Pregnenolone Sulfate Restores the Glutamate-Nitric-Oxide-cGMPPathway and Extracellular GABA in Cerebellum and Learning and MotorCoordination in Hyperammonemic Rats

摘要

Around 40% of cirrhotic patients show minimal hepatic encephalopathy (MHE), with mild cognitive impairment which reduces their quality of life and life span. Treatment of MHE is unsatisfactory, and there are no specific treatments for the neurological alterations in MHE. Hyperammonemia is the main contributor to neurological alterations in MHE. New agents acting on molecular targets involved in brain mechanisms leading to neurological alterations are needed to treat MHE. Chronic hyperammonemia impairs learning of a Y-maze task by impairing the glutamate-nitric-oxide (NO)-cGMP pathway in cerebellum, in part by enhancing GABAA receptor activation, which also induces motor in-coordination. Acute pregnenolone sulfate (PregS) restores the glutamate-NO-cGMP pathway in hyperammonemic rats. This work aimed to assess whether chronic treatment of hyperammonemic rats with PregS restores (1) motor coordination; (2) extracellular GABA in cerebellum; (3) learning of the Y-maze task; (4) the glutamate-NO-cGMP pathway in cerebellum. Chronic intracerebral administration of PregS normalizes motor coordination likely due to extracellular GABA reduction.PregS restores learning ability by restoring the glutamate-NO-cGMPpathway, likely due to both enhanced NMDA receptor activation andreduced GABAA receptor activation. Similar treatments wouldimprove cognitive and motor alterations in patients with MHE.