Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA.
Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA 17033, USA.
Transl Res. 2024 Dec;274:21-34. doi: 10.1016/j.trsl.2024.08.007. Epub 2024 Sep 7.
Endoplasmic reticulum (ER) stress is recognized as a crucial contributor to the progression of traumatic brain injury (TBI) and represents a potential target for therapeutic intervention. This study aimed to assess the potential of J147, a novel neurotrophic compound, in alleviating ER stress by modulating related signaling pathways, thereby promoting functional recovery in TBI. To this end, adult mice underwent controlled cortical impact (CCI) injury to induce TBI, followed by oral administration of J147 one-hour post-injury, with daily dosing for 3 to 7 days. Multiple behavioral assessments were conducted over 35 days, revealing a significant, dose-dependent improvement in neurofunctional recovery with J147 treatment. The neuropathological analysis demonstrated reduced acute neurodegeneration (observed at three days through FJC staining), enhanced long-term neuron survival (H&E and Nissl staining), and improved neuroplasticity (Golgi staining) at 35 days post-TBI. At the molecular level, TBIinduced AMP-activated protein kinase (AMPK) dephosphorylation, sterol regulatory element binding protein-1 (SREBP-1) activation, and upregulation of ER stress marker proteins, including phosphorylated eukaryotic initiation factor-2α (p-eIF2a), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in perilesional cortex neurons at three days post-injury. Notably, the J147 treatment significantly attenuated AMPK dephosphorylation, SERBP-1 activation, and expression of the ER stress markers. In summary, this study reveals the therapeutic promise of J147 in mitigating secondary brain damage associated with TBI and improving long-term functional recovery by modulating ER stress pathways.
内质网（ER）应激被认为是创伤性脑损伤（TBI）进展的关键因素，代表了治疗干预的潜在靶点。本研究旨在评估新型神经营养化合物 J147 通过调节相关信号通路缓解 ER 应激的潜力，从而促进 TBI 后的功能恢复。为此，成年小鼠接受皮质控制冲击（CCI）损伤以诱导 TBI，然后在损伤后 1 小时进行 J147 口服给药，每天给药 3 至 7 天。在 35 天内进行了多项行为评估，结果显示 J147 治疗可显著改善神经功能恢复，且呈剂量依赖性。神经病理学分析显示，J147 治疗可减少急性神经退行性变（通过 FJC 染色在 3 天观察到），增强长期神经元存活（H&E 和尼氏染色），并改善 TBI 后 35 天的神经可塑性（高尔基染色）。在分子水平上，TBI 诱导 AMP 激活蛋白激酶（AMPK）去磷酸化、固醇调节元件结合蛋白-1（SREBP-1）激活以及内质网应激标志物蛋白的上调，包括磷酸化真核起始因子-2α（p-eIF2a）、激活转录因子 4（ATF4）和 C/EBP 同源蛋白（CHOP）在损伤后 3 天的皮质损伤区神经元中。值得注意的是，J147 治疗显著减弱了 AMPK 去磷酸化、SREBP-1 激活和 ER 应激标志物的表达。综上所述，本研究揭示了 J147 通过调节 ER 应激途径减轻与 TBI 相关的继发性脑损伤和改善长期功能恢复的治疗潜力。
