Vida moderna y déficit de sueño : la fisiología no se globaliza

Fil: Cardinali, Daniel P. Universidad de Buenos Aires. Facultad de Medicina; Argentina.Para tener una buena vida resulta indispensable disfrutar de un buen sueño. Sin embargo, las\nexigencias propias de la vida moderna, impuestas por un modelo productivo que da lugar a una\nsociedad que está en marcha las 24 horas de manera permanente, está alterando nuestros ciclos\nnaturales de sueño y vigilia. Los seres humanos estamos durmiendo menos horas que las que\nnecesitamos y cada vez sufrimos más trastornos del sueño. Esta situación está provocando graves\nconsecuencias, tanto en el orden individual como en el social

Trastornos del sueño y seguridad vial : un tema no resuelto

Fil: Cardinali, Daniel P. Universidad de Buenos Aires. Facultad de Medicina; Argentina.Fil: Pérez Chada, Daniel. Hospital Universitario Austral. Departamento de Medicina Interna; ArgentinaLos mayores accidentes industriales y vehiculares de nuestros días pueden vincularse a la utilización de\n"las máquinas humanas" más allá de sus especificaciones naturales. En nuestro país, y a pesar de la\ncreciente preocupación pública por la seguridad vial, se presta poco interés al hecho de que la influencia\ndel sueño insuficiente es causa en una importante proporción de accidentes vehiculares

Neuroimmunoendocrinology of the cervical autonomic nervous system

This article reviews several peripheral neuroendocrine relationships in the cervical region, namely the effect of the sympathetic innervation on adenohypophysial, thyroid and parathyroid hormone release, and the effect of parasympathetic innervation in thyroid and parathyroid glands. The possible pathways through which the central nervous system modulates the circadian organization of the immune response are also reviewed and the relative importance of circadian control of immune reactivity through local sympathetic and parasympathetic nerves and of neuroendocrine signals, like melatonin, is also discussed. Altogether the present article argues in favor of the concept that nerves arriving to the endocrine and lymphoid tissue constitute alternate pathways through which the brain controls immunoendocrine phenomena.Biomedical Reviews 1998; 9: 47-59

Cadmium-Induced Disruption in 24-h Expression of Clock and Redox Enzyme Genes in Rat Medial Basal Hypothalamus: Prevention by Melatonin

In a previous study we reported that a low daily p.o. dose of cadmium (Cd) disrupted the circadian expression of clock and redox enzyme genes in rat medial basal hypothalamus (MBH). To assess whether melatonin could counteract Cd activity, male Wistar rats (45 days of age) received CdCl2 (5 ppm) and melatonin (3 μg/mL) or vehicle (0.015% ethanol) in drinking water. Groups of animals receiving melatonin or vehicle alone were also included. After 1 month, MBH mRNA levels were measured by real-time PCR analysis at six time intervals in a 24-h cycle. In control MBH Bmal1 expression peaked at early scotophase, Per1 expression at late afternoon, and Per2 and Cry2 expression at mid-scotophase, whereas neither Clock nor Cry1 expression showed significant 24-h variations. This pattern was significantly disrupted (Clock, Bmal1) or changed in phase (Per1, Per2, Cry2) by CdCl2 while melatonin counteracted the changes brought about by Cd on Per1 expression only. In animals receiving melatonin alone the 24-h pattern of MBH Per2 and Cry2 expression was disrupted. CdCl2 disrupted the 24-h rhythmicity of Cu/Zn- and Mn-superoxide dismutase (SOD), nitric oxide synthase (NOS)-1, NOS-2, heme oxygenase (HO)-1, and HO-2 gene expression, most of the effects being counteracted by melatonin. In particular, the co-administration of melatonin and CdCl2 increased Cu/Zn-SOD gene expression and decreased that of glutathione peroxidase (GPx), glutathione reductase (GSR), and HO-2. In animals receiving melatonin alone, significant increases in mean Cu/Zn and Mn-SOD gene expression, and decreases in that of GPx, GSR, NOS-1, NOS-2, HO-1, and HO-2, were found. The results indicate that the interfering effect of melatonin on the activity of a low dose of CdCl2 on MBH clock and redox enzyme genes is mainly exerted at the level of redox enzyme gene expression

