Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Neuroscience. 2022 Sep 1;499:130-141. doi: 10.1016/j.neuroscience.2022.07.021. Epub 2022 Jul 22.
Traumatic brain injury (TBI) is known to impair synaptic function, and subsequently contribute to observed cognitive deficits. Retinoic Acid (RA) signaling modulates expression of synaptic plasticity proteins and is involved in hippocampal learning and memory. All trans-retinoic acid (ATRA), a metabolite of Vitamin A, has been identified as a potential pharmacotherapeutic for other neurological disorders due to this role. This study conducted an ATRA dose response to determine its therapeutic effects on cognitive behaviors and expression of hippocampal markers of synaptic plasticity and RA signaling proteins after experimental TBI. Under isoflurane anesthesia, adult male Sprague Dawley rats received either controlled cortical impact (CCI, 2.5 mm deformation, 4 m/s) or control surgery. Animals received daily intraperitoneal injection of 0.5, 1, 5, or 10 mg/kg of ATRA or vehicle for 2 weeks. Animals underwent motor and spatial learning and memory testing. Hippocampal expression of synaptic plasticity proteins neurogranin (Ng), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 sub-unit, as well as RA signaling proteins STRA6, ADLH1a1, CYP26A1 and CYP26B1 were evaluated by western blot at 2-weeks post-injury. ATRA treatment significantly recovered Ng synaptic protein expression, while having no effect on motor performance, spatial learning, and memory, and GluA1 expression after TBI. RA signaling protein expression is unchanged 2 weeks after TBI. Overall, ATRA administration after TBI showed limited therapeutic benefits compared to the vehicle.
创伤性脑损伤 (TBI) 已知会损害突触功能，并随后导致观察到的认知缺陷。视黄酸 (RA) 信号调节突触可塑性蛋白的表达，参与海马体学习和记忆。全反式视黄酸 (ATRA) 是维生素 A 的一种代谢物，由于其在其他神经疾病中的治疗作用，已被确定为一种潜在的药物治疗方法。本研究进行了 ATRA 剂量反应，以确定其对实验性 TBI 后认知行为以及海马体突触可塑性和 RA 信号蛋白标志物表达的治疗作用。在异氟烷麻醉下，成年雄性 Sprague Dawley 大鼠接受皮质控制冲击 (CCI，2.5mm 变形，4m/s) 或对照手术。动物每天接受 0.5、1、5 或 10mg/kg 的 ATRA 或载体腹膜内注射，持续 2 周。动物接受运动和空间学习及记忆测试。海马体突触可塑性蛋白神经颗粒蛋白 (Ng) 和 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 受体 GluA1 亚基以及 RA 信号蛋白 STRA6、ADLH1a1、CYP26A1 和 CYP26B1 的表达通过 Western blot 在损伤后 2 周进行评估。ATRA 治疗显著恢复了 Ng 突触蛋白的表达，而对 TBI 后的运动表现、空间学习和记忆以及 GluA1 表达没有影响。RA 信号蛋白表达在 TBI 后 2 周保持不变。总体而言，与载体相比，TBI 后 ATRA 给药的治疗益处有限。
