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

AHN649, an analog of dextromethorphan (DM) and a relatively selective low-a ffinity N-methyl-D-aspartate antagonist, was evaluated for neuroprotective effects using the rat intraluminal filament model of temporary middle cereb ral artery occlusion. Rats were subjected to 2 h of focal ischemia followed by 72 h of reperfusion. In vehicle-treated rats, middle cerebral artery oc clusion resulted in neurological deficits and severe infarction measuring 2 32 +/- 25 mm(3), representing approximately 25% contralateral hemispheric i nfarction. 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% com pared with vehicle-control treatments. AHN649 neuroprotection was linear an d 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/k g). Although impaired neurological function scores improved in all groups b y 24 to 72 h, the most dramatic improvement was associated with AHN649 trea tments. In a rat electroencephalographic model of brain function, separate neurotoxicity experiments revealed that acute i.v. doses of DM caused seizu res (ED50 = 19 mg/kg) and death (LD50 = 27 mg/kg). In contrast, AHN649 fail ed to induce seizure activity at doses up to 100 mg/kg (LD50 = 79 mg/kg). C ollectively, AHN649 is described as a potent, efficacious neuroprotective a gent devoid of serious central nervous system neurotoxicity and possessing potential therapeutic value as antistroke treatment. Furthermore, the feasi bility of targeting low-affinity N-methyl-D-aspartate-site ligands as posti njury therapy for ischemic brain injury has been confirmed.