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-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 mm(3), 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 (ED(50) = 0.80 mg/kg), whereas DM neuroprotection (ED(50) = 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 (ED(50) = 19 mg/kg) and death (LD(50) = 27 mg/kg). In contrast, AHN649 failed to induce seizure activity at doses up to 100 mg/kg (LD(50) = 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.
Tortella
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Department of Neuropharmacology and Molecular Biology, Walter Reed Army Institute of Research, Washington, D.C., USA. frank.tortella@na.amedd.army.mil
Britton
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Williams
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Newman
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D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control; D002536:Cerebral Arteries; D003915:Dextromethorphan / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018846:Excitatory Amino Acids; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015424:Reperfusion
C121608:AHN 649; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D003915:Dextromethorphan