New Concept Concerning Glutamate Mediated Excitotoxicity

As noted above, a major target of past neuroprotective drug discovery and development has been the glutamate-NMDA receptor complex. The approaches taken have been to block NMDA receptor activation and the opening of its associated calcium channel with various types of compounds that either reduce glutamate release (e.g., riluzole), competitively inhibit glutamate binding to its recognition site (e.g., selfotel), one of its modulatory polyamine (e.g., ifenprodil, eliprodil, CP-101,606) or glycine (e.g., HA-966?) positive regulatory sites, or to noncompetitively block the associated calcium channel (e.g., MgCl2, MK-801, aptiganel). Although these approaches resulted in neuroprotective effects in stroke, TBI, and even SCI models, those that have been the subject of stroke or TBI clinical trials failed to produce a significant effect on recovery or survival. A recent report has shed light on why this may be the case. Biegon etal.43 found in a mouse TBI model using MK-801 autoradiography that, while the glutamate receptor and channel are hyperactivated immediately after injury, this is short lived (<1 h), and is followed by a long-lasting (>7days) loss of function. Thus, attempts to pharmacologically block glutamate receptor activation beyond the first hour after injury are ineffective due to loss of receptor function and the concomitant loss of their neuroprotective activity. In contrast, administration of NMDA can actually promote posttraumatic neurological recovery if given between 24 h and 2 weeks postinjury, whereas NMDA antagonists actually blunt recovery in mice compared with no treatment. This study, together with the lack of any positive effects in past clinical trials, severely limits enthusiasm for the discovery of new glutamate antagonist compounds.

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