Pharmacology of N-methyl-D-aspartate-induced brain injury in an in vivo perinatal rat model.
Intrastriatal injection of the glutamate analogue N-methyl-D-aspartate (NMDA, 25 nmol) in postnatal day (PND) 7 rats provides a rapid, sensitive, and reproducible assay in which potential neuroprotective strategies against excitotoxic neuronal injury can be examined in vivo. Brain injury is quantified 5 days postinjection by comparison of the weights of the injected and contralateral cerebral hemispheres. Intraperitoneal injections (15 minutes post-NMDA) of competitive and noncompetitive NMDA receptor antagonists attenuated the severity of NMDA-induced brain injury. The rank order of neuroprotective potency of these antagonists was CGS-19755 greater than DOIPG greater than dextromethorphan greater than HA-966. Of these compounds only the competitive antagonist CGS-19755 provided complete neuroprotection. NMDA-mediated brain injury was also reduced by the specific sigma receptor ligands +PPP and haloperidol (35% reduction). In contrast, drugs that reduce presynaptic neurotransmitter release (adenosine) or enhance neuronal inhibition (baclofen) were not effective against NMDA toxicity. Although all five of the anticonvulsants tested limited NMDA-induced seizure activity, only carbamazepine reduced NMDA-mediated brain injury (36% reduction). These findings extend earlier observations that NMDA receptor antagonists can limit NMDA-induced toxicity in vivo and suggest that sigma receptors contribute to the pathophysiology of NMDA-mediated brain injury in vivo. Furthermore, NMDA-induced seizures and brain injury appear dissociable in this in vivo model. The results illustrate important practical limitations of neuroprotection in vivo vs. in vitro.
McDonald
J W
JW
Department of Neurology, Kennedy Research Institute, Baltimore, Maryland.
Johnston
M V
MV
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000927:Anticonvulsants / Q000494:pharmacology; D001927:Brain Diseases / Q000139:chemically induced* / Q000517:prevention & control; D005260:Female; D005998:Glycine / Q000502:physiology; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000378:metabolism / Q000502:physiology; D011957:Receptors, Opioid / Q000502:physiology; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma
D000927:Anticonvulsants; D018377:Neurotransmitter Agents; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D011957:Receptors, Opioid; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D016202:N-Methylaspartate; D005998:Glycine