Editorial
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Dec 28, 2006; 12(48): 7737-7743
Published online Dec 28, 2006. doi: 10.3748/wjg.v12.i48.7737
Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy
Vicente Felipo
Vicente Felipo, Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Valencia, Spain
Supported by grants from the Ministerio de Ciencia y Tecnología, No. SAF2002-00851 and SAF2005-06089 and from Ministerio de Sanidad, No. Red G03-155 and PI050253 of Spain and by grants from Consellería de Empresa, Universidad y Ciencia, and de Sanidad, Generalitat Valenciana, No. Grupos03/001, GV04B-055, GV04B-012, GVS05/082 and ACOMP06/005 and AP-005/06
Correspondence to: Vicente Felipo, Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Avda Autopista del Saler, 16, Valencia 46013, Spain. vfelipo@cipf.es
Telephone: +34-963-289680 Fax: +34-963-289701
Received: August 17, 2006
Revised: August 28, 2006
Accepted: September 19, 2006
Published online: December 28, 2006
Abstract

Patients with liver disease may present hepatic enceph-alopathy (HE), a complex neuropsychiatric syndrome covering a wide range of neurological alterations, including cognitive and motor disturbances. HE reduces the quality of life of the patients and is associated with poor prognosis. In the worse cases HE may lead to coma or death.

The mechanisms leading to HE which are not well known are being studied using animal models. The neurological alterations in HE are a consequence of impaired cerebral function mainly due to alterations in neurotransmission. We review here some studies indicating that alterations in neurotransmission associated to different types of glutamate receptors are responsible for some of the cognitive and motor alterations present in HE.

These studies show that the function of the signal transduction pathway glutamate-nitric oxide-cGMP associated to the NMDA type of glutamate receptors is impaired in brain in vivo in HE animal models as well as in brain of patients died of HE. Activation of NMDA receptors in brain activates this pathway and increases cGMP. In animal models of HE this increase in cGMP induced by activation of NMDA receptors is reduced, which is responsible for the impairment in learning ability in these animal models. Increasing cGMP by pharmacological means restores learning ability in rats with HE and may be a new therapeutic approach to improve cognitive function in patients with HE. However, it is necessary to previously assess the possible secondary effects.

Patients with HE may present psychomotor slowing, hypokinesia and bradykinesia. Animal models of HE also show hypolocomotion. It has been shown in rats with HE that hypolocomotion is due to excessive activation of metabotropic glutamate receptors (mGluRs) in substantia nigra pars reticulata. Blocking mGluR1 in this brain area normalizes motor activity in the rats, suggesting that a similar treatment for patients with HE could be useful to treat psychomotor slowing and hypokinesia. However, the possible secondary effects of mGluR1 antagonists should be previously evaluated.

These studies are setting the basis for designing therapeutic procedures to specifically treat the individual neurological alterations in patients with HE.

Keywords: Hepatic encephalopathy, Glutamate receptors, Neurological alterations, Cognitive function, Motor func-tion, NMDA receptors, Metabotropic glutamate receptors, Nitric oxide, cGMP