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Research ArticleArticle

Neuroprotection (Focal Ischemia) and Neurotoxicity (Electroencephalographic) Studies in Rats with AHN649, a 3-Amino Analog of Dextromethorphan and Low-Affinity N-Methyl-d-Aspartate Antagonist

Frank C. Tortella, Paul Britton, Anthony Williams, Xi Chung May Lu and Amy H. Newman
Journal of Pharmacology and Experimental Therapeutics October 1999, 291 (1) 399-408;
Frank C. Tortella
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Paul Britton
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Anthony Williams
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Xi Chung May Lu
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Amy H. Newman
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Abstract

AHN649, an analog of dextromethorphan (DM) and a relatively selective low-affinity N-methyl-d-aspartate antagonist, was evaluated for neuroprotective effects using the rat intraluminal filament model of temporary middle cerebral artery occlusion. Rats were subjected to 2 h of focal ischemia followed by 72 h of reperfusion. In vehicle-treated rats, middle cerebral artery occlusion resulted in neurological deficits and severe infarction measuring 232 ± 25 mm3, representing approximately 25% contralateral hemispheric infarction. Post-treatment with AHN649 (0.156–20 mg/kg i.v.) or DM (0.156–10 mg/kg i.v.) significantly reduced cortical infarct volume by 40 to 60% compared with vehicle-control treatments. AHN649 neuroprotection was linear and dose dependent (ED50 = 0.80 mg/kg), whereas DM neuroprotection (ED50 = 1.25 mg/kg) was nonlinear and less effective at the higher doses (2.5–10 mg/kg). Although impaired neurological function scores improved in all groups by 24 to 72 h, the most dramatic improvement was associated with AHN649 treatments. In a rat electroencephalographic model of brain function, separate neurotoxicity experiments revealed that acute i.v. doses of DM caused seizures (ED50 = 19 mg/kg) and death (LD50 = 27 mg/kg). In contrast, AHN649 failed to induce seizure activity at doses up to 100 mg/kg (LD50= 79 mg/kg). Collectively, AHN649 is described as a potent, efficacious neuroprotective agent devoid of serious central nervous system neurotoxicity and possessing potential therapeutic value as antistroke treatment. Furthermore, the feasibility of targeting low-affinityN-methyl-d-aspartate-site ligands as postinjury therapy for ischemic brain injury has been confirmed.

Footnotes

  • Send reprint requests to: Dr. Frank C. Tortella, Department of Neuropharmacology and Molecular Biology, Division of Neurosciences, Walter Reed Army Institute of Research, Washington, DC 20307-5100. E-mail:frank.tortella{at}na.amedd.army.mil

  • ↵1 The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense (para 4-3, AR 360-5). Preliminary versions of these data were published in abstract form in Pharmacologist [(1997)39:84] and Neurosci Abstr [(1997)23:1946].

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    MCAo
    middle cerebral artery occlusion
    EEG
    electroencephalogram
    NS
    neurological scores
    AHN649
    3-amino-17-methyl morphinan
    DM
    dextromethorphan
    PCP
    phencyclidine
    SWS
    slow-wave sleep
    TTC
    2,3,5-triphenyltetrazolium chloride
    TI
    therapeutic index
    • Received May 3, 1999.
    • Accepted June 16, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 1
1 Oct 1999
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Research ArticleArticle

Neuroprotection (Focal Ischemia) and Neurotoxicity (Electroencephalographic) Studies in Rats with AHN649, a 3-Amino Analog of Dextromethorphan and Low-Affinity N-Methyl-d-Aspartate Antagonist

Frank C. Tortella, Paul Britton, Anthony Williams, Xi Chung May Lu and Amy H. Newman
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 399-408;

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Research ArticleArticle

Neuroprotection (Focal Ischemia) and Neurotoxicity (Electroencephalographic) Studies in Rats with AHN649, a 3-Amino Analog of Dextromethorphan and Low-Affinity N-Methyl-d-Aspartate Antagonist

Frank C. Tortella, Paul Britton, Anthony Williams, Xi Chung May Lu and Amy H. Newman
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 399-408;
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