Löscher W, Wlaź P, Szabo L
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Neurosci Lett. 1998 Jan 2;240(1):33-6. doi: 10.1016/s0304-3940(97)00919-1.
Recent clinical trials with non-competitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists in patients with stroke have shown that these patients develop more adverse effects, particularly psychomimetic effects such as hallucinations and agitation, than normal volunteers at equivalent doses. We therefore examined whether such increased adverse effect potential of NMDA antagonists also occurs in a rat model of permanent focal ischemia. For this purpose, the right middle cerebral artery was occluded under halothane anesthesia, and behavioral alterations in response to the non-competitive NMDA antagonist, MK-801 (dizocilpine), were recorded after recovery from anesthesia. Behavioral alterations in ischemic rats were compared with those in sham-lesioned rats in a blinded fashion. MK-801 (0.4 mg/kg) induced psychomimetic-like stereotyped behaviors which were about twice as intense in ischemic than in non-ischemic rats. A similar trend for enhanced adverse effects was seen with the competitive NMDA antagonist CGS 19755 (Selfotel). Although more NMDA antagonists have to be tested to draw definite conclusions, the present data may indicate that enhanced sensitivity of stroke patients to adverse effects of NMDA antagonists can be predicted by use of a focal ischemia model in rats, thus allowing use of this model for developing novel cytoprotective strategies targeted to minimize glutamatergic excitotoxicity with reduced adverse effect potential.
近期针对中风患者使用非竞争性和竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的临床试验表明，与同等剂量的正常志愿者相比，这些患者会出现更多不良反应，尤其是诸如幻觉和激越等拟精神病效应。因此，我们研究了NMDA拮抗剂这种增加的不良反应可能性在永久性局灶性脑缺血大鼠模型中是否也会出现。为此，在氟烷麻醉下阻断右侧大脑中动脉，并在大鼠从麻醉中恢复后记录其对非竞争性NMDA拮抗剂MK-801（地佐环平）的行为改变。以盲法将缺血大鼠的行为改变与假手术大鼠的行为改变进行比较。MK-801（0.4毫克/千克）诱发了拟精神病样刻板行为，缺血大鼠的这种行为强度约为非缺血大鼠的两倍。竞争性NMDA拮抗剂CGS 19755（Selfotel）也出现了类似的不良反应增强趋势。虽然还需要测试更多的NMDA拮抗剂才能得出明确结论，但目前的数据可能表明，通过使用大鼠局灶性脑缺血模型可以预测中风患者对NMDA拮抗剂不良反应的敏感性增加，从而使该模型可用于开发新的细胞保护策略，旨在将谷氨酸能兴奋性毒性降至最低并降低不良反应可能性。
