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

J. W. McDonald, Michael V Johnston

Research output: Contribution to journalArticle

Abstract

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>DOIPG>dextromethorphan>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 haloperiodol (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.

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

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N-Methylaspartate
Brain Injuries
Pharmacology
selfotel
sigma Receptors
N-Methyl-D-Aspartate Receptors
Seizures
Dextromethorphan
Baclofen
Carbamazepine
Cerebrum
Intraperitoneal Injections
Anticonvulsants
Adenosine
Neurotransmitter Agents
Glutamic Acid
Ligands
Weights and Measures
Injections

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)
  • Pharmacology

Cite this

Pharmacology of N-methyl-D-aspartate-induced brain injury in an in vivo perinatal rat model. / McDonald, J. W.; Johnston, Michael V.

In: Synapse, Vol. 6, No. 2, 1990, p. 179-188.

Research output: Contribution to journalArticle

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