Probenecid, a Pannexin1 inhibitor, restores deranged NMDA receptor and nNOS profiles in cerebellum of minimal hepatic encephalopathy rats

Abstract

Abstract Modulating Pannexin1 (Panx1), an ATP exit channel, in brain cells as a therapeutic option for neurological disorders, is an evolving concept. Our previous report on concordant increase in Panx1 vs neuronal nitric oxide synthase (nNOS) in cerebellum of the minimal hepatic encephalopathy (MHE) rats led us to explore whether Panx1 could be modulated to ameliorate the neurochemical aberrations related to MHE pathogenesis. This article describes the effect of Panx1 inhibition by probenecid (PB) on the relative profile of NMDA receptor (NMDAR)-nNOS axis and the level of degenerating cerebellar Purkinje cells vs recovery in the motor function deficit in a neurobehaviorily characterized MHE rats developed by administering 50 mg/kg bw thioacetamide intraperitoneally for 14 days. As compared to the control group rats, cerebellum of the MHE rats showed concordant increases in the level and activities of Panx1 and nNOS with a concomitant decline in the ratio of NMDAR subunit 2A/2B coinciding with atrophy of the purkinje cells. Moreover, all these parameters were observed to be recovered back to their control levels due to the treatment with a Panx1 inhibitor, Probenecid (PB), to the MHE rats. Such a recovery in the neurochemical parameters were found to be consistent with the restoration of Purkinje cell population and the MHE associated impaired rota-rod performance tests. The findings underscore PB-mediated Panx1 inhibition as a promising therapeutic avenue for ameliorating the MHE pathogenesis related neurochemical aberration and motor coordination deficits.