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GENETIC INACTIVATION OF POLY ( ADP-RIBOSE ) POLYMERASE AND ENDOTHELIAL NITRIC OXIDE SYNTHASE PREVENTS ENERGY FAILURE AND OXIDATIVE DAMAGE IN THE MOUSE BRAIN DURING SEPTIC SHOCK

It was suggested that inducible nitric oxide synthase (iNOS) plays the key role in septic shock. However, little is known about the constitutive isoform(s) of NOS (cNOS) that may be also involved in excessive NO release, leading to lipid and protein oxidation, DNA damage, overactivation of poly(ADP-ribose) polymerase-1 (PARP-1), dramatic energy failure and cell death. The aim of our study was to analyze the role of cNOS and PARP-1 in the brain during endotoxic shock. Wild type and eNOS and PARP-1 knock-out C57BL/6 and 129/sv mice were injected ip with lipopolysaccharide (LPS; 1–10 mg/kg) alone or together with NOS and PARP-1 inhibitors. Concentrations of carbonyl groups, thiobarbituric acid reactive substances and NAD were determined during 48 h after LPS injection, and correlated with the level of poly(ADPribose) and apoptosis inducing factor released from mitochondria. Our data showed that systemic injection of LPS significantly decreased NAD concentration and enhanced oxidative damage to macromolecules in the brain. Increased concentration of PAR and AIF translocation from mitochondria into nucleus were observed. These alterations depend on the dose of LPS, time of inflammation and on the integrity of blood-brain barrier. Genetic inactivation of PARP-1 and eNOS protects mouse brain against LPS toxicity, suggesting that PARP-1 overactivation is an important target in the cascade induced by LPS which indicates that eNOS is a significant source of NO in the brain during sepsis. Pharmacological intervention confirmed that depending on the intensity of inflammation, inhibition of cNOS or PARP-1 might have a significant neuroprotective effect.