Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats

Background: P38 mitogen activated protein kinase (MAPK) alpha modulates microglia-mediated inflammatory responses and a number of neuronal physiological processes. Objective: To evaluate pre-clinically the pharmacological effects in the brain of p38 MAPK alpha inhibition with a brain-penetrant specific chemical antagonist. Methods: VX-745, a blood-brain barrier penetrant, highly selective p38 MAPK alpha inhibitor, and clinical stage investigational drug, was utilized. Initially, a pilot study in 26-month-old Tg2576 mice was conducted. Subsequently, a definitive dose-response study was conducted in aged (20-22 months) rats with identified cognitive deficits; n = 15 per group: vehicle, 0.5, 1.5, and 4.5 mg/kg VX-745 by oral gavage twice daily for 3 weeks. Assessments in aged rats included IL-1 beta, PSD-95, TNF alpha protein levels in hippocampus; and Morris water maze (MWM) test for cognitive performance. Results: Drug effect could not be assessed in Tg2576 mice, as little inflammation was evident. In cognitively-impaired aged rats, VX-745 led to significantly improved performance in the MWM and significant reduction in hippocampal IL-1 beta protein levels, though the effects were dissociated as the MWM effect was evident at a lower dose level than that required to lower IL-1 beta. Drug concentration-effect relationships and predicted human doses were determined. Conclusions: Selective inhibition of p38 MAPK alpha with VX-745 in aged rats reduces hippocampal IL-1 beta levels and improves performance in the MWM. As the two effects occur at different dose levels, the behavioral effect appears to be via a mechanism that is independent of reducing cytokine production. The predicted human doses should minimize risks of systemic toxicity.