Attenuation of postoperative cognitive dysfunction by amantadine

金刚烷胺减轻术后认知功能障碍

• 批准号: 9125718
• 负责人: ZHIYI ZUO
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9125718
• 关键词: Affect; Age; Amantadine; American; Anesthesia procedures; Anesthetics; Animals; Antiviral Agents; Area; Attention; Attenuated; Biochemical; Brain; Brain region; Cardiac Surgery procedures; Cell Culture Techniques; Clinical; Effectiveness; Elderly; Functional disorder; Future; General Anesthesia; Growth; Harvest; Hippocampus (Brain); Human; Impaired cognition; Intention; Intervention; Isoflurane; Learning; Length; Mediating; Memory; Memory impairment; Methods; Neurodegenerative Disorders; Neuroglia; Operative Surgical Procedures; Parkinson Disease; Patients; Pharmaceutical Preparations; Population; Process; Production; Quality of life; Rattus; Risk Factors; Role; Testing; Translations; Traumatic Brain Injury; Viral; aged; attenuation; base; conditioned fear; design; improved; improved outcome; in vivo; male; mortality; neuroinflammation; neurotrophic factor; older patient; post-operative cognitive dysfunction; pre-clinical; public health relevance; research study; therapy design; young adult

 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.

 描述（由申请人提供）：在美国，每年有超过2000万人接受手术。术后认知功能障碍（POCD）是一种记录在案的临床实体，在老年患者中更常见，已引起公众和专业人士的极大关注。由于这个问题显然是重要的，迫切需要确定干预措施，以减轻POCD。我们的初步研究表明，金刚烷胺，一种临床上使用的抗病毒药物，也用于治疗各种神经退行性疾病，减少手术（右颈动脉探查）诱导的学习和记忆障碍以及年轻成年大鼠的神经炎症。金刚烷胺还增加了脑中胶质细胞衍生的生长因子（GDNF）。在先前的研究中，GDNF已被证明可以减少小胶质细胞的激活。此外，我们的初步研究表明，金刚烷胺减轻老年大鼠手术诱导的学习和记忆障碍。我们推测GDNF介导了金刚烷胺对老年大鼠手术诱导的神经炎症以及学习记忆障碍的影响。在这个项目中，我们将确定：1）金刚烷胺应用的持续时间是否影响金刚烷胺减轻老年大鼠手术诱导的学习和记忆障碍的有效性; 2）金刚烷胺通过GDNF减少手术诱导的神经炎症; 3）GDNF的抑制阻断金刚烷胺诱导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其进行右颈动脉探查。将使用挥发性麻醉剂异氟烷麻醉动物。将通过巴恩斯迷宫和恐惧条件反射评价学习和记忆。将采集不同的脑区进行生化检查。这些研究可能为金刚烷胺减轻POCD提供临床前证据。我们的研究还可能揭示金刚烷胺作用的靶分子，这可能有助于设计POCD的干预措施。