Endothelin-1-Induced Ischemic Damage and Functional Impairment Is Mediated Primarily by NR2B-Containing NMDA Receptors

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  • Andrew W. Hume, Univ Prince Edward Isl, University of Prince Edward Island, Dept Biomed Sci
  • ,
  • R. Andrew Tasker

Ischemic stroke accounts for 70-80% of stroke cases worldwide and survivors are frequently left with compromising sensorimotor deficits localized to one or more body regions. Most animal models of stroke involve transient or permanent occlusion of one or more major vessels such as the middle cerebral artery and are characterized by widespread damage to cortical and subcortical structures that result in deficits that can confound studies of neuroprotection and neurorehabilitation. Localized microinjections of the vasoconstricting peptide endothelin-1 (ET-1) into specific brain regions are becoming increasingly popular for such studies, but the pharmacology of endothelin-induced ischemic damage is poorly understood. To test the hypothesis that NMDA receptors, and particularly those containing the NR2B subunit, are involved in ET-1-mediated excitotoxicity and functional impairment, male CD1 rats (N = 32) were pre-treated with either the non-competitive NMDA antagonist MK-801 or the NR2B-selective antagonist Ro25-6981 (or vehicle) prior to unilateral microinjections of endothelin-1 into the somatosensory cortex and striatum. Rats were then tested using 4 established tests of sensory and/or motor function over 14 days. Lesion volumes were quantified post-mortem using standard histology and image analysis. Results confirmed reproducible lesions and significant deficits in all tests in vehicle-treated rats that were significantly reduced in both drug groups but were not different between drugs, providing evidence that endothelin-induced ischemic damage is mediated almost exclusively by NR2B-containing NMDA receptors.

Original languageEnglish
JournalNeurotoxicity Research
Volume37
Issue2
Pages (from-to)349-355
Number of pages7
ISSN1029-8428
DOIs
Publication statusPublished - Feb 2020

    Research areas

  • Ischemia, Endothelin, NMDA receptor, Excitotoxicity, Somatosensory function, CEREBRAL-ARTERY OCCLUSION, STROKE, FORELIMB, BRAIN, RECOVERY, MODEL, NEUROPROTECTION, PLASTICITY, INDUCTION, DEFICITS

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