Abstract
The hypothesis that excitoxicity is a mechanism of damage following different types of cerebral injury including global and focal ischemia (34), and head and spinal cord trauma (6,7,9,25) has been supported by numerous findings. During ischemia for example, glutamate neurotoxicity is mediated in part through N-methyl-D-aspartate (NMDA) receptors, since selective antagonists to this receptor protect against hypoxic-ischemic injury (10,35,41). In the last few years, different NMDA antagonists have been developed and tested; they can be divided into competitive and noncompetitive antagonists. Noncompetitive NMDA antagonists are extremely lipophilic and reach high levels in the brain after systemic administration. Various studies have demonstrated that these agents provide neuroprotection against hypoxic-ischemic injury (for review see ref. 29). Many competitive NMDA antagonists are hydrophilic and require direct cerebral administration to obtain high brain levels. Newer competitive NMDA blockers, such as cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755, selfotel), provide neuroprotection against global ischemia, focal ischemia, and trauma when given systemically (2,3,32,33). Selfotel is currently being studied in multicenter safety and efficacy trials for stroke (17) and head trauma (6).