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)

A molecular form of memory protects the brain from the effects of acute hypoxia [abstract]

Long-term potentiation (LTP) is a molecular engram of memory. Previous work has demonstrated that LTP decreases the sensitivity of glutamate receptors in the rat hippocampus. Glutamate has beem implicated in the pathogenesis of hypoxic/ischaemic damage. We therefore tested the hypothesis that LTP could reduce the effects of LTP on hypoxia in the rat hippocampus. The effects of LTP on hypoxia were measured by the changes in the extracellular potentials recorded from the hippocampal slice. Hypoxia was induced by perfusing the slice with artificial cerebrospinal fluid that contained varying concentrations of oxygen. Each slice was initially exposed to the hypoxic medium for 1.5-3.0 minutes. This led to a decrease in the potentials, which recovered to control levels within 5 minutes. Repeat exposure to the same hypoxic medium for the same duration as the first, also caused a reduction in the potentials. There was no significant difference between the degree of reduction caused by the first or second exposure for all types of hypoxic media tested (p >0.05; paired t test). In some slices, LTP was induced after the first hypoxic exposure. LTP brought about an inhibition of the reduction in potentials caused by the second hypoxic insult; the differences in reducation in potentials were highly significant for all the hypoxic media used (p <0.01; paired t test). The neuroprotective effects of LTP were not prevented by cyclothiazide (an inhibitor of AMPA receptor desensitization) or NOS inhibitors (antagonists of intracellular nitric oxide production). These compounds have been shown to be effective in blocking the effects of LTP on the actions of exogenously applied AMPA and NMDA, respectively. The neuroprotective effects of LTP were similar to that of propentofylline, a known neuroprotective compound. We conclude that LTP causes an appreciable protection of the hippocampus slices to in-vitro models of acute hypoxia. There have been reports that there is a possible inverse relationship between educational attainment and the development of dementia and the results of our study may have a role to play in this relationship. (AU)