Inhibition of Transient Receptor Potential Vanilloid 1 Attenuates Blood-Brain Barrier Disruption after Traumatic Brain Injury in Mice.

Transient receptor potential vanilloid 1 (TRPV1) is widely expressed in the central nervous system and is activated by various stimuli. Inhibiting TRPV1 has neuroprotective effects in cerebral ischemia. However, the role of inhibiting TRPV1 to maintain blood-brain barrier (BBB) integrity following traumatic brain injury (TBI) remains unclear. Therefore, we investigated the effects of capsazepine-mediated TRPV1 inhibition on the BBB in a mouse model of TBI. Adult male C57BL/6 mice were subjected to controlled cortical impact injury and received capsazepine (1 µmol/kg body weight, twice daily, intraperitoneally) until sacrifice. Further, mouse brain microvascular endothelial (bEnd.3) cells were cultured and subjected to biaxial stretch injury to investigate the mechanisms underlying the protective effects of capsazepine. TRPV1 expression was upregulated in the peri-contusional area following TBI, peaking at 24 h post-TBI. Capsazepine-treated mice demonstrated decreased brain edema (p = 0.010), Evans Blue extravasation (p = 0.001), tissue hemoglobin levels (p = 0.002), and loss of tight junction proteins (p = 0.016 ZO-1 expression; p = 0.013 occludin expression) after TBI compared with the vehicle-treated group. Capsazepine significantly alleviated early-stage apoptosis by attenuating activation of JNK, P38, and caspase-3, resulting in a protective effect on the level of ZO-1 in bEnd.3 cells after stretch injury. We conclude that the expression of TRPV1 is upregulated following TBI, and inhibition of TRPV1 attenuated disruption of the BBB in a mouse model of TBI, at least partly, through its anti-apoptotic effects on brain endothelial cells. Blocking TRPV1 may be a promising pharmacotherapeutic intervention to protect against BBB disruption after TBI.