Inhibition of caspase-1 in rat brain reduces spontaneous nonrapid eye movement sleep and nonrapid eye movement sleep enhancement induced by lipopolysaccharide

Abstract

Evidence suggests that IL-1beta is involved in promoting physiological nonrapid eye movement (NREM) sleep. IL-1beta has also been proposed to mediate NREM sleep enhancement induced by bacteria or their components. Mature and biologically active IL-1beta is cleaved from an inactive precursor by a cysteinyl aspartate-specific protease (caspase)-1. This study aimed to test the hypothesis that inhibition in brain of the cleavage of biologically active IL-1beta will reduce in rats both spontaneous NREM sleep and NREM sleep enhancement induced by the peripheral administration of components of the bacterial cell wall. To test this hypothesis, rats were intracerebroventricularly administered the caspase-1 inhibitor Ac-Tyr-Val-Ala-Asp chloromethyl ketone (YVAD; 3, 30, 300, and 1,500 ng) or were pretreated intracerebroventricularly with YVAD (300 ng) and then intraperitoneally injected with the gram-negative bacterial cell wall component LPS (250 microg/kg). Subsequent sleep-wake behavior was determined by standard polygraphic recordings. YVAD administration at the beginning of the light phase of the light-dark cycle significantly reduced time spontaneously spent in NREM sleep during the first 12 postinjection hours. YVAD pretreatment also completely prevented NREM sleep enhancement induced by peripheral LPS administration at the beginning of the dark phase. These results, in agreement with previous evidence, support the involvement of brain IL-1beta in physiological promotion of NREM sleep and in mediating NREM sleep enhancement induced by peripheral immune challenge.

A critical review of human endotoxin administration as an experimental paradigm of depression

“…The effects of endotoxin on sleep are mediated by cytokines (Imeri et al 2006). Consistent with human studies discussed above, in rodents administration of endotoxin, IL-1, TNF, or IFN-γ suppresses REM sleep and enhances the duration of slow-wave sleep (Krueger et al 1986; Shoham et al 1987; Krueger et al 1995).…”

Neurobiological mechanisms for the regulation of mammalian sleep–wake behavior: Reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence

“…These actions involve cortical-reticular thalamic communication as well as activation of VLPO and other hypothalamic areas. Substances that inhibit IL-1b production, such as IL receptor antagonist (ILRA), CRH and anti-IL-1 antibodies, or inhibition of cleavage of biologically active IL-1, decrease spontaneous sleep in the rabbit (Imeri et al, 2006;Opp and Krueger, 1994b;Takahashi et al, 1996a).…”

The neuron-specific interleukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to influenza viral challenge in mice

“…Brain levels of IL1 mRNA vary with the time of day with highest levels occurring at Zeitgeber Time (ZT) 0, the beginning of the sleep period (Taishi et al 1997; 2012). Inhibiting caspase-1, the enzyme cleaves the pro-form of IL1 to produce mature IL1, reduces spontaneous NREMS and attenuates sleep responses to lipopolysaccharide (LPS; Imeri et al 2006). Lastly, after sleep loss and infectious challenge, sleep and brain levels of IL1 mRNA or IL1 protein are enhanced (Taishi et al 1998; Leyva-Grado et al 2009; reviewed Imeri and Opp 2009).…”