Mechanism-Targeted Therapeutic Strategies for Traumatic Brain Injury: From Molecular Pathways to Functional Recovery

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Abstract
Traumatic brain injury (TBI) is characterized by a “translational paradox”, where robust preclinical successes rarely achieve clinical efficacy. This review provides a critical appraisal of emerging therapeutics, moving beyond traditional silos to propose a unified, stage-dependent roadmap for neurorestoration. Reflecting on translational insights from past trials, specifically the limitations of standardized timing and phenotypic heterogeneity, we introduce the “Temporal Precision Medicine” framework. Central to this synthesis is the Dual-Axis Theory, which posits that successful emerging modalities, including repurposed agents such as glibenclamide, amantadine, and statins, alongside cell-free biologics and neuromodulation, converge on two shared pathological targets: the Inflammatory Axis (M1-to-M2 microglial polarization) and the Metabolic Axis (restoration of mitochondrial bioenergetics). We operationalize these biological insights into a Triple-Axis Framework, a dynamic clinical roadmap that aligns stage-dependent interventions with phase-specific biomarkers and pathological mechanisms. By integrating these biological signals with bioengineered delivery systems and artificial intelligence (AI)-driven precision phenotyping, the field can transition from acute neuroprotection toward genuine circuit-level regeneration. We conclude with a blueprint for the next generation of TBI trials, emphasizing biomarker-based stratification and multidimensional endpoints to bridge the translational gap.

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