Tomitaka S, Hashimoto K, Narita N, Sakamoto A, Minabe Y, Tamura A
Division of Cortical Function Disorders, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
Brain Res. 1996 Nov 18;740(1-2):1-5. doi: 10.1016/s0006-8993(96)00842-6.
High-affinity N-methyl-D-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.
像MK-801这样的高亲和力N-甲基-D-天冬氨酸（NMDA）受体拮抗剂已知可在大鼠脑的后扣带回皮质和压后皮质中诱导热休克蛋白HSP70。美金刚是一种低亲和力非竞争性NMDA受体拮抗剂，在欧洲已被用于治疗帕金森病。与像MK-801这样的高亲和力NMDA拮抗剂相反，美金刚阻断和解除阻断NMDA受体操纵离子通道的动力学更快，这被认为是美金刚安全性的原因。本研究使用大鼠脑中HSP70免疫反应性的诱导来评估美金刚和金刚烷胺的神经毒性潜力。美金刚（25、50、75毫克/千克）在大鼠脑的后扣带回、压后皮质和齿状回中诱导HSP70。相比之下，金刚烷胺（50、100、200毫克/千克）在大鼠脑中未诱导HSP70。这些结果表明美金刚在体内对NMDA受体有拮抗作用，并增加了高剂量美金刚可能导致与其他高亲和力NMDA受体拮抗剂所观察到的类似神经元损伤的可能性。
