Donepezil Is Ineffective in Promoting Motor and Cognitive Benefits after Controlled Cortical Impact Injury in Male Rats
Donepezil Is Ineffective in Promoting Motor and Cognitive Benefits after Controlled Cortical Impact Injury in Male Rats
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DOI：
10.1089/neu.2012.2782
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发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
Kline, Anthony E.
中科院分区：
文献类型：
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作者：
Shaw, Kaitlyn E.;Bondi, Corina O.;Kline, Anthony E.
乙酰胆碱酯酶(AChE)抑制剂多奈哌齐被用于治疗阿尔茨海默病，并已被推荐用于提高创伤性脑损伤(TBI)后的注意力和记忆力。虽然精选的临床病例研究支持使用多奈哌齐来增强认知，但很少有实验性的脑损伤研究评估这种药物疗法的潜在疗效。因此，这项临床前研究的目的是评估几种剂量的多奈哌齐，以确定其对脑外伤后功能预后的影响。90只麻醉成年雄性大鼠接受控制性皮质撞击(CCI，皮层深度2.8 mm，4m/s)或假损伤，然后随机分为6个创伤性脑损伤组和6个假手术组(多奈哌齐0.25，0.5，1.0，2.0，3.0 mg/kg，生理盐水1.0mL/kg)。治疗开始于术后24小时，并予腹腔注射。每日一次，连续19天。运动(平衡木/步行)和认知(Morris水迷宫)测试分别在第1-5天和14-19天进行。在任何评估中，假对照组之间都没有观察到显著差异，无论剂量如何，因此数据被合并。此外，在急性神经功能评估(例如，翻正反射)方面，不同的脑外伤组之间没有显著差异，这表明所有组的损伤严重程度相同。与服用车辆的对照组相比，五种剂量的多奈哌齐都没有改善运动或认知功能。此外，与车辆相比，最高剂量的两个剂量显著损害了横梁平衡(3.0 mg/kg)、横梁行走(2.0 mg/kg和3.0 mg/kg)以及认知能力(3.0 mg/kg)。这些数据表明，长期服用多奈哌齐不仅在促进中度CCI损伤后的功能改善方面无效，而且依赖于剂量实际上也不利于康复过程。还需要进一步的工作来确定其他AChE抑制剂是否在脑损伤后发挥类似的作用。
The acetylcholinesterase (AChE) inhibitor donepezil is used as a therapy for Alzheimer's disease and has been recommended as a treatment for enhancing attention and memory after traumatic brain injury (TBI). Although select clinical case studies support the use of donepezil for enhancing cognition, there is a paucity of experimental TBI studies assessing the potential efficacy of this pharmacotherapy. Hence, the aim of this pre-clinical study was to evaluate several doses of donepezil to determine its effect on functional outcome after TBI. Ninety anesthetized adult male rats received a controlled cortical impact (CCI; 2.8mm cortical depth at 4 m/sec) or sham injury, and then were randomly assigned to six TBI and six sham groups (donepezil 0.25, 0.5, 1.0, 2.0, or 3.0 mg/kg, and saline vehicle 1.0 mL/kg). Treatments began 24 h after surgery and were administered i.p. once daily for 19 days. Function was assessed by motor (beam balance/walk) and cognitive (Morris water maze) tests on days 1-5 and 14-19, respectively. No significant differences were observed among the sham control groups in any evaluation, regardless of dose, and therefore the data were pooled. Furthermore, no significant differences were revealed among the TBI groups in acute neurological assessments (e. g., righting reflex), suggesting that all groups received the same level of injury severity. None of the five doses of donepezil improved motor or cognitive function relative to vehicle-treated controls. Moreover, the two highest doses significantly impaired beam-balance (3.0 mg/kg), beam-walk (2.0 mg/kg and 3.0 mg/kg), and cognitive performance (3.0 mg/kg) versus vehicle. These data indicate that chronic administration of donepezil is not only ineffective in promoting functional improvement after moderate CCI injury, but depending on the dose is actually detrimental to the recovery process. Further work is necessary to determine if other AChE inhibitors exert similar effects after TBI.