Lipopolysaccharide Induces Early Tolerance to Excitotoxicity via Nitric Oxide and cGMP

Abstract

Sublethal injury induces tolerance to a subsequent lethal insult, a phenomenon termed preconditioning (PC). PC occurs within hours (early tolerance) or days (delayed tolerance) after the inducing stimulus. In the brain, delayed tolerance has been studied extensively, but very little is known about early tolerance. We investigated whether the proinflammatory agent lipopolysaccharide (LPS), a well-established inducer of delayed tolerance, can also induce early tolerance and, if so, whether nitric oxide (NO) is involved in its mechanisms. In C57BL/6 mice, LPS was administered and N-methyl-D-aspartate (NMDA) was microinjected into the neocortex 30 minutes to 24 hours later. Lesion volume was assessed 24 hours after NMDA administration in thionine-stained sections. LPS reduced NMDA lesions when administered 1 hour (-25+/-1%; P<0.05, n=5 per group) or 24 hours (-25+/-4%; P<0.05, n=5 per group) before NMDA application. LPS administration 30 minutes or 2 to 4 hours before NMDA administration was not neuroprotective (P>0.05). The protection at 1 hour was independent of protein synthesis and was blocked by inhibition of neuronal NO synthase or soluble guanylyl cyclase. Furthermore, early protection was not observed in neuronal or endothelial NO synthase-null mice, but it was present in inducible NO synthase-null mice. The data demonstrate that LPS induces both early and late tolerance. At variance with delayed tolerance, which depends on inducible NO synthase and peroxynitrite, early tolerance is mediated by endothelial and neuronal NO through production of cGMP. The findings suggest that LPS can trigger signaling between endothelial cells and neurons, leading to NO production and cGMP-dependent neuroprotection.