Neuroprotective effects of MK-801, TCP, PCP and CPP against N-methyl- d-aspartate induced neurotoxicity in an in vivo perinatal rat model

Abstract

Three non-competitive antagonists (MK-801, TCP, PCP) and one competitive antagonist (CPP) of N-methyl- d-aspartate (NMDA) receptors, were compared for their ability to antagonize neurotoxic actions of NMDA injected into the brains of 7-day-old rats. Unilateral intracerebral injection of NMDA (25 nmol/0.5 μl) into the corpus striatum of pups consistently produced severe confluent neuronal necrosis in the striatum extending into the dorsal hippocampus and overlying neocortex. The distribution of damage corresponded to the topography of NMDA type glutamate receptors in the vulnerable regions. With this lesion in developing brain, the weight of the injected hemisphere 5 days later can be used as a quantitative measure of brain injury. Intraperitoneal administration of MK-801 (0.02–42.0 μmol/kg), TCP (3.5–54.0 μmol/kg), PCP (1.0–41.0 μmol/kg), and CPP (1.0–60.0 μmol/kg) 15 min after NMDA injection had prominent dose-dependent neuroprotective effects. MK-801 was 14 times more potent than other compounds tested and the 50% protective dose (PD 50, that dose which reduced damage by 50% relative to untreated NMDA-injected controls) was 0.63 μmol/kg. Corresponding values for CPP, PCP, and TCP were 8.84, 10.85, and 24.05 μmol/kg respectively. The lowest dose of MK-801 that provided significant protection was 0.2 μmol/kg (0.04 mg/kg, 37.9 ± 4.6% protection). Four μmol/kg (0.8 mg/kg) of MK-801 completely protected against NMDA-mediated damage. The study provides the first direct in vivo comparison of the neuroprotective abilities of these compounds. Systemic administrations of MK-801, TCP, PCP, and CPP all limit NMDA-induced neuronal injury in this model. The susceptibility of the immature brain to the neurotoxicity of NMDA provides a sensitive, reproducible, and quantitative in vivo system for comparing the effectiveness of drugs with protective actions against excitotoxic neuronal injury. Similarities between the neonatal NMDA model of injury and experimental hypoxic-ischemic brain damage suggest that neuroprotective activity in this system may predict activity against hypoxic-ischemic neuronal injury.