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Hyperammonemia alters the modulation by different neurosteroids of the glutamate–nitric oxide–cyclic GMP pathway through NMDA‐ GABA A ‐ or sigma receptors in cerebellum in vivo
Author(s) -
GonzálezUsano Alba,
Cauli Omar,
Agustí Ana,
Felipo Vicente
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12119
Subject(s) - pregnenolone sulfate , neuroactive steroid , allopregnanolone , hyperammonemia , pregnenolone , pregnanolone , endocrinology , gabaa receptor , medicine , nmda receptor , chemistry , agonist , glutamate receptor , biology , receptor , steroid , hormone
Several neurosteroids modulate the glutamate–nitric oxide (NO)–cGMP pathway in cerebellum through modulation of NMDA‐ GABA A ‐ or sigma receptors. Hyperammonemia alters the concentration of several neurosteroids and impairs the glutamate–NO–cGMP pathway, leading to impaired learning ability. This work aimed to assess whether chronic hyperammonemia alters the modulation by different neurosteroids of GABA A , NMDA, and/or sigma receptors and of the glutamate–NO–cGMP pathway in cerebellum. Neurosteroids were administered through microdialysis probes, and extracellular cGMP and citrulline were measured. Then NMDA was administered to assess the effects on the glutamate–NO–cGMP pathway activation. Hyperammonemia completely modifies the effects of pregnanolone and pregnenolone. Pregnanolone acts as a GABA A receptor agonist in controls, but as an NMDA receptor antagonist in hyperammonemic rats. Pregnenolone does not induce any effect in controls, but acts as a sigma receptor agonist in hyperammonemic rats. Hyperammonemia potentiates the actions of tetrahydrodeoxy‐corticosterone ( THDOC ) as a GABA A receptor agonist, allopregnanolone as an NMDA receptor antagonist, and pregnenolone sulfate as an NMDA receptor activation enhancer. Neurosteroids that reduce the pathway (pregnanolone, THDOC, allopregnanolone, DHEAS) may contribute to cognitive impairment in hyperammonemia and hepatic encephalopathy. Pregnenolone would impair cognitive function in hyperammonemia. Neurosteroids that restore the pathway in hyperammonemia (pregnenolone sulfate) could restore cognitive function in hyperammonemia and encephalopathy.