title: Pregnenolone sulfate restores the glutamate-nitric-oxide-cGMP pathway and extracellular GABA in cerebellum and learning and motor coordination in hyperammonemic rats.
abstract: 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 GABA(A) 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-cGMP pathway, likely due to both enhanced NMDA receptor activation and reduced GABA(A) receptor activation. Similar treatments would improve cognitive and motor alterations in patients with MHE.
authors.affiliation: Laboratory of Neurobiology, Centro Investigación Príncipe Felipe , Valencia 46012, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Gonzalez-Usano
authors.forename: Omar
authors.initials: O
authors.lastname: Cauli
authors.forename: Ana
authors.initials: A
authors.lastname: Agusti
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D022124:Hyperammonemia / Q000188:drug therapy*; D007858:Learning / Q000187:drug effects*; D008297:Male; D017551:Microdialysis; D009569:Nitric Oxide / Q000378:metabolism; D011284:Pregnenolone / Q000494:pharmacology / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D011963:Receptors, GABA-A; C018370:pregnenolone sulfate; D009569:Nitric Oxide; D018698:Glutamic Acid; D011284:Pregnenolone; D006152:Cyclic GMP