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Quantitative assessment of neuroprotection against NMDA-induced brain injury
J W McDonald1, N F Roeser, F S Silverstein
1Neuroscience and Medical Scientist Training Program, University of Michigan, Ann Arbor 48109.
Insights
Excitatory amino acid (EAA) receptor agonists like N-methyl-D-aspartate (NMDA) cause brain lesions in immature rodents. NMDA receptor antagonists reduce this damage, offering neuroprotection.
Area of Science:
- Neuroscience
- Neuropharmacology
- Developmental Neuroscience
Background:
- Excitatory amino acid (EAA) receptor agonists, specifically N-methyl-D-aspartate (NMDA), induce significant forebrain lesions in immature rodents.
- NMDA receptor antagonists have demonstrated efficacy in mitigating NMDA-induced neurotoxicity.
Purpose of the Study:
- To compare three quantitative methods for assessing NMDA-induced brain injury severity and neuroprotection by antagonists.
- To characterize NMDA-induced brain injury in PND 7 rats using hemisphere weight, choline acetyltransferase (ChAT) activity, and regional brain cross-sectional areas.
Main Methods:
- Intrastriatal injections of NMDA (1-50 nmol) in Postnatal Day (PND) 7 rats.
- Assessment of brain injury via comparison of cerebral hemisphere weights, assay of ChAT activity, and measurement of regional brain cross-sectional areas.
- Evaluation of neuroprotection using NMDA receptor antagonists.
Main Results:
- NMDA-induced brain injury severity, assessed by hemisphere weight reduction, increased linearly with NMDA dose up to 25 nmol.
- A strong correlation (r2 = 0.97) was observed between the magnitude of injury and the reduction in ChAT activity.
- NMDA receptor antagonists significantly reduced the severity of NMDA-induced damage.
Conclusions:
- Hemisphere weight comparison and ChAT activity assays are reliable quantitative methods for evaluating NMDA-induced neurotoxicity.
- These methods can effectively assess the neuroprotective efficacy of NMDA receptor antagonists in immature rodent brains.
Abstract:
In immature rodent brain, unilateral intrastriatal injections of selected excitatory amino acid (EAA) receptor agonists, such as N-methyl-D-aspartate (NMDA), produce prominent ipsilateral forebrain lesions. In Postnatal Day (PND) 7 rats that receive a right intrastriatal injection of NMDA (25 nmol) and are sacrificed 5 days later, there is a considerable and consistent reduction in the weight of the injected cerebral hemisphere relative to that of the contralateral side (-28.5 +/- 1.9%, n = 6). In animals treated with specific NMDA receptor antagonists, the severity of NMDA-induced damage is markedly reduced. We have previously reported that the efficacy of potential neuroprotective drugs in limiting NMDA-induced lesions can be assessed quantitatively by comparison of hemisphere weights after a unilateral NMDA injection. In this study, we compared three quantitative methods to evaluate the severity of NMDA-induced brain injury and the degree of neuroprotection provided by NMDA receptor antagonists. We characterized the severity of brain injury resulting from intrastriatal injections of 1-50 nmol NMDA in PND 7 rats sacrificed on PND 12 by (i) comparison of cerebral hemisphere weights; (ii) assay of the activity of the cholinergic neuronal marker, choline acetyltransferase (ChAT) activity; and (iii) measurement of regional brain cross-sectional areas. The severity of the resulting brain injury as assessed by comparison of hemisphere weights increased linearly with the amount of NMDA injected into the striatum up to 25 nmol NMDA. The magnitude of injury was highly correlated with the degree of reduction in ChAT activity (r2 = 0.97).(ABSTRACT TRUNCATED AT 250 WORDS)