PHARMACOLOGICAL MODULATION OF BRAIN-ORGAN CROSSTALK IN TRAUMATIC BRAIN INJURY-INDUCED MULTI-ORGAN DYSFUNCTION USING AN EPROSARTAN- SINAPIC ACID COMBINATION IN MICE

Traumatic brain injury (TBI) is an acute, non-degenerative neurological insult caused by external mechanical forces and represents a major global health burden. Beyond focal brain damage, TBI initiates a systemic pathological cascade that disrupts the function of distant organs, including the heart, lungs, liver, and kidneys, culminating in multi-organ dysfunction syndrome (MODS), driven by excessive systemic inflammation, episodic sympathetic hyperactivation, and progressive immune suppression; however, the underlying regulatory mechanisms remain poorly understood. The present study hypothesises that a combined synthetic–herbal therapeutic strategy could synergistically mitigate TBI-induced MODS by modulating key regulatory networks involving the renin–angiotensin system (RAS), autonomic nervous system (ANS), high-mobility group box-1 (HMGB1), and immune checkpoint signalling through programmed death-ligand 1 (PD-L1). A weight-drop model was used to induce injury in Swiss albino mice, and E+S was orally administered. Neurobehavioral performance, blood–brain barrier permeability, cerebral edema, plasma norepinephrine, inflammatory mediators, organ-specific serum biomarkers, and gene expression of sepsis-associated markers (PD-L1 and IL-10) were evaluated at 24 hours and 21 days post-injury, along with histopathological examination. The E+S combination significantly improved neurological outcomes, reduced cerebral edema, suppressed sympathetic hyperactivity, attenuated systemic inflammation, normalized serum markers of organ injury, and upregulated PD-L1 and IL-10 expression, accompanied by a marked restoration of cellular architecture across organs. These findings suggest that the coordinated regulation of RAS/ANS/HMGB1 and PD-L1 signalling by E+S effectively interrupts the pathological cycle driving TBI-induced MODS. Thus, combination therapy conferred superior neuroprotective and organ-protective efficacy compared with monotherapy, supporting enhanced functional recovery after TBI.