Maresin-1 prevents blood-spinal cord barrier disruption associated with TRPV4 elevation in the experimental model of spinal cord injury

Abstract

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.