Propranolol attenuates systemic inflammatory response in aged traumatic brain injury patients

Aged traumatic brain injury (TBI) patients typically have a worse prognosis than younger individuals, though the underlying mechanisms remain incompletely understood. Secondary neuroinflammation is a key determinant of outcomes following TBI, but how aging reshapes the neuroinflammatory response post-TBI remains poorly understood. Propranolol, a clinically available non-selective beta-adrenergic receptor blocker, has garnered increasing interest for its potential therapeutic value in TBI management. Published clinical studies have shown that early administration of propranolol reduces mortality, shortens hospital stays, and improves outcomes in patients with moderate-to-severe TBI. However, its effects and underlying mechanisms in aged patients remain unclear. Here, we investigated the regulatory mechanisms by which propranolol modulates systemic inflammatory responses in aged TBI mice and conducted a retrospective exposure-based clinical cohort study enrolling aged TBI patients. We found that propranolol significantly reduced the production of peripheral blood-derived neutrophils and classical monocytes, and inhibited their infiltration into the brain. In contrast, both peripheral and brain-infiltrating non-classical monocyte populations were expanded. Mechanistically, propranolol substantially reversed the inflammatory transcriptomic profiles in both the bone marrow and brain of aged TBI mice, as evidenced by the downregulation of myeloid cell differentiation and inflammation-related signaling pathways. Behavioral outcomes of aged TBI mice were also significantly improved. It is worth noting that transcriptomic analysis of patient-derived peripheral blood mononuclear cells (PBMCs) and proteomic analysis of cerebrospinal fluid (CSF) also indicated that systemic inflammatory responses are attenuated in aged TBI patients treated with propranolol. In summary, our study suggests that propranolol holds significant clinical potential for alleviating systemic inflammation and improving outcomes in aged TBI patients.