Clinical Aspects of Melatonin Intervention in Alzheimer’s Disease Progression

Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called “sundowning”). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were “Alzheimer” and “melatonin”. Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated

Experimental allergic encephalomyelitis in pituitary-grafted Lewis rats

Treatment of susceptible rats with dopaminergic agonists that reduce prolactin release decreases both severity and duration of clinical signs of experimental allergic encephalomyelitis (EAE). To assess to what extent the presence of an ectopic pituitary (that produces an increase in plasma prolactin levels mainly derived from the ectopic gland) affects EAE, 39 male Lewis rats were submitted to pituitary grafting from littermate donors. Another group of 38 rats was sham-operated by implanting a muscle fragment similar in size to the pituitary graft. All rats received subcutaneous (s.c.) injections of complete Freund's adjuvant (CFA) plus spinal cord homogenate (SCH) and were monitored daily for clinical signs of EAE. Animals were killed by decapitation on days 1, 4, 7, 11 or 15 after immunization and plasma was collected for prolactin RIA. In a second experiment, 48 rats were immunized by s.c. injection of a mixture of SCH and CFA, and then received daily s.c. injections of bromocriptine (1 mg/kg) or saline. Groups of 8 animals were killed on days 8, 11 or 15 after immunization and plasma prolactin was measured. Only sham-operated rats exhibited clinical signs of the disease when assessed on day 15 after immunization. A progressive decrease in plasma prolactin levels was observed in pituitary-grafted rats, attaining a minimum 15 days after immunization, whereas plasma prolactin levels were increased during the course of the disease in sham-operated rats. Plasma prolactin levels were higher in pituitary-grafted rats than in sham-operated rats 1 day after immunization, but lower on days 7, 11 and 15 after immunogen injection. Further supporting a correlation of suppressed prolactin levels with absence of clinical signs of EAE, rats that were administered the dopaminergic agonist bromocriptine showed very low plasma prolactin levels and did not exhibit any clinical sign of EAE. These results indicate that low circulating prolactin levels coincide with absence of clinical signs of EAE in Lewis rats

New concepts in the neurophysiology of sleep and wakefulness

The neural substrates of sleep and wakefulness form a highly distributed and, to some extent, redundant network, with hypocretin, monoaminergic and cholinergic systems largely promoting wakefulness and GABAergic systems in the preoptic area, hypothalamus and brainstem promoting sleep. The hypocretin/orexin system plays a special role in the promotion of wakefulness and suppression of REM sleep by providing excitatory input to the monoaminergic and cholinergic systems. Sleep is not a unitary state but involves a cyclic alternation between NREM and REM sleep; the pons is critical for generating the multiple components (ie, EEG synchronization, eye movements and muscle atonia) that characterize REM sleep. Recent findings have implicated the participation of hypothalamus, through MCH/GABA that provide a critical input to pontine generator of REM sleep. The timing of sleep and wakefulness is regulated by an interaction between the circadian pacemaker located in the hypothalamic SCN and a sleep homeostatic system whose anatomic location is yet to be definitively identified. Among various neurochemicals, extracellular AD and nNOS/NK1 accumulate in the BF as wakefulness is extended and inhibits cortically projecting cholinergic neurons, thereby influencing cortical activity. In the future, it seems reasonable to expect a spreading of these insights from basic to clinical grounds for a better understanding of the causes and mechanisms of sleep disorders and the generation of novel therapeutics in sleep medicine.Sociedad Argentina de Fisiologí

Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer's Disease and Melatonin

Alzheimer’s disease (AD) is associated with altered eating behavior and metabolic disruption. Amyloid plaques and neurofilament tangles are observed in many hypothalamic nuclei from AD brains. Some of these areas (suprachiasmatic nuclei, lateral hypothalamic area) also play a role in the regulation of the sleep/wake cycle and may explain the comorbidity of eating and sleep disorders observed in AD patients. Inadequate sleep increases the neurodegenerative process, for example, the decrease of slow-wave sleep impairs clearance of β-amyloid peptide (Aβ) and tau protein from cerebral interstitial fluid. Cerebrospinal fluid (CSF) melatonin levels decrease even in preclinical stages (Braak-1 stage) when patients manifest no cognitive impairment, suggesting that reduction of melatonin in CSF may be an early marker (the cause for which is still unknown) of oncoming AD. Melatonin administration augments glymphatic clearance of Aβ and reduces generation and deposition of Aβ in transgenic animal models of AD. It may also set up a new equilibrium among hypothalamic feeding signals. While melatonin trials performed in the clinical phase of AD have failed to show or showed only modest positive effects on cognition, in the preclinical stage of dementia (minimal cognitive impairment) the effect of melatonin is demonstrable with significant improvement of sleep and quality of life. In this review, we discuss the main aspects of hypothalamic alterations in AD, the association between interrupted sleep and neurodegeneration, and the possible therapeutic effect of melatonin on these processes.Facultad de Ciencias MédicasCentro de Endocrinología Experimental y Aplicad

Nonmotor Symptoms Groups in Parkinson's Disease Patients: Results of a Pilot, Exploratory Study

Nonmotor symptoms (NMS) like neuropsychiatric symptoms, sleep disturbances or autonomic symptoms are a common feature of Parkinson's disease (PD). To explore the existence of groups of NMS and to relate them to PD characteristics, 71 idiopathic non-demented PD out-patients were recruited. Sleep was evaluated by the PD Sleep Scale (PDSS). Several neuropsychiatric, gastrointestinal and urogenital symptoms were obtained from the NMSQuest. Sialorrhea or dysphagia severity was obtained from the Unified PD Rating Scale activities of daily living section. MADRS depression scale was also administered. Exploratory factor analysis revealed the presence of 5 factors, explaining 70% of variance. The first factor included PDSS measurement of sleep quality, nocturnal restlessness, off-related problems and daytime somnolence; the second factor included nocturia (PDSS) and nocturnal activity; the third one included gastrointestinal and genitourinary symptoms; the forth one included nocturnal psychosis (PDSS), sialorrhea and dysphagia (UPDRS); and the last one included the MADRS score as well as neuropsychiatric symptoms. Sleep disorders correlated with presence of wearing-off, nocturia with age >69 years, and nocturnal psychosis with levodopa equivalent dose or UPDRS II score. Neuropsychiatric symptoms correlated with UPDRS II+III score and non-tricyclic antidepressants. These results support the occurrence of significant NMS grouping in PD patients

Immune response after experimental allergic encephalomyelitis in rats subjected to calorie restriction

Male Lewis rats (6 weeks-old) were submitted to a calorie restriction equivalent to 33% or 66% of food restriction. Fifteen days later, groups of 7 animals were injected with complete Freund's adjuvant plus spinal cord homogenate (SCH) to induce experimental allergic encephalomyelitis (EAE) or with complete Freund's adjuvant alone. EAE was defined solely on clinical grounds. Rats were assessed daily for clinical signs of EAE and were killed on day 15 after immunization. Both diet and SCH injection diminished body weight significantly. In contrast to rats receiving a normal diet or a 33% calorie-restricted diet, rats subjected to severe calorie restriction did not exhibit clinical signs of EAE. Concomitantly with the lack of disease manifestation, 66% of calorie-restricted rats injected with SCH showed significantly less splenic and lymph node mitogenic response to concanavalin A (Con A) and a higher splenic response to lipopolysaccharide. Fewer splenic, lymph node and thymic CD4(+ )cells, greater numbers of splenic and lymph node CD8(+ )and CD4(+)- CD8(+ )cells, and fewer splenic T, B and T-B cells, and lymph node and thymic B and T-B cells were observed. There was impaired interferon (IFN)-γ production occurred in the three examined tissues. The results are compatible with the view that the acute phase of EAE can be curtailed by severe calorie restriction, presumably through impaired IFN-γ production