Edaravone abrogates LPS-induced behavioral anomalies, neuroinflammation and PARP-1.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA nick-sensor enzyme that functions at the center of cellular stress response and affects the immune system at several key points, and thus modulates inflammatory diseases. Our previous study demonstrated that lipopolysaccharide (LPS)-induced depressive-like behavior in mice can be ameliorated by 3-aminobenzamide, which is a PARP-1 inhibitor. In the present study we've examined the effect of a free radical scavenger, edaravone pretreatment against LPS-induced anxiety and depressive-like behavior as well as various hippocampal biochemical parameters including PARP-1. Male Swiss albino mice were treated with edaravone (3 & 10mg/kgi.p.) once daily for 14days. On the 14th day 30min after edaravone treatment mice were challenged with LPS (1mg/kgi.p.). After 3h and 24h of LPS administration we've tested mice for anxiety and depressive-like behaviors respectively. Western blotting analysis of PARP-1 in hippocampus was carried out after 12h of LPS administration. Moreover, after 24h of LPS administration serum corticosterone, hippocampal BDNF, oxido-nitrosative stress and pro-inflammatory cytokines were estimated by ELISA. Results showed that pretreatment of edaravone (10mg/kg) ameliorates LPS-induced anxiety and depressive-like behavior. Western blotting analysis showed that LPS-induced anomalous expression of PARP-1 significantly reverses by the pretreatment of edaravone (10mg/kg). Biochemical analyses revealed that LPS significantly diminishes BDNF, increases pro-inflammatory cytokines and oxido-nitrosative stress in the hippocampus. However, pretreatment with edaravone (10mg/kg) prominently reversed all these biochemical alterations. Our study emphasized that edaravone pretreatment prevents LPS-induced anxiety and depressive-like behavior, mainly by impeding the inflammation, oxido-nitrosative stress and PARP-1 overexpression.

Poly (ADP-ribose) polymerase-1 inhibitor, 3-aminobenzamide pretreatment ameliorates lipopolysaccharide-induced neurobehavioral and neurochemical anomalies in mice.

Poly (ADP-ribose) polymerase-1 (PARP-1) functions at the center of cellular stress and sways the immune system at several key points, thus modulates inflammatory diseases. The antiinflammatory properties of PARP-1 inhibitors have been demonstrated ameliorating effect in various neuroinflammatory disorders. It has been reported that there is a close relationship between the inflammatory processes and major depressive disorder. In the present study, we have elucidated the role of oxidative-nitrosative stress-PARP-1 pathway in lipopolysaccharide (LPS)-induced neurobehavioral and neurochemical alterations in mice. 3-Aminobenzamide (10 and 30mg/kg) and imipramine (10 and 30mg/kg) were administered once daily for 14days. Mice were challenged with LPS (1mg/kg, i.p.) 30min after drug administration on the 14th day. The mRNA expression level of PARP-1 (12h after LPS injection) in the hippocampus was measured through quantitative real-time PCR. All the behavioral and biochemical parameters were assessed at 24h after LPS injection. The expression level of PARP-1mRNA was found significantly up-regulated in the hippocampus at 12h after LPS administration. Results showed that the LPS-challenged mice exhibited an increase in immobility time seen in forced swimming test and tail suspension test. LPS increased the levels of proinflammatory cytokines and oxido-nitrosative stress parameters in the hippocampus. However, pretreatment with 3-aminobenzamide (30mg/kg) significantly reversed the LPS-induced alterations in behavioral parameters, proinflammatory cytokines, oxidative-nitrosative stress and PARP-1 mRNA levels. Imipramine failed to prevent the up-regulation of PARP-1 induced by LPS administration. Our results emphasized that oxidative-nitrosative stress-PARP-1 cascade can play a key role in LPS-induced neurobehavioral and neurochemical anomalies.