Rubio G. Melatonin precludes cytoskeletal collapse caused by hydrogen peroxide: participation of protein kinase C. Therapy 2005;2:762-778.
Fukuda M, Hasezawa S, Nakajima N, Kondo N. Changes in tubulin protein expression in guard cells of Vicia faba L. accompanied with dynamic organization of microtubules during the diurnal cycle. Plant Cell Physiol 2000;41:600-607.
Lonergan TA. Regulation of Cell Shape in Euglena gracilis: I. Involvement of the biological clock, respiration, photosynthesis, and cytoskeleton. Plant Physiol 1983;71:719-730.
Ramírez-Rodríguez G, Meza I, Hernández ME, Castillo A et al. Melatonin induced cyclic modulation of vectorial water transport in kidneyderived MDCK cells. Kidney International 2003;63:1356-1364.
Iovanna J, Dusetti N, Calvo E, Cardinali DP. Diurnal changes in actin mRNA levels and incorporation of 35S-methionine into actin in the rat hypothalamus. Cell Mol Neurobiol 1990;10:207-216.
Iovanna J, Dusetti N, Cadenas B, Cardinali DP. Time-dependent effect of melatonin on actin mRNA levels and incorporation of 35S-methionine into actin and proteins by the rat hypothalamus. J Pineal Res 1990;9:51-63.
Bredow S, Guha-Thakurta N, Taishi P, Obál F Jr et al. Diurnal variations of tumor necrosis factor alpha mRNA and alpha-tubulin mRNA in rat brain. Neuroimmunomodulation 1997;4:84-90.
Taishi P, Bredow S, Guha-Thakurta N, Obál F et al. Diurnal mRNA variations of interleukin 1-beta mRNA and beta-actin mRNA in rat brain. J Neuroinmunol 1997;75:69-79.
Full text