Studies on new drugs for delayed and progressive learning and memory impairment using kappa-opioid related drugs

我们已经报道了kappa-阿片受体激动剂（如dynorphin A）改善了几种胆碱能功能障碍动物模型的学习和记忆障碍。痛觉肽是阿片受体样1 （ORL1）受体的内源性配体，与运动啡a具有一定的结构同源性。我们认为，低剂量痛觉肽对学习和/或记忆障碍的改善作用可能不是由ORL1受体介导的。在ORL1受体敲除小鼠海马中，kappa_1阿片受体mRNA表达降低，而dynorphin和痛感肽前体蛋白mRNA表达显著升高。这些变化在β -淀粉样肽（25-35）处理的小鼠中出现。ORL1受体敲除小鼠给予β -淀粉样肽（25-35）1周后，海马中肌啡肽前体蛋白mRNA表达水平显著降低。我们采用约束水浸应激模型和脂多糖（LPS）诱导大鼠迟发性和进行性学习记忆障碍，以检测dynorphin A和nociceptin的作用。水浸应激后第5天短期记忆受损，第7天被动回避学习受损。抗抑郁药地西帕明和乙酰胆碱酯酶抑制剂他克林显著改善了这些损伤。此外，通过反复给药，儿茶素等抗氧化剂也能改善这些症状。此外，反复给药儿茶素也能改善LPS诱导的延迟性学习和记忆障碍。我们需要在这些动物模型中阐明dynorphin A相关肽的机制。

We have reported that kappa-opioid receptor agonist such as dynorphin A improved learning and memory impairment in several animal models with cholinergic dysfunction. Nociceptin is an endogenous ligand for the opioid receptor-like 1 (ORL1) receptor and has some structural homology with the dynorphin A. We have suggested that the ameliorating effect of low doses nociceptin in learning and/or memory impairment may not be mediated by ORL1 receptor. In the hippocampus of ORL1 receptor knockout mouse, expression of kappa_1 opioid receptor mRNA decreased, while mRNA expression of dynorphin and nociceptin precursor protein significantly increased. These changes were presented in beta-amyloid peptide (25-35)-treated mice. The mRNA expression levels of dynorphin precursor protein in the hippocampus 1 week after beta-amyloid peptide (25-35) administration significantly decreased in ORL1 receptor knockout mouse. We used restraint water-immersion stress model and lipopolysaccharide (LPS) to induce delayed and progressive learning and memory impairment to test the effect of dynorphin A and nociceptin. After water-immersion stress, short-term memory was impaired 5 days after stress exposure and the passive avoidance learning was impaired 7 days after stress exposure. These impairments were significantly ameliorated by the antidepressant, desipramine and the acetylcholine esterase inhibitor, tacrine. In addition, they were also ameliorated by antioxidants such as catechin by repeated administration. Further, delayed impairment of learning and memory induced by LPS was also ameliorated by repeated administration of catechin. We need to elucidate the mechanisms of dynorphin A related peptides in these animal models.