Pharmacological modification of glutamate neurotoxicity in vivo

H. Fujisawa, D. Dawson, S. E. Browne, K. B. MacKay, R. Bullock, J. McCulloch

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

The ability of five agents (dizocilpine [MK-801], 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline [NBQX], enadoline [CI-977], l-nitroarginine methyl ester [l-NAME] and BW 1003c87) with well defined, distinct pharmacological profiles and with established anti-ischemic efficacy, to modify neuronal damage has been examined in a simple in vivo model of glutamate excitotoxicity. Cortical lesions were produced in physiologically-monitored, halothane-anesthestised rats by reverse dialysis of glutamate. The volume of the lesion was quantified histologically by image analysis of approximately 20 sections taken at 200 μm intervals throughout the lesion. The AMPA and NMDA receptor antagonists (NBQX and MK-801) and the inhibitor of nitric oxide synthase (l-NAME) significantly reduced the lesion volume by a similar extent (by approximately 30% from vehicle). Two agents (the kappa opioid agonist, CI-977 and the sodium channel blocker, BW 1003c87) which putatively inhibit the release of endogenous glutamate presynaptically, had dissimilar effects on lesion size. CI-977 failed to alter the amount of damage produced by exogenous glutamate, whereas BW 1003c87 reduced the lesion size by approximately 50%. Using this model, the neuroprotective effects of anti-ischemic drugs can be explored in vivo, uncomplicated in contrast to experimental ischemia by reduced oxygen delivery, drug effects on tissue blood flow and compromised energy generation. In consequence, additional mechanistic insight into anti-ischemic drug action in vivo can be obtained.

Original languageEnglish (US)
Pages (from-to)73-78
Number of pages6
JournalBrain Research
Volume629
Issue number1
DOIs
StatePublished - Nov 26 1993

Keywords

  • Excitotoxicity
  • Glutamate antagonist
  • Nitric oxide

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology
  • Clinical Neurology
  • Neuroscience(all)

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    Fujisawa, H., Dawson, D., Browne, S. E., MacKay, K. B., Bullock, R., & McCulloch, J. (1993). Pharmacological modification of glutamate neurotoxicity in vivo. Brain Research, 629(1), 73-78. https://doi.org/10.1016/0006-8993(93)90483-4