Beagle puppy model of perinatal asphyxia: blockade of excitatory neurotransmitters

The N-methyl-D-aspartate receptor antagonist MK801 has been reported to prevent neuronal change in models of ischemia in adult animal systems. We studied the hypothesis that blockade of the N-methyl-D-aspartate receptor would prevent the depression of cerebral high-energy phosphates found in perinatal asphyxia without producing alterations in cerebral blood flow, and thus prevent neuropathologic damage. Newborn beagle puppies were anesthetized, tracheotomized, ventilated, and randomized to asphyxial insult (I = discontinuation of ventilatory support for 5 min) or no insult (NI) and drug treatment with MK801 (10 mg/kg intravenously) or an equal volume of saline (S). Puppies received MK801 or saline 15 min prior to I/NI. In S/I pups during insult, blood flow increased to brainstem structures but decreased elsewhere. MK801 had no effect on cerebral blood flow in either control or insulted puppies. 1H NMR studies demonstrated no effect of the MK801 on NI brains. Phosphocreatine levels were 1.7 +/- 0.1, 0.6 +/- 0.1, and 0.9 +/- 0.1 mmole/kg (mean: +/- S.D.) for the S/NI, S/I, and MK801/I pups, respectively. Cerebral lactate was 1.3 +/- 0.2, 3.0 +/- 0.7, and 2.0 +/- 0.4, respectively. The pH fell 0.8 units in the S/I puppies, compared to 0.4 units in the MK801/I puppies. We conclude that pretreatment with the N-methyl-D-aspartate receptor antagonist MK801 in part protects the developing brain against severe metabolic insult.