J147 treatment protects against traumatic brain injury by inhibiting neuronal endoplasmic reticulum stress potentially via the AMPK/SREBP-1 pathway

IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY
Rong Jin , Min Wang , Manish Shukla , Yuguo Lei , Dong An , Jiwen Du , Guohong Li
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Abstract

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.

Abstract Image

J147 可通过 AMPK/SREBP-1 途径抑制神经元内质网应激,从而保护大脑免受创伤性脑损伤。
内质网(ER)应激被认为是创伤性脑损伤(TBI)进展的关键因素,也是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,从而促进创伤性脑损伤功能恢复的潜力。为此,成年小鼠接受可控皮质冲击(CCI)损伤以诱发创伤性脑损伤,然后在损伤后一小时口服 J147,每天服药 3 到 7 天。在35天的时间里进行了多项行为评估,结果显示,J147治疗对神经功能的恢复有显著的剂量依赖性改善。神经病理学分析表明,在创伤后 35 天,急性神经变性减少(通过 FJC 染色在三天内观察到),神经元长期存活率提高(H&E 和 Nissl 染色),神经可塑性改善(高尔基体染色)。在分子水平上,创伤后三天,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)活化,以及ER应激标志蛋白的上调,包括磷酸化真核细胞起始因子-2α(p-eIF2a)、激活转录因子4(ATF4)和C/EBP同源蛋白(CHOP)。值得注意的是,J147 治疗能显著减轻 AMPK 去磷酸化、SERBP-1 激活和 ER 应激标志物的表达。总之,这项研究揭示了 J147 通过调节 ER 应激途径减轻创伤性脑损伤引起的继发性脑损伤并改善长期功能恢复的治疗前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Translational Research
Translational Research 医学-医学:内科
CiteScore
15.70
自引率
0.00%
发文量
195
审稿时长
14 days
期刊介绍: Translational Research (formerly The Journal of Laboratory and Clinical Medicine) delivers original investigations in the broad fields of laboratory, clinical, and public health research. Published monthly since 1915, it keeps readers up-to-date on significant biomedical research from all subspecialties of medicine.
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