PACAP mitigates traumatic brain injury progression via ELF3/ZO-1 axis-mediated blood-brain barrier repair

Traumatic brain injury (TBI) often leads to significant damage to the blood-brain barrier (BBB), contributing to the progression of neurological dysfunction and exacerbating inflammatory responses. BBB disruption is a critical factor in TBI pathology, as it facilitates neuroinflammation and edema, thereby worsening brain injury. For the first time, this study investigates the neuroprotective role of Human Pituitary Adenylate Cyclase Activating Peptide (PACAP) in mitigating the progression of TBI by addressing BBB dysfunction. Using a murine TBI model, the research demonstrates a significant reduction in PACAP levels in both serum and cortical tissues post-injury. Administration of PACAP was found to ameliorate neurological deficits, as evidenced by improved modified Neurological Severity Scores (mNSS) and enhanced motor coordination. Furthermore, PACAP treatment attenuated neutrophil infiltration and pro-inflammatory cytokine secretion, including TNF-α and IL-6, while reducing endothelial inflammation markers VCAM-1 and ICAM-1. PACAP also preserved BBB integrity by decreasing brain water content and Evans blue dye extravasation, alongside upregulating tight junction protein ZO-1. In vitro studies on human brain microvascular endothelial cells (HBMVECs) corroborated these findings, showing PACAP's efficacy in reducing endothelial permeability and enhancing transendothelial electrical resistance (TEER). The protective effects were mediated through the upregulation of ELF3, as its silencing negated PACAP's benefits. Collectively, these findings underscore PACAP's potential as a therapeutic agent in TBI management by fortifying BBB integrity and curtailing inflammatory responses.