Traumatic Brain Injury-Induced Cognitive and Histological Deficits Are Attenuated by Delayed and Chronic Treatment with the 5-HT1A-Receptor Agonist Buspirone
Traumatic Brain Injury-Induced Cognitive and Histological Deficits Are Attenuated by Delayed and Chronic Treatment with the 5-HT1A-Receptor Agonist Buspirone
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DOI：
10.1089/neu.2012.2358
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发表时间：
2012-07-01
影响因子：
4.2
通讯作者：
Kline, Anthony E.
中科院分区：
文献类型：
--
作者：
Olsen, Adam S.;Sozda, Christopher N.;Kline, Anthony E.
本研究的目的是评估5-羟色胺（1A）（5-HT 1A）受体激动剂丁螺环酮（BUS）对创伤性脑损伤（TBI）后行为和组织学结果的潜在疗效。将96只异氟烷麻醉的成年雄性大鼠随机分配接受受控皮质撞击或假损伤，然后分配至6个TBI组和6个假损伤组，接受5种剂量的BUS（0.01、0.05、0.1、0.3或0.5 mg/kg）或生理盐水溶剂（VEH，1.0 mL/kg）。手术后24小时开始治疗，每天腹腔内给药一次，持续3周。分别在术后第1-5天和第14-19天评估运动功能（平衡梁/行走梁试验）和空间学习/记忆（Morris水迷宫）。在3周时定量形态学上完整的CA 1/CA 3细胞和皮质病变体积。BUS和VEH假手术组之间在任何终点指标方面均未观察到差异，因此将数据合并。关于TBI组，重复测量ANOVA显示，相对于VEH和其他BUS剂量，0.3 mg/kg剂量的BUS增强了认知表现（p < 0.05），但没有显著影响运动功能。此外，相同的剂量赋予选择性的组织学保护，证明了较小的皮质病变，但没有更大的CA 1/CA 3细胞存活。在其他BUS剂量与VEH之间未观察到显著的行为或组织学差异。这些数据表明BUS具有窄的治疗剂量反应，并且0.3mg/kg对于增强该TBI模型中的空间学习和记忆是最佳的。BUS可能成为临床TBI的一种新的药物治疗方法。
The aim of this study was to evaluate the potential efficacy of the serotonin(1A) (5-HT1A) receptor agonist bus-pirone (BUS) on behavioral and histological outcome after traumatic brain injury (TBI). Ninety-six isoflurane-anesthetized adult male rats were randomized to receive either a controlled cortical impact or sham injury, and then assigned to six TBI and six sham groups receiving one of five doses of BUS (0.01, 0.05, 0.1, 0.3, or 0.5 mg/kg) or saline vehicle (VEH, 1.0 mL/kg). Treatments began 24 h after surgery and were administered intraperitoneally once daily for 3 weeks. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative days 1-5 and 14-19, respectively. Morphologically intact CA1/CA3 cells and cortical lesion volume were quantified at 3 weeks. No differences were observed among the BUS and VEH sham groups in any end-point measure and thus the data were pooled. Regarding the TBI groups, repeated-measures ANOVAs revealed that the 0.3 mg/kg dose of BUS enhanced cognitive performance relative to VEH and the other BUS doses (p < 0.05), but did not significantly impact motor function. Moreover, the same dose conferred selective histological protection as evidenced by smaller cortical lesions, but not greater CA1/CA3 cell survival. No significant behavioral or histological differences were observed among the other BUS doses versus VEH. These data indicate that BUS has a narrow therapeutic dose response, and that 0.3 mg/kg is optimal for enhancing spatial learning and memory in this model of TBI. BUS may have potential as a novel pharmacotherapy for clinical TBI.