Attenuation of postoperative cognitive dysfunction by amantadine

 描述(由申请人提供)：美国每年有超过2000万人接受手术。术后认知功能障碍(POCD)是一种有文献记载的临床实体，更常发生在老年患者中，已引起公众和专业人士的极大关注。由于这一问题显然很重要，因此迫切需要确定减轻POCD的干预措施。我们的初步研究表明，金刚烷胺是一种临床使用的抗病毒药物，也用于治疗各种神经退行性疾病，减少手术(右颈动脉探查)导致的学习和记忆障碍以及年轻成年大鼠的神经炎症。金刚烷胺还增加了大脑中胶质细胞衍生生长因子(GDNF)的含量。先前的一项研究表明，GDNF可以减少小胶质细胞的激活。此外，我们的初步研究表明，金刚烷胺减轻了手术诱导的老年大鼠的学习和记忆障碍。我们假设GDNF介导金刚烷胺对手术诱导的神经炎症以及老年大鼠学习和记忆障碍的影响。在这个项目中，我们将确定：1)金刚烷胺的应用时间是否影响金刚烷胺减轻手术诱导的老年大鼠学习和记忆障碍的有效性；2)金刚烷胺通过GDNF减少手术引起的神经炎症；以及3)抑制GDNF阻断金刚烷胺导致的颈动脉探查后认知障碍的减轻。我们将使用老年成年雄性大鼠，并对它们进行右侧颈动脉探查。动物将被挥发性麻醉剂异氟醚麻醉。学习和记忆将通过巴恩斯迷宫和恐惧条件反射进行评估。将采集不同的大脑区域进行生化检查。这些研究可能为使用金刚烷胺减轻POCD提供临床前证据。我们的研究还可能揭示金刚烷胺效应的靶分子，这可能有助于设计对POCD的干预措施。

 DESCRIPTION (provided by applicant): More than 20 million people each year undergo surgery in the U.S.A. Post-operative cognitive dysfunction (POCD), a documented clinical entity that occurs more frequently in elderly patients, has drawn significant attention from the public and professionals. Because the issue is obviously significant, there is an urgent need to identify interventions to attenuate POCD. Our preliminary study showed that amantadine, a clinically used anti-viral agent that is also used in treating various neurodegenerative diseases, reduced surgery (right carotid exploration)-induced learning and memory impairment as well as neuroinflammation in young adult rats. Amantadine also increased glial cell-derived growth factor (GDNF) in the brain. GDNF has been shown to reduce microglial activation in a previous study. In addition, our preliminary study showed that amantadine attenuated surgery-induced learning and memory impairment in elderly rats. We hypothesize that GDNF mediates the amantadine effects on surgery-induced neuroinflammation as well as learning and memory impairment in aged rats. In this project, we will determine whether: 1) the duration of amantadine application affects the effectiveness of amantadine to attenuate surgery-induced learning and memory impairment in aged rats; 2) amantadine reduces surgery-induced neuroinflammation through GDNF; and 3) inhibition of GDNF blocks amantadine-induced attenuation of cognitive impairment after carotid arterial exploration. We will use old adult male rats and subject them to right carotid arterial exploration. Animals will be anesthetized by the volatile anesthetic isoflurane. Learning and memory will be evaluated by Barnes maze and fear conditioning. Various brain regions will be harvested for biochemical examination. These studies may provide preclinical evidence for using amantadine to attenuate POCD. Our studies may also reveal target molecules for the amantadine effects, which may help design interventions for POCD.