Institute for Medical and Dental Engineering
Tokyo Medical and Dental University
Tokyo 101, Japan
he brain is composed of billions of neurons. Neurons are characterized by their instantaneous consumption of a large amount of energy for the excitation and resultant transmission of neural information, being vulnerable to fatigue and excitotoxity. Neurons in the mammalian brain are further characterized by their inability of proliferation after a certain ontogenetic stage, being unable to be replaced by their succeeding generations. Hence a crucial problem arises as to how to maintain these special brain cells for their appropriate activity as well as longevity. Sleep appears to be one of the best solutions for the problem. It seems likely that phylogenetically advanced animals have evolved sleep in order to resolve this particular problem. Sleep is regulated by the dynamic interplay of the neural and humoral systems in the brain. A number of endogenous sleep substances, messengers of the humoral system, are known to differentially modulate sleep-regulatory activities of the neural system. Oxidized glutathione (GSSG) is a sleep substance originally extracted from brain tissues of long-term sleep-deprived rats with elevated sleep demand, and it accumulates in the brain during prolonged wakefulness. If exogenously administered at proper timing and dosage by means of infusion, either intracerebroventricularly (icv) in the third ventricle or microdialytically in the hypothalamic preoptic area (POA), GSSG induces both non-rapid-eye-movement sleep and rapid-eye-movement sleep in freely behaving rats. In vitro studies reveal that GSSG inhibits excitatory neurotransmission at the synaptic level of the glutamate receptor, and that GSSG modulates firing activity of neurons in the POA and the suprachiasmatic nucleus. GSSG may counteract excitotoxic events in the brain, since the conversion from reduced glutathione (GSH) into GSSG plays an essential role in the attenuation of oxidative stress. Indeed, t-butyl hydroperoxide (TBHP), an oxidative-stress inducer, biphasically modulates sleep; icv infusion of lower and higher doses causes an enhancement and a suppression of sleep, respectively, in rats. Presumably, the lower grade of oxidative stress induced by the lower level of TBHP is completely eliminated by the stimulated production of endogenous GSH, which eventually results in the promotion of sleep by GSH-derived GSSG. The higher grade of oxidation induced by the excessive TBHP exerts a toxic effect on sleep-regulating neurons, which eventually results in the suppression of sleep. Similarly administered N-ethylmaleimide (NEM), an inhibitor of GSH peroxidase, which blocks the conversion of GSH into GSSG along with detoxification, dose-dependently suppresses sleep in rats. This fact suggests that NEM-induced depletion of GSSG is responsible for the sleep alteration. Taking together, it seems plausible that a process of neuronal detoxification by glutathione against oxidative stress is closely related to the modulation of sleep. Hence sleep at the behavioral level is functionally associated with a process of neuronal detoxification at the cellular level. Such a concept can be regarded as a modern version of the Ishimori-Pieron hypnotoxin theory proposed early in this century.
