Zajaczkowski W, Danysz W
Department of Pharmacology, Merz + Co. GmbH & Co., Frankfurt/Main, Germany.
Pharmacol Biochem Behav. 1997 Jan;56(1):21-9. doi: 10.1016/S0091-3057(96)00133-5.
A great body of behavioural and neurophysiological evidence suggests that excitatory amino acids are involved in mechanisms of learning and memory. Moreover, degeneration of glutamatergic pathways may underlie the cognitive deficits seen in various disorders such as Alzheimer's dementia. As direct stimulation of glutamatergic receptors with agonists may increase the risk of toxicity and accelerate neuropathological changes, a more valid approach seems to be positive modulation of glutamatergic receptors that may reverse the symptoms with a lower risk of excitotoxic effects. Such a possibility offered by partial agonists of the strychnine-insensitive glycine site of the NMDA receptor (Gly-B site) or positive modulators of AMPA receptors, such as aniracetam. In the present study, the effects of d-cycloserine and aniracetam were tested in two animal models of cognitive deficits (entorhinal cortex lesion-induced deficits evaluated in the radial maze and scopolamine-induced amnesia evaluated in passive avoidance test). D-cycloserine (6 mg/kg, for 10 days) had no effect on spatial working memory deficit induced by entorhinal cortex lesions. It did, however, reverse scopolamine-induced deficits in the passive avoidance test when given acutely at the same dose. In contrast, aniracetam (50 mg/kg, for 10 days) produced beneficial effects in the radial maze test in rats with entorhinal cortex lesions, but given at the same dose acutely did not influence scopolamine-induced amnesia. The positive effect of d-cycloserine against scopolamine-induced amnesia may be probably related to the cholinergic-glutamatergic interaction in the hippocampus. The negative data obtained with d-cycloserine in the model of entorhinal cortex lesions-induced cognitive deficits could be taken as a hint that it is probably not suitable for the symptomatological therapy of Alzheimer's disease. The mechanism of positive action of aniracetam cannot be explained on the basis of AMPA receptor modulation, as the dose used (50 mg/kg) is well below that required for the effect at AMPA receptors. Other actions such as peripheral effects or modulation of metabotropic receptors seem more likely.
大量行为学和神经生理学证据表明，兴奋性氨基酸参与学习和记忆机制。此外，谷氨酸能通路的退化可能是阿尔茨海默病等各种疾病中出现认知缺陷的基础。由于用激动剂直接刺激谷氨酸能受体会增加毒性风险并加速神经病理变化，一种更有效的方法似乎是对谷氨酸能受体进行正向调节，这种调节可能以较低的兴奋毒性作用风险逆转症状。NMDA受体（甘氨酸-B位点）的士的宁不敏感甘氨酸位点的部分激动剂或AMPA受体的正向调节剂（如阿尼西坦）提供了这样一种可能性。在本研究中，在两种认知缺陷动物模型中测试了d-环丝氨酸和阿尼西坦的作用（在放射状迷宫中评估内嗅皮质损伤诱导的缺陷，在被动回避试验中评估东莨菪碱诱导的失忆）。d-环丝氨酸（6mg/kg，持续10天）对内嗅皮质损伤诱导的空间工作记忆缺陷没有影响。然而，当以相同剂量急性给药时，它确实逆转了东莨菪碱在被动回避试验中诱导的缺陷。相比之下，阿尼西坦（50mg/kg）在持续10天给药时，对患有内嗅皮质损伤的大鼠在放射状迷宫试验中产生了有益作用，但以相同剂量急性给药时，并未影响东莨菪碱诱导的失忆。d-环丝氨酸对抗东莨菪碱诱导的失忆的积极作用可能与海马体中的胆碱能-谷氨酸能相互作用有关。在由内嗅皮质损伤诱导的认知缺陷模型中用d-环丝氨酸获得的阴性数据可以被视为一个提示，即它可能不适合用于阿尔茨海默病的症状治疗。阿尼西坦的积极作用机制不能基于AMPA受体调节来解释，因为所用剂量（50mg/kg）远低于对AMPA受体产生作用所需的剂量。其他作用，如外周作用或对代谢型受体的调节，似乎更有可能。
