Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, USA.
J Neurotrauma. 2013 Apr 1;30(7):557-64. doi: 10.1089/neu.2012.2782. Epub 2013 Mar 26.
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; 2.8 mm 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.
乙酰胆碱酯酶（AChE）抑制剂多奈哌齐被用作治疗阿尔茨海默病的药物，并被推荐用于治疗创伤性脑损伤（TBI）后的注意力和记忆力。尽管一些临床案例研究支持使用多奈哌齐来改善认知，但很少有实验性 TBI 研究评估这种药物治疗的潜在疗效。因此，本临床前研究的目的是评估多奈哌齐的几种剂量，以确定其对 TBI 后功能结果的影响。90 只麻醉成年雄性大鼠接受了控制性皮质撞击（CCI；4m/sec 时皮层深度为 2.8mm）或假损伤，然后随机分为 TBI 组和假损伤组各 6 组（多奈哌齐 0.25、0.5、1.0、2.0 或 3.0mg/kg，以及生理盐水载体 1.0mL/kg）。治疗于手术后 24 小时开始，每日腹腔注射一次，共 19 天。功能通过运动（平衡木/行走）和认知（Morris 水迷宫）测试在第 1-5 天和第 14-19 天分别进行评估。无论剂量如何，假损伤对照组在任何评估中均未观察到显著差异，因此数据合并。此外，TBI 组之间在急性神经学评估（例如，翻正反射）中未显示出显著差异，表明所有组均受到相同严重程度的损伤。与载体处理的对照组相比，多奈哌齐的五个剂量均未改善运动或认知功能。此外，两个最高剂量（2.0mg/kg 和 3.0mg/kg）显著损害了平衡木（3.0mg/kg）、平衡木行走（2.0mg/kg 和 3.0mg/kg）和认知表现（3.0mg/kg）。这些数据表明，慢性给予多奈哌齐不仅不能促进中度 CCI 损伤后的功能改善，而且取决于剂量实际上对恢复过程有害。还需要进一步研究以确定其他乙酰胆碱酯酶抑制剂在 TBI 后是否具有相似的作用。
