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Vol. 291, Issue 1, 399-408, October 1999
Department of Neuropharmacology and Molecular Biology, Walter Reed
Army Institute of Research, Washington, D.C. (F.C.T., P.B., A.W.,
X.C.M.L.); and Drug Development Group, National Institute for Drug
Abuse Addiction Research Center, Baltimore, Maryland (A.H.N.)
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-affinity
N-methyl-D-aspartate-site ligands as postinjury therapy for ischemic brain injury has been confirmed.
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