Hydrogen sulfide inhibits preoptic prostaglandin E2 production during endotoxemia

Hydrogen sulfide (H2S) is a gaseous neuromodulator endogenously produced in the brain by the enzyme cystathionine beta-synthase (CBS). We tested the hypothesis that H2S acts within the anteroventral preoptic region of the hypothalamus (AVPO) modulating the production of prostaglandin (PG) E-2 (the proximal mediator of fever) and cyclic AMP (cAMP). To this end, we recorded deep body temperature (Tb) of rats before and after pharmacological modulation of the CBS-H2S system combined or not with lipopolysaccharide (LPS) exposure, and measured the levels of H2S, cAMP, and PGE(2) in the AVPO during systemic inflammation. Intra-cerebroventricular (icy) microinjection of aminooxyacetate (AOA, a CBS inhibitor: 100 pmol) did not affect basal PGE(2) production and Tb, but enhanced LPS-induced PGE(2) production and fever, indicating that endogenous 1125 plays an antipyretic role. In agreement, icy microinjection of a H2S donor (Na2S; 260 nmol) reduced the LPS-induced PGE(2) production and fever. Interestingly, we observed that the AVPO levels of H2S were decreased following the immunoinflammatory challenge. Furthermore, fever was associated with decreased levels of AVPO cAMP and increased levels of AVPO PGE(2). The LPS-induced decreased levels of cAMP were reduced to a lesser extent by the H2S donor. The LPS-induced PGE(2) production was potentiated by AOA (the CBS inhibitor) and inhibited by the H2S donor. Our data are consistent with the notion that the gaseous messenger H2S synthesis is downregulated during endotoxemia favoring PGE(2) synthesis and lowering cAMP levels in the preoptic hypothalamus. (C) 2012 Elsevier Inc. All rights reserved.