PRETREATMENT WITH ANTISENSE OLIGODEOXYNUCLEOTIDES DIRECTED AGAINST THE NMDA-R1 RECEPTOR ENHANCES SURVIVAL AND BEHAVIORAL RECOVERY FOLLOWINGTRAUMATIC BRAIN INJURY IN RATS

Treatment with N-methyl-D-aspartate (NMDA) receptor antagonists limits tissue damage following CNS ischemia or trauma, supporting the hypoth esis that NMDA receptors participate in the pathophysiology of such in juries. An alternative approach for evaluating this hypothesis is to e xamine the effects of selective inhibition of NMDA receptor synthesis, using antisense oligodeoxynucleotides. In the present studies, the ef fects of antisense oligodeoxynucleotides directed at NMDA-R1 receptor subunit, administered intracerebroventricularly (i.c.v.) prior to inju ry, were evaluated in a well-defined traumatic brain injury model in r ats. Outcome measures included survival, motor recovery, and histologi cal changes. Administration of antisense oligodeoxynucleotides (15 nmo l/ml twice daily X 2 days) did not alter physiological variables or mo tor function prior to trauma. However, such treatment significantly de creased mortality and improved behavioral recovery at 2 weeks after tr auma as compared to animals treated with the corresponding sense oligo deoxynucleotides. Although cell counts in hippocampus did not differ b etween treatment groups, astrocyte activation as reflected by glial fi brillary astrocytic protein (GFAP) immunocytochemistry was significant ly reduced in antisense treated animals. These findings provide additi onal evidence that NMDA receptors contribute to secondary injury after brain trauma and may suggest an alternative treatment approach.