p38 MAP kinase is a therapeutic target for hepatic encephalopathy in rats with portacaval shunts

Objective Inflammation plays a role in neurological alterations in patients with hepatic encephalopathy (HE). Animal models of HE show neuroinflammation. Treatment with ibuprofen, a non-steroidal anti-nflammatory drug (NSAID), reduces neuroinflammation and restores cognitive and motor function in rats with HE due to portacaval shunts (PCS). This suggests that reducing neuroinflammation would improve neurological status in patients with minimal or clinical HE. NSAID induce kidney damage in patients with cirrhosis and PCS rats and are not suitable for clinical use. It is therefore necessary to look for procedures to eliminate neuroinflammation without inducing secondary effects in the kidney. Inhibition of p38 MAPK is being tested as a therapeutic target in inflammatory diseases and reduces microglial activation. This study aimed to assess whether inhibiting p38 with SB239063 reduces neuroinflammation and improves cognitive and motor function in PCS rats without affecting the kidney. Results p38 activity is increased in the brains of PCS rats and treatment with SB239063 reduces microglial activation, as well as inflammatory markers in brain (prostaglandin E2, cyclooxygenase activity, iNOS, IL-1 beta, TNF alpha) and blood (prostaglandin E2 and TNF alpha). PCS rats showed increased ammonia and glutamine in the brain, which was not affected by SB239063. PCS rats showed reduced ability to learn a Y-maze conditional discrimination task, reduced motor activity and impaired motor coordination, as assessed in the rotarod. Treatment with SB239063 completely restored learning ability, motor activity and coordination in PCS rats. SB239063 did not affect creatinine or sodium levels in serum, indicating that it does not induce kidney damage. Conclusion These findings suggest that reducing neuroinflammation by using inhibitors of p38 would improve the neurological status in HE without inducing secondary effects in the kidney.