Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15213, United States.
Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA 15213, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15213, United States; Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, United States; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, United States.
Exp Neurol. 2019 Apr;314:67-73. doi: 10.1016/j.expneurol.2019.01.010. Epub 2019 Jan 17.
Typical antipsychotic drugs (APDs) with Dantagonistic properties impede functional outcome after experimental traumatic brain injury (TBI) and reduce the effectiveness of environmental enrichment (EE). Here we test the hypothesis that aripiprazole (ARIP), an atypical APD with partial Dand 5-HTreceptor agonist activities will improve recovery after TBI and when combined with EE will further enhance the benefits. Anesthetized adult male rats received either a controlled cortical impact of moderate severity or sham injury and then were randomly assigned to EE or standard (STD) housing and once daily intraperitoneal injections of ARIP (0.1 mg/kg) or vehicle (VEH; 1.0 mL/kg) beginning 24 h after injury for 19 days. Motor (beam-walking time and beam-walk score) and cognitive (acquisition of spatial learning and memory) outcomes were assessed on post-operative days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. There were no statistical differences among the sham groups, regardless of housing or treatment, so the data were pooled. The SHAM group performed better than all TBI groups on motor and spatial learning (p < 0.05) but did not differ from either EE group on memory retention. Regarding TBI, both EE groups improved motor and cognitive outcomes vs. the VEH-treated STD group (p < 0.05) but did not differ from one another (p > 0.05). The ARIP-treated STD group performed better than the VEH-treated STD group on beam-walk score and spatial learning (p < 0.05), but not beam-walking time or memory retention (p > 0.05). Cortical lesion volume was smaller in all treated groups compared to the TBI + STD + VEH group (p < 0.05). The data replicate previous work and extend the findings by demonstrating that 1) ARIP promotes recovery after TBI, but combining treatments does not yield additional benefits, which is contrary to the hypothesis, and 2) unlike APDs that exhibit D receptor antagonism, ARIP does not impede rehabilitation (i.e., EE).
典型的抗精神病药物（APD）具有拮抗作用，会阻碍实验性创伤性脑损伤（TBI）后的功能恢复，并降低环境富集（EE）的效果。在这里，我们测试了一个假设，即阿立哌唑（ARIP）是一种具有部分 D 和 5-HT 受体激动剂活性的非典型 APD，它将改善 TBI 后的恢复，并且当与 EE 结合使用时，将进一步增强其益处。麻醉的成年雄性大鼠接受中度严重程度的皮质控制冲击或假损伤，然后随机分配到 EE 或标准（STD）住房，并在损伤后 24 小时内每天一次腹膜内注射 ARIP（0.1mg/kg）或载体（VEH；1.0ml/kg）19 天。术后第 1-5 天和第 14-19 天分别评估运动（走梁时间和走梁评分）和认知（空间学习和记忆的获取）结果。在第 21 天量化皮质损伤体积。无论住房或治疗如何，假手术组之间均无统计学差异，因此汇总数据。SHAM 组在运动和空间学习方面的表现优于所有 TBI 组（p<0.05），但在记忆保留方面与 EE 组无差异。关于 TBI，与 VEH 治疗的 STD 组相比，两个 EE 组在运动和认知结果方面均有所改善（p<0.05），但彼此之间没有差异（p>0.05）。与 VEH 治疗的 STD 组相比，ARIP 治疗的 STD 组在走梁评分和空间学习方面表现更好（p<0.05），但在走梁时间或记忆保留方面没有差异（p>0.05）。与 TBI+STD+VEH 组相比，所有治疗组的皮质损伤体积均较小（p<0.05）。该数据复制了先前的工作，并通过证明以下两点扩展了研究结果：1）ARIP 促进 TBI 后的恢复，但联合治疗不会带来额外的益处，这与假设相反；2）与表现出 D 受体拮抗作用的 APD 不同，ARIP 不会阻碍康复（即 EE）。
