title: Chronic hyperammonemia, glutamatergic neurotransmission and neurological alterations.
abstract: This mini-review focus on our studies on alterations in glutamatergic neurotransmission and their role in neurological alterations in rat models of chronic hyperammonemia and hepatic encephalopathy (HE). Hyperammonemia impairs the glutamate-nitric oxide (NO)-cGMP pathway in cerebellum, which is responsible for reduced learning ability. We studied the underlying mechanisms and designed treatments to restore the pathway and learning. This was achieved by treatment with: phosphodiesterase 5 inhibitors, cGMP, anti-inflammatories (ibuprofen), p38 inhibitors or GABAA receptor antagonists (bicuculline). Hyperammonemia alters signal transduction associated to metabotropic glutamate receptors (mGluRs). Hypokinesia in hyperammonemia and HE is due to increased extracellular glutamate and mGluR1 activation in substantia nigra; blocking this receptor restores motor activity. The motor responses to mGluRs activation in nucleus accumbens (NAcc) are altered in hyperammonemia and HE, with reduced dopamine and increased glutamate release. This leads to activation of different neuronal circuits and enhanced motor responses. These studies show that altered responses to activation of NMDA receptors and mGluRs play essential roles in cognitive and motor alterations in hyperammonemia and HE and provide new treatments restoring cognitive and motor function.
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Eduardo Primo Yufera, 3. 46012 Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Llansola
authors.forename: Carmina
authors.initials: C
authors.lastname: Montoliu
authors.forename: Omar
authors.initials: O
authors.lastname: Cauli
authors.forename: Vicente
authors.initials: V
authors.lastname: Hernández-Rabaza
authors.forename: Ana
authors.initials: A
authors.lastname: Agustí
authors.forename: Andrea
authors.initials: A
authors.lastname: Cabrera-Pastor
authors.forename: Carla
authors.initials: C
authors.lastname: Giménez-Garzó
authors.forename: Alba
authors.initials: A
authors.lastname: González-Usano
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003072:Cognition Disorders / Q000209:etiology; D018698:Glutamic Acid / Q000502:physiology*; D006801:Humans; D022124:Hyperammonemia / Q000150:complications / Q000503:physiopathology*; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D018698:Glutamic Acid