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
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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
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↵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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