Neuroprotection (focal ischemia) and neurotoxicity (electroencephalographic) studies in rats with AHN649, a 3-amino analog of dextromethorphan and low-affinity <i>N</i>-methyl-D-aspartate antagonist

作     者：Tortella, FC Britton, P Williams, A Lu, XCM Newman, AH 

作者机构：Walter Reed Army Inst Res Dept Neuropharmacol & Mol Biol Div Neurosci Washington DC 20307 USA NIDA Addict Res Ctr Drug Dev Grp Baltimore MD 21224 USA 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：1999年第291卷第1期

页      面：399-408页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：脑缺血/预防和控制 脑动脉 右美沙芬/类似物和衍生物 右美沙芬/药理学 右美沙芬/治疗应用 剂量效应关系 药物 脑电描记术/药物作用 兴奋性氨基酸拮抗剂/药理学 兴奋性氨基酸拮抗剂/治疗应用 兴奋性氨基酸类 神经保护药/药理学 神经保护药/治疗应用 神经毒素类/药理学 大鼠 Sprague-Dawley 受体 N-甲基-D-天冬氨酸/拮抗剂和抑制剂 再灌注 动物 男(雄)性 大鼠 

摘      要：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 (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.