Husain Mohammed Amir, Smith Reed, Sorge Robert E, Kaimari Abdulraheem, Si Ying, Hassan Ali Z, Guha Abhishek, Smith Katherine A, Cardozo Christopher P, DeBerry Jennifer J, Andrabi Shaida A, Nabors L Burt, Filippova Natalia, Webb Caroline K, King Peter H
Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Killion Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
FASEB J. 2025 May 15;39(9):e70588. doi: 10.1096/fj.202500236R.
Neuroinflammation is a major driver of secondary tissue damage after spinal cord injury (SCI). Within minutes after SCI, activated microglia and astrocytes produce proinflammatory mediators such as TNF-α, IL-6, iNOS, and COX-2 which induce tissue injury through cytotoxicity, vascular hyperpermeability, and secondary ischemia. The inflammatory cascade is amplified by chemokines like CCL2 and CXCL1 which recruit immune cells to the injured site. HuR is an RNA regulator that promotes glial expression of many proinflammatory factors by binding to adenylate- and uridylate-rich elements in the 3' untranslated regions of their mRNAs. SRI-42127 is a small molecule which blocks HuR function by preventing its nucleocytoplasmic translocation. This study aimed to evaluate the potential of SRI-42127 to suppress neuroinflammation after SCI and improve functional outcome. Adult female mice underwent a T10 contusion injury and received SRI-42127 1 h post injury for up to 5 days. Locomotor function was assessed by open field testing, balance beam, and rotarod. Immunohistochemistry was used to assess lesion size, neuronal loss, myelin sparing, microglial/astroglial activation, and HuR localization. Inflammatory mediator expression was assessed by qPCR, immunohistochemistry, ELISA, or western blot. We found that SRI-42127 treatment significantly attenuated loss of locomotor function and post-SCI pain. There was a reduction in lesion size and neuronal loss with an increase in myelin sparing. Microglia and astrocytes showed reduced activation and reduced nucleocytoplasmic translocation of HuR. There was a striking suppression of proinflammatory mediators at the epicenter along with peripheral suppression of inflammatory responses in serum, liver, and spleen. In conclusion, HuR inhibition with SRI-42127 may be a viable therapeutic approach for suppressing neuroinflammatory responses after SCI and improving functional outcome.
神经炎症是脊髓损伤（SCI）后继发性组织损伤的主要驱动因素。在脊髓损伤后的几分钟内，活化的小胶质细胞和星形胶质细胞会产生促炎介质，如肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2），这些介质通过细胞毒性、血管通透性增加和继发性缺血诱导组织损伤。趋化因子如CCL2和CXCL1会放大炎症级联反应，它们将免疫细胞招募到损伤部位。HuR是一种RNA调节剂，它通过与许多促炎因子mRNA的3'非翻译区中富含腺苷酸和尿苷酸的元件结合，促进这些因子在胶质细胞中的表达。SRI-42127是一种小分子，它通过阻止HuR的核质转运来阻断其功能。本研究旨在评估SRI-42127抑制脊髓损伤后神经炎症并改善功能结局的潜力。成年雌性小鼠接受T10挫伤性损伤，并在损伤后1小时接受SRI-42127治疗，持续5天。通过旷场试验、平衡木试验和转棒试验评估运动功能。采用免疫组织化学法评估损伤大小、神经元丢失、髓鞘保留、小胶质细胞/星形胶质细胞活化以及HuR定位。通过qPCR、免疫组织化学、酶联免疫吸附测定（ELISA）或蛋白质免疫印迹法评估炎症介质表达。我们发现，SRI-42127治疗显著减轻了运动功能丧失和脊髓损伤后疼痛。损伤大小和神经元丢失减少，髓鞘保留增加。小胶质细胞和星形胶质细胞的活化减少，HuR的核质转运减少。在损伤中心，促炎介质受到显著抑制，同时血清、肝脏和脾脏中的炎症反应在外周也受到抑制。总之，用SRI-42127抑制HuR可能是一种可行的治疗方法，用于抑制脊髓损伤后的神经炎症反应并改善功能结局。
