Overcoming Translational Barriers in Neuroprotection: From Molecular Targets to Biomarkers

Abstract

Neuroprotection encompasses strategies aimed at preserving neuronal structure and function by mitigating pathological processes such as oxidative stress, excitotoxicity, neuroinflammation, and regulated cell death (RCD). Despite promising preclinical findings, translation to