Correlation of CGS 19755 neuroprotection against in vitro excitotoxicity and focal cerebral ischemia

Miguel A. Pérez-Pinzón, Carolina M. Maier, Edward J. Yoon, Guo Hua Sun, Rona G. Giffard, Gary K. Steinberg

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The in vivo neuroprotective effect and brain levels of cis-4- phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), a competitive N- methyl-D-aspartate (NMDA) antagonist, were compared with its in vitro neuroprotective effects. The dose-response for in vitro neuroprotection against both NMDA toxicity and combined oxygen-glucose deprivation (OGD) was determined in murine neocortical cultures. Primary cultures of neocortical cells from fetal mice were injured by exposure to 500 μM NMDA for 10 min or to OGD for 45 min. The effect of CGS 19755 in both injury paradigms was assessed morphologically and quantitated by determination of lactate dehydrogenase release. Near complete neuroprotection was found at high doses of CGS 19755. The ED50 for protection against NMDA toxicity was 25.4 μmM, and against OGD the ED50 was 15.2 μM. For the in vivo paradigm rabbits underwent 2 h of left internal carotid, anterior cerebral, and middle cerebral artery occlusion followed by 4 h reperfusion; ischemic injury was assessed by magnetic resonance imaging and histopathology. The rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after arterial occlusion. CSF and brain levels of CGS 19755 were 12 μM and 5 μM, respectively, at 1 h, 6 μM and 5 μM at 2 h, and 13 μM and 7 μM at 4 h. These levels were neuroprotective in this model, reducing cortical ischemic edema by 48% and ischemic neuronal damage by 76%. These results suggest that a single i.v. dose penetrates the blood-brain barrier, attaining sustained neuroprotective levels that are in the range for in vitro neuroprotection.

Original languageEnglish (US)
Pages (from-to)865-876
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume15
Issue number5
DOIs
StatePublished - 1995

Keywords

  • Blood flow
  • Evoked potentials
  • Glutamate
  • Ischemia
  • Neuroprotection
  • Neurotoxicity
  • NMDA

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Neuroscience(all)

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