DEXTROMETHORPHAN AMELIORATES EFFECTS OF NEONATAL HYPOXIA ON BRAIN MORPHOLOGY AND SEIZURE THRESHOLD IN RATS

Hypoxic injury to the brain is mediated in part by NMDA receptors. The refore, NMDA receptor blockade with dextromethorphan (DM), a non-compe titive channel blocker, was hypothesized to ameliorate injury even whe n given after the hypoxic insult. Rats were exposed to 8% oxygen for 3 h on postnatal day 7. Within 20 min of exposure, animals received 30 mg/kg i.p. DM or normal saline. Littermates maintained in room air for 3 h also received DM or saline. At 14 days of age, 7 days after expos ure, cortical thickness and hippocampal area were measured. At 70-90 d ays of age, approximately two months after exposure, in a separate gro up of rats, seizure threshold using pentylenetetrazol (PTZ) and passiv e avoidance learning and retention were determined. There were no gros s changes in cellular morphology and no evidence for cellular necrosis in any of the exposure groups. However, cortical thickness was decrea sed in animals exposed to hypoxia. DM administration prevented this de crease. Hippocampal area was unaffected. Seizure susceptibility in adu lthood was increased in animals exposed to hypoxia in the neonatal per iod. DM prevented the decrease in seizure threshold. There was no diff erence in passive avoidance learning or retention as a function of neo natal exposure condition. Mild to moderate hypoxia, previously thought not to produce any histologic changes, causes significant short-term loss of cortical thickness and long-term decrease in seizure threshold . DM appears to ameliorate these effects even when given after the hyp oxic insult. These results implicate the glutamate receptor system in the pathophysiology of hypoxia damage and suggest that treatment with a glutamate receptor blocker when neonatal asphyxia is suspected would help ameliorate the consequences of such an insult. (C) Elsevier Scie nce B.V.