Recently, we reported the TRPV4 ion channel activation and its association with secondary damage after spinal cord injury (SCI). TRPV4 activation is linked with blood-spinal cord barrier (BSCB) disruption, endothelial damage, and inflammation after SCI. Specialized pro-resolving mediators (SPM) are endogenous lipid mediators released for inflammation resolution. Studies suggest that SPM could act as an endogenous antagonist of ion channels directly or indirectly at the plasma membrane. Herein, we studied the effect of maresin-1, a docosahexaenoic acid (DHA)-derived SPM, in SCI-induced TRPV4 expression and subsequent associated damage. First, employing a particular agonist (4αPDD) in endothelial and neuronal cell lines, we examined the potential of maresin-1 to block TRPV4 activation. Then we quantify the DHA levels in plasma and epicenter of the spinal cord in sham and at 1, 3, 7, 14, 21, and 28-days post-injury (DPI) using LC-MS. Then, we exogenously administered maresin-1 using two dosing regimens i.e., single-dose (1 μg) and multiple-dose (1 μg/day for seven days), to confirm its role in the TRPV4 inhibition and its linked damage. After SCI, DHA levels decrease in the spinal cord epicenter area as well as in the plasma. Treatment with maresin-1 attenuates TRPV4 expression, inflammatory cytokines, and chemokines and impedes neutrophil infiltration. Furthermore, treatment with maresin-1 prevents BSCB disruption, alleviates glial scar formation, and improves functional recovery. Thus, our results suggest that maresin-1 could modulate TRPV4 expression and could be a safe and promising approach to target inflammation and BSCB damage after SCI.

最近，我们报道了 TRPV4 离子通道激活及其与脊髓损伤 (SCI) 后继发性损伤的关系。TRPV4 激活与 SCI 后血脊髓屏障 (BSCB) 破坏、内皮损伤和炎症有关。专门的促消退介质 (SPM) 是为消退炎症而释放的内源性脂质介质。研究表明，SPM 可以直接或间接充当质膜离子通道的内源性拮抗剂。在此，我们研究了 maresin-1（一种二十二碳六烯酸 (DHA) 衍生的 SPM）在 SCI 诱导的 TRPV4 表达和随后的相关损伤中的作用。首先，在内皮细胞和神经元细胞系中使用特定的激动剂 (4αPDD)，我们检查了 maresin-1 阻断 TRPV4 激活的潜力。然后，我们使用 LC-MS 量化假手术中以及损伤后 1、3、7、14、21 和 28 天 (DPI) 的血浆和脊髓中心的 DHA 水平。然后，我们使用两种给药方案外源性施用 maresin-1，即单剂量（1 μg）和多剂量（1 μg/天，持续 7 天），以证实其在 TRPV4 抑制及其相关损伤中的作用。SCI 后，脊髓中心区域以及血浆中的 DHA 水平下降。maresin-1 治疗可减弱 TRPV4 表达、炎性细胞因子和趋化因子，并阻止中性粒细胞浸润。此外，maresin-1 治疗可防止 BSCB 破坏、减轻神经胶质疤痕形成并改善功能恢复。因此，我们的结果表明 maresin-1 可以调节 TRPV4 表达，并且可能是一种安全且有前景的针对 SCI 后炎症和 BSCB 损伤的方法。