Expression and activity of PARP family members in the hippocampus during systemic inflammation: their role in the regulation of prooxidative genes.

Poly(ADP-ribose)polymerase-1 (PARP-1) plays an important role in DNA repair processes during oxidative/genotoxic stress, in regulation of transcription factors and in cell death mechanisms. However, little is known about the physiopathological role of other PARP family members. In this study we analyzed, for the first time, expression of PARP family genes in the hippocampus of mice subjected to lipopolysaccharide (LPS)-evoked systemic inflammatory response (SIR). Moreover, the effect of SIR on PARP activity and on its role in gene expression was evaluated. Our data indicated that SIR enhances PARP-1, -3, -9, -12 and -14 gene expressions in mouse hippocampus. PARP activity in the hippocampus was also considerably elevated during SIR with a maximum value at 12h after LPS administration, indicating significant formation and accumulation of poly(ADP-ribose) (PAR) - this reaction's product. Concomitantly, higher expression of genes for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and NADPH oxidase subunits occurred in the hippocampus during the first hours of SIR. The inhibitor of PARP, i.e. 3-aminobenzamide (3-AB; 30mg/kg b.w.), protected the hippocampal cells against PAR formation and expression of the gene for iNOS. However, PARP activity had no effect on the mRNA level of COX-2, TNF-α and NADPH oxidase in the hippocampus. Bioinformatic analysis predicted that interaction between PARP/PAR and 41 transcription factors may be important for regulation of expression of 139 genes from the group of 262 that changed expression in the hippocampus during SIR. Summarizing, enhancement of gene expression and activity of PARP family members by SIR could lead, through modification of the protein poly(ADP-ribosylation) process, to changes in the proteins' activity. A higher level of PAR and PARP/PAR protein interaction may affect the functioning of several transcription factors. PARP activity plays a role in regulation of expression of iNOS, the main enzyme responsible for oxidative/nitrosative stress in SIR.