Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation

Although the inducible isoform of nitric oxide synthase (iNOS) is a well-established source of nitric oxide (NO center dot) during inflammation of the central nervous system (CNS), little is known about the involvement of constitutive isoforms of NOS (cNOS) in the inflammatory process. The aim of this study was to compare the responses of the expression and activity of NOS and the two cNOS isoforms, neuronal and endothelial (nNOS and eNOS, respectively), in the brain to systemic inflammation and their roles in the cascade of events leading to degeneration and apoptosis. A systemic inflammatory response in C57BL/6 mice was induced by intraperitoneal injection of lipopolysaccharide [LPS; 1 mg/kg body weight (b.w.)]. The relative roles of the NOS isoforms were evaluated after injection of N-G-nitro-L-arginine (NNLA; 30 mg/kg b.w.), which preferentially inhibits cNOS, or 1400W (5 mg/kg lo.w.), an inhibitor of NOS. Biochemical and morphological alterations were analyzed up to 48 hr after administration of LPS. Systemic LPS administration evoked significant ultrastructural alterations in brain capillary vessels, neuropils, and intracellular organelles of neurons, astrocytes, and microglia. Apoptotic/autophagic processes occurred in many neurons of the substantia nigra (SN), which coincided with exclusive enhancement of NOS expression and activity in this brain region. Moreover, inhibitors of both NOS and cNOS prevented LPS-evoked release of apoptosis-Inducing factor (AIF) from SN mitochondria. Collectively, the results indicate that synthesis of NO center dot by both the inducible and constitutive NOS isoforms contribute to the activation of apoptotic pathways in the brain during systemic inflammation. (c) 2007 Wiley-Liss, Inc.