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Research ArticleNEUROPHARMACOLOGY

Neuroprotective Efficacy and Therapeutic Window of the High-Affinity N-Methyl-d-aspartate Antagonist Conantokin-G: In Vitro (Primary Cerebellar Neurons) and In Vivo (Rat Model of Transient Focal Brain Ischemia) Studies

Anthony J. Williams, Jitendra R. Dave, James B. Phillips, Yu Lin, R. Tyler McCabe and Frank C. Tortella
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 378-386;
Anthony J. Williams
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Jitendra R. Dave
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James B. Phillips
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Yu Lin
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R. Tyler McCabe
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Frank C. Tortella
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Abstract

Conantokin-G (Con-G), a 17-amino-acid peptide derived from marine snails and a potent N-methyl-d-aspartate (NMDA) antagonist, was evaluated for its neuroprotective properties in vitro and in vivo. In primary cerebellar neurons, Con-G was shown to decrease excitotoxic calcium responses to NMDA and to exhibit differential neuroprotection potencies against hypoxia/hypoglycemia-, NMDA-, glutamate-, or veratridine-induced injury. Using the intraluminal filament method of middle cerebral artery occlusion as an in vivo rat model of transient focal brain ischemia, the neuroprotective dose-response effect of Con-G administration beginning 30 min postocclusion was evaluated after 2 h of ischemia and 22 h of reperfusion. In the core region of injury, an 89% reduction in brain infarction was measured with significant neurological and electroencephalographic recovery at the maximal dose tested (2 nmol), although mild sedation was noted. Lower doses of Con-G (0.001–0.5 nmol) were significantly neuroprotective without causing sedation. Postinjury time course experiments demonstrated a therapeutic window out to at least 4 to 8 h from the start of the injury, providing a 47% reduction in core injury. The neuroprotective effect of Con-G (0.5 nmol) was also evaluated after 72 h of injury, where a 54% reduction in core brain infarction was measured. Critically, in both recovery models (i.e., 24 and 72 h), the reduction in brain infarction was associated with significant improvements in neurological and electroencephalographic recovery. These data provide evidence for the potent and highly efficacious effect of Con-G as a neuroprotective agent, with an excellent therapeutic window for the potential intervention against ischemic/excitotoxic brain injury.

Footnotes

  • Send reprint requests to: Dr. Frank C. Tortella, Department of Neuropharmacology & Molecular Biology, Division of Neurosciences, Walter Reed Army Institute of Research, Bldg. 503, Forney Dr., Forest Glen Annex, Silver Spring, MD 20910. E-mail:Frank.Tortella{at}na.amedd.army.mil

  • ↵1 The views of the authors do not purport or reflect the position of the Department of the Army or the Department of Defense (para 4-3, AR 360-5). This work was supported in part by Cognetix, Inc. and funds from DOD/U.S. Army. Preliminary versions of this data were published in abstract form in SocNeurosci Abstr (1998) 24(1):978 and FASEB Abstr (1999) 13(5):A1099.

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    MCAo
    middle cerebral artery occlusion
    EEG
    electroencephalogram
    Con-G
    conantokin-G
    TTC
    2,3,5-triphenyltetrazolium chloride
    H/H
    hypoxia/hypoglycemia
    MABP
    mean arterial blood pressure
    HR
    heart rate
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
    [Ca2+]i
    intraneuronal calcium concentration
    • Received December 9, 1999.
    • Accepted March 10, 2000.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Neuroprotective Efficacy and Therapeutic Window of the High-Affinity N-Methyl-d-aspartate Antagonist Conantokin-G: In Vitro (Primary Cerebellar Neurons) and In Vivo (Rat Model of Transient Focal Brain Ischemia) Studies
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Research ArticleNEUROPHARMACOLOGY

Neuroprotective Efficacy and Therapeutic Window of the High-Affinity N-Methyl-d-aspartate Antagonist Conantokin-G: In Vitro (Primary Cerebellar Neurons) and In Vivo (Rat Model of Transient Focal Brain Ischemia) Studies

Anthony J. Williams, Jitendra R. Dave, James B. Phillips, Yu Lin, R. Tyler McCabe and Frank C. Tortella
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 378-386;

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Research ArticleNEUROPHARMACOLOGY

Neuroprotective Efficacy and Therapeutic Window of the High-Affinity N-Methyl-d-aspartate Antagonist Conantokin-G: In Vitro (Primary Cerebellar Neurons) and In Vivo (Rat Model of Transient Focal Brain Ischemia) Studies

Anthony J. Williams, Jitendra R. Dave, James B. Phillips, Yu Lin, R. Tyler McCabe and Frank C. Tortella
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 378-386;
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