Pharmacology of N‐methyl‐D‐aspartate‐induced brain injury in an in vivo perinatal rat model

John W. McDonald, Michael V. Johnston

Research output: Contribution to journalArticlepeer-review

Abstract

Intrastratal injection of the glutamate analogue N‐methyl‐D‐aspartate (NMDA, 25 nmol) in postnatal (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 noncometitive NMDA receptor antagonists attenuated the severity of NMDA‐induced brain injury. The rank order of neuroprotective potency of these antagonists was CGS‐19755<DOIPG<dextromethorphan<HA‐996. Of these compounds only the competitive antagonist CGS‐19755 provided complete neuroprotection. NMDA‐mdeiated 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 improtant practial limitations of neuroprotection in vivo vs.in vitro.

Original languageEnglish (US)
Pages (from-to)179-188
Number of pages10
JournalSynapse
Volume6
Issue number2
DOIs
StatePublished - 1990

Keywords

  • Excitotoxicity
  • NMDA antagonists
  • Neuronal injury
  • Neuroprotection
  • Phencyclidine
  • Rat brain

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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