Submitted on November 28, 2005
Accepted on January 30, 2006
Inhibition of caspase-1 in rat brain reduces spontaneous non-rapid eye movement (NREM) sleep and NREM sleep enhancement induced by lipopolysaccharide
Luca Imeri1*, Susanna Bianchi2, and Mark R Opp3
1 Institute of Human Physiology II, University of Milan Medical School, Milan, Italy; Giuseppe Moruzzi Centre for Experimental Sleep Research, University of Milan Medical School, Milan, Italy; Anesthesiology, University of Michigan Medica School, Ann Arbor, MI, USA
2 Institute of Human Physiology II, University of Milan Medical School, Milan, Italy; Giuseppe Moruzzi Centre for Experimental Sleep Research, University of Milan Medical School, Milan, Italy
3 Anesthesiology, University of Michigan Medica School, Ann Arbor, MI, USA; Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, Mi, USA
* To whom correspondence should be addressed. E-mail: luca.imeri{at}unimi.it.
Evidence suggests that interleukin-1
(IL-1) is involved in promoting physiological nonrapid eye movements (NREM) sleep. IL-1 has also been proposed to mediate NREM sleep enhancement induced by bacteria or their components. Mature and biologically active IL-1 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-1 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 administered intracerebroventricularly (ICV) the caspase-1 inhibitor Ac-Tyr-Val-Ala-Asp chloromethyl ketone (YVAD; 3, 30, 300 and 1500 ng) or were pretreated ICV with YVAD (300 ng) and then injected intraperitoneally (IP) with the Gramnegative bacterial cell wall component lipopolysaccharide (LPS; 250 µg/kg). Subsequent sleepwake 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 post-injection 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-1 in physiological promotion of NREM sleep and in mediating NREM sleep enhancement induced by peripheral immune challenge.
