These authors contributed equally to this work.
Hyperammonemia alters the modulation by different neurosteroids of the glutamate–nitric oxide–cyclic GMP pathway through NMDA- GABAA- or sigma receptors in cerebellum in vivo
Article first published online: 17 FEB 2013
© 2012 International Society for Neurochemistry
Journal of Neurochemistry
Volume 125, Issue 1, pages 133–143, April 2013
How to Cite
J. Neurochem. (2013) 125, 133–143.
- Issue published online: 21 MAR 2013
- Article first published online: 17 FEB 2013
- Accepted manuscript online: 10 DEC 2012 06:41PM EST
- Manuscript Accepted: 4 DEC 2012
- Manuscript Revised: 3 DEC 2012
- Manuscript Received: 17 AUG 2012
- Ministerio de Ciencia Innovacion Spain. Grant Numbers: SAF2011-23051, CSD2008-00005
- Consellería Educación. Grant Numbers: PROMETEO-2009-027, ACOMP/2011/053, ACOMP/2012/066
- Sanitat. Grant Number: AP-004/11
- Generalitat Valenciana
- NMDA receptor
Several neurosteroids modulate the glutamate–nitric oxide (NO)–cGMP pathway in cerebellum through modulation of NMDA- GABAA- 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 GABAA, 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 GABAA 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 GABAA 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.