Tetsuya Kushikata

Brain-derived neurotrophic factor enhances spontaneous sleep in rats and rabbits

Various growth factors are involved in sleep regulation. Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family; it and its receptors are found in normal brain. Furthermore, cerebral cortical levels of BDNF mRNA have a diurnal variation and increase after sleep deprivation. Therefore, we investigated whether BDNF would promote sleep. Twenty-four male Sprague-Dawley rats (320-380 g) and 25 male New Zealand White rabbits (4.5-5.5 kg) were surgically implanted with electroencephalographic (EEG) electrodes, a brain thermistor, and a lateral intracerebroventricular cannula. The animals were injected intracerebroventricularly with pyrogen-free saline and, on a separate day, one of the following doses of BDNF: 25 or 250 ng in rabbits; 10, 50, or 250 ng in rats. The EEG, brain temperature, and motor activity were recorded for 23 h after the intracerebroventricular injections. BDNF increased time spent in non-rapid eye movement sleep (NREMS) in rats and rabbits and REMS in rabbits. Current results provide further evidence that various growth factors are involved in sleep regulation.Various growth factors are involved in sleep regulation. Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family; it and its receptors are found in normal brain. Furthermore, cerebral cortical levels of BDNF mRNA have a diurnal variation and increase after sleep deprivation. Therefore, we investigated whether BDNF would promote sleep. Twenty-four male Sprague-Dawley rats (320-380 g) and 25 male New Zealand White rabbits (4.5-5.5 kg) were surgically implanted with electroencephalographic (EEG) electrodes, a brain thermistor, and a lateral intracerebroventricular cannula. The animals were injected intracerebroventricularly with pyrogen-free saline and, on a separate day, one of the following doses of BDNF: 25 or 250 ng in rabbits; 10, 50, or 250 ng in rats. The EEG, brain temperature, and motor activity were recorded for 23 h after the intracerebroventricular injections. BDNF increased time spent in non-rapid eye movement sleep (NREMS) in rats and rabbits and REMS in rabbits. Current results provide further evidence that various growth factors are involved in sleep regulation.

Nuclear factor-κB-like activity increases in murine cerebral cortex after sleep deprivation

Several well-defined sleep regulatory substances, e.g., interleukin-1β, activate the heterodimeric transcription factor nuclear factor-κB (NF-κB). Several substances that inhibit sleep, e.g., interleukin-4, inhibit NF-κB activation. NF-κB activation promotes production of several additional substances thought to be involved in sleep regulation, e.g., nitric oxide. We investigated, therefore, whether there are diurnal rhythms of NF-κB activation in brain and changes in the activation after sleep deprivation. Mice were kept on a 12:12-h light-dark cycle. In one experiment, groups of mice were killed every 3 h across the 24-h cycle. In another experiment, mice were killed at 1500 after 6 h of sleep deprivation, and a group of control mice were killed at the same time. Nuclear proteins were extracted from each brain tissue sample, and NF-κB-like activity was determined with an electrophoretic mobility shift assay. In cerebral cortex, but not other areas of brain, there was a diurnal rhythm in NF-κB-like activation; highest levels were found during the light period. NF-κB-like activation was higher in cerebral cortex after sleep deprivation compared with values obtained from control mice. The results are consistent with the hypothesis that sleep regulation involves multiple gene events, some of which include enhanced production of sleep regulatory substances, the actions of which involve NF-κB activation.

Interleukin-10 inhibits spontaneous sleep in rabbits.

Proinflammatory cytokines, including interleukin-1beta(IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are involved in sleep regulation. IL-10 is an anti-inflammatory cytokine that inhibits proinflammatory cytokine production. We hypothesized that IL-10 could attenuate sleep. Thirty-one male rabbits were used. Three doses of IL-10 (5 ng, 50 ng, and 250 ng) were injected intracerebroventricularly during the rest (light) period. One dose of IL-10 (250 ng) was injected during the active (dark) cycle. Appropriate time-matched control injections of saline were given to the same rabbits on different days. The two highest doses of IL-10 significantly inhibited spontaneous nonrapid eye movement sleep if IL-10 was given during the light cycle. The highest dose of IL-10 (250 ng) also significantly decreased rapid eye movement sleep. IL-10 administered at dark onset had no effect on sleep. The sleep inhibitory properties of IL-10 provide additional evidence for the hypothesis that a brain cytokine network is involved in regulation of physiologic sleep.

Interleukin-4 inhibits spontaneous sleep in rabbits

Proinflammatory cytokines, including interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha, are involved in sleep regulation. IL-4 is an antiinflammatory cytokine that inhibits proinflammatory cytokine production. The hypothesis that IL-4 should attenuate sleep was studied by determining the effects of IL-4 on rabbit spontaneous sleep. Thirty-six rabbits were used. Four doses of IL-4 (0.25, 2.5, 25, and 250 ng) were injected intracerebroventricularly during the rest (light) period. One dose of IL-4 (25 ng) was injected during the active (dark) cycle. Appropriate time-matched control injections of saline were done in the same rabbits on different days. The three highest doses of IL-4 significantly inhibited spontaneous non-rapid eye movement sleep if IL-4 was given during the light cycle. The highest dose of IL-4 (250 ng) also significantly decreased rapid eye movement sleep. On the other hand, IL-4 administered at dark onset had no effect on sleep. The sleep inhibitory properties of IL-4 provide additional evidence for the hypothesis that a brain cytokine network is involved in the regulation of physiological sleep.Proinflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α, are involved in sleep regulation. IL-4 is an antiinflammatory cytokine that inhibits proinflammatory cytokine production. The hypothesis that IL-4 should attenuate sleep was studied by determining the effects of IL-4 on rabbit spontaneous sleep. Thirty-six rabbits were used. Four doses of IL-4 (0.25, 2.5, 25, and 250 ng) were injected intracerebroventricularly during the rest (light) period. One dose of IL-4 (25 ng) was injected during the active (dark) cycle. Appropriate time-matched control injections of saline were done in the same rabbits on different days. The three highest doses of IL-4 significantly inhibited spontaneous non-rapid eye movement sleep if IL-4 was given during the light cycle. The highest dose of IL-4 (250 ng) also significantly decreased rapid eye movement sleep. On the other hand, IL-4 administered at dark onset had no effect on sleep. The sleep inhibitory properties of IL-4 provide additional evidence for the hypothesis that a brain cytokine network is involved in the regulation of physiological sleep.

Epidermal growth factor enhances spontaneous sleep in rabbits

Several growth factors are implicated in sleep regulation. Epidermal growth factor (EGF) is found in the brain, and it influences the production of several sleep-promoting substances. We determined, therefore, whether administration of exogenous EGF affected spontaneous sleep in rabbits. Twenty-five rabbits were implanted with electroencephalographic electrodes, a brain thermistor, and an intracerebroventricular guide cannula. Three doses of EGF (0.5, 5, and 25 microg) were used. The animals were injected intracerebroventricularly with saline as control and one dose of EGF on 2 separate days. Five and twenty-five micrograms of EGF enhanced non-rapid eye movement sleep and increased brain temperature. The 25-microg dose of EGF also inhibited rapid eye movement sleep across the 23-h postinjection recording period. Results are consistent with the hypothesis that EGF, like other growth factors, could be involved in sleep regulation.

An interleukin-1 receptor fragment blocks ambient temperature-induced increases in brain temperature but not sleep in rabbits

The effects of intracerebroventricular injection (i.c.v.) of an interleukin-1 (IL-1) inhibitor, a soluble IL-1 receptor fragment (IL-1RF), on sleep and brain temperature (Tbr) responses of rabbits induced by mild increases in ambient temperature (Tamb) were determined. Each rabbit was recorded under three conditions: (1) 21 degrees C Tamb plus pyrogen-free saline (PFS); (2) 27 degrees C Tamb plus PFS; (3) 27 degrees C Tamb plus the IL-1RF. The higher Tamb significantly increased Tbr during the warming period; this effect was attenuated by pretreatment with the IL-1RF. The higher Tamb alone (6 h exposure) significantly increased non-rapid eye movement sleep (NREMS) across the 23-h recording period. However, during the 6-h warming period NREMS values, obtained after IL-1 RF treatment, were not significantly different from those obtained from PFS-treated animals at 27 degrees C Tamb. The ability of the IL-1 RF to block Tamb-induced changes in Tbr and the failure of the IL-1RF to block Tamb-induced NREMS responses is different from previous results which indicated that a tumor necrosis factor receptor fragment (TNF-RF) inhibits warm Tamb-induced sleep but not Tbr responses. Thus, brain IL-1 and TNF sleep and thermo mechanisms are, in part, different.

Crisis Management for Perioperative Complications (Seizure, Hemorrhage, Neurogenic Pulmonary Edema, and Venous Embolism)

Seizures, hemorrhage, neurogenic pulmonary edemas, and venous embolisms are all potential perioperative complications. Although they are not usually life-threatening, the anesthesiologist should be familiar with their pathophysiology, diagnosis, and treatment, all of which will be described in this chapter.