Neuroimmune pharmacology of infliximab and lycopene in repetitive traumatic brain injury: Targeting SIRT1/miR-21-mediated brain-lung crosstalk.

Traumatic brain injury (TBI) is a critical reason of neurological impairment globally, with increasing evidence suggesting that its impact extends beyond the brain to peripheral organs. This study investigates the potential brain-lung crosstalk in mild repetitive TBI (RTBI) and explores the therapeutic potential of Infliximab (INF) and Lycopene (LYC) in mitigating the associated neuroinflammatory and pulmonary complications. Using a weight-drop rat model of mild RTBI, we tracked the histological changes and inflammatory markers in both brain and lung tissues across control, RTBI, and treatment groups with INF, LYC, and their combination. Our findings revealed that RTBI induced significant neuroinflammation and oxidative stress, characterized by sirtuin 1 (SIRT1) suppression, activation of NLRP3 (Nod-like receptor protein containing pyrin 3), apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and caspase-1 inflammasome, as well as elevated brain levels of tumor necrosis factor alpha (TNF-α) and nuclear factor kappa B (NF-ҡB). These changes were associated with the increased pulmonary micro-ribonucleic acid-21 (micRNA-21) expression, pulmonary inflammasome activation, and pyroptosis-associated damage, suggesting systemic inflammation and oxidative stress. However, the post-treatment with INF and LYC significantly reduced neuroinflammation, partially restored SIRT1 levels, and inflammasome activity. Therefore, these effects may contribute to the restoration of systemic homeostasis and attenuation of lung injury markers. Notably, the combination therapy showed superior protective effects compared with individual treatments. These results suggest an interconnected pathology of RTBI and lung injury, emphasizing how oxidative stress and systemic inflammation contribute to secondary organ damage. The anti-inflammatory and neuroprotective effects of INF and LYC highlight their potential as therapeutic agents for reducing multi-organ complications in RTBI. Further investigations are required to explore their translational applications in clinical settings and establish mechanistic and inter-organ relationships.