Carvacrol improves neurological function by inhibiting TRPM7-mediated BBB disruption and hemorrhage after TBI.

Traumatic brain injury (TBI) triggers a cascade of secondary pathophysiological events, including blood-brain barrier (BBB) disruption, intracerebral hemorrhage, neuroinflammation, neuronal death, and persistent neurological deficits. Although transient receptor potential melastatin 7 (TRPM7) is known to regulate cellular stress responses, its role in TBI-induced vascular dysfunction remains unclear. This study aimed to investigate the involvement of TRPM7 in BBB damage and hemorrhage after TBI and to evaluate the therapeutic potential of carvacrol, a TRPM7 inhibitor. TBI was induced in male mice using a controlled cortical impact model. Carvacrol (50 mg/kg, i.p.) was administered immediately and 8 h post-injury, then once daily for 7 days. In this model, TBI caused marked BBB disruption and cortical and hippocampal hemorrhage, accompanied by increased TRPM7 and JMJD3 expression, matrix metalloproteinase (MMP) activation, SUR1/TRPM4 upregulation, and motor and cognitive deficits. Carvacrol treatment significantly attenuated BBB disruption and hemorrhage, preserved tight junction proteins, and reduced the expression of MMP-3 and MMP-9, and SUR1/TRPM4–known contributor to post-TBI hemorrhage–in vivo and in vitro. Mechanistically, carvacrol inhibited JMJD3 expression and activity, thereby limiting the recruitment of JMJD3 and NF-κB p65 to the promoters of MMP-3, MMP-9, Abcc8, and TRPM4. Behaviorally, carvacrol improved neurological scores, motor performance, and cognitive function after TBI. These findings identify TRPM7 as a key mediator of BBB disruption and hemorrhage the JMJD3–MMP–SUR1/TRPM4 axis after TBI and suggest that targeting TRPM7 may represent a promising strategy for mitigating TBI-associated vascular damage and neurological dysfunction.