The pharmacological manipulation of glutamate receptors and neuroprotection

The overactivation of glutamate receptors is a major cause of Ca2+ overload in cells, potentially leading to cell damage and death. There is an abundance of agents and mechanisms by which glutamate receptor activation can be prevented or modulated in order to control these effects. They include the well-established, competitive and non-competitive antagonists at the N-methyl-D-aspartate (NMDA) receptors and modulators of desensitisation of the  -amino-3-hydroxy-5-mmethyl-4-isoxazole-propionic acid (AMP) receptors. More recently, it has emerged that some compounds can acrt selectively at different subnuits of glutamate receptors,allowing a different blockade of subtypes. It is also becoming clear that a number of endogenous compounds, including purines, can modify glutamate receptor senistivity. The kynurenine pathway is an alternative but distinct pathway to the generation glutamate receptor ligands. The products of tryptophan metablism via kynurenine pathway include both quinolinic acid, a selective agonist at several glutamate receptor subtypes. The levels of these metabolites change as a result of the activation of inflammatory processes and immune-competent cells, and may have a significant impact on Ca2+ fluxes and neuronal damage. Drugs which target some of these various sites and processes, or which change the balance between the excitotoxin quinolinic acid and the neuroprotective kynurenic acid, could also have potential as neuroprotective drugs (AU)

Ionotropic glutamate receptors during the development of the chick retina.

Glutamate is the main neurotransmitter of photoreceptors, bipolar cells, and ganglion cells of the vertebrate retina. Three main classes of ionotropic glutamate receptors comprising different subunits can be distinguished: AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxasolepropionate), KA (kainate), and NMDA (N-methyl-D-aspartate). This study was undertaken to characterize the AMPA (GluR1, GluR2/3, and GluR4), KA (GluR5/6/7), and NMDA (NR1) ionotropic glutamate receptor subunits and to determine their distribution during the development of the chick retina by Western blotting and immunohistochemistry. Western blotting analysis at 1 day after hatching indicated that the antibodies against GluR1, 2/3, 4, and 5/6/7 and NR1 recognized specifically a single band of 100-110 kDa. In turn, immunohistochemistry at P1 showed that all subunits were expressed in cells of the inner nuclear and ganglion cell layers of the chick retina, mostly amacrine and ganglion cells, and their processes in the inner plexiform layer. In addition, stained processes in the outer plexiform layer were observed with the antibodies against GluR2/3, GluR4, and GluR5/6/7. Although all subunits appeared around E5-E6 in the prospective ganglion cell layer, and later in the prospective inner nuclear layer, the distribution of cells containing these glutamate receptor subunits revealed distinct ontogenetic patterns. This multiplicity of glutamate receptors may contribute to different processes that occur in the chick retina during development.

Mecanismo de acao do etanol: envolvimento de glutamato, gaba e dopamina / Mechanism of action of ethanol: involvement of glutamate, gaba and dopamine

O fenomeno da excitoxicidade resulta da ativacao excessiva da neurotransmissao glutamatergica, onde pode ocorrer degeneracao neuronal em algumas regioes especificas do SNC, sendo o receptor NMDA o principal canal envolvido na morte neuronal...