Advancing Understanding of TBI Injury: Pathophysiological Mechanism, Secondary Damage, and Emerging Neuroprotective Strategies

Traumatic brain injury (TBI) is among the leading causes of mortality and long-term disability worldwide, particularly in younger populations. Despite extensive research, there are currently no clinically effective neuroprotective therapies capable of fully preventing secondary neurological damage after TBI. The pathological progression of TBI involves both primary and secondary injury mechanisms. Primary injury occurs immediately after mechanical trauma and results in irreversible structural damage, whereas secondary injury develops progressively over hours to days and significantly contributes to neuronal degeneration and neurological dysfunction. Secondary injury cascades include excitotoxicity, oxidative stress, mitochondrial dysfunction, blood-brain barrier (BBB) disruption, cerebral edema, neuroinflammation, calcium overload, and apoptotic cell death. These interconnected mechanisms aggravate tissue injury and impair cognitive, behavioural, and motor functions. Experimental animal models have substantially improved the understanding of TBI pathophysiology and facilitated the development of potential therapeutic approaches; however, successful translation from experimental studies to clinical application remains limited. Recent advances in molecular diagnostics have identified extracellular vesicles, microRNAs, and other circulating biomarkers as promising tools for early diagnosis and prognosis. In addition, growing interest has emerged in natural and herbal neuroprotective compounds because of their antioxidant and anti-inflammatory properties. This review comprehensively discusses the major pathophysiological mechanisms underlying TBI, translational limitations of current therapeutic strategies, and future directions for developing effective multimodal neuroprotective interventions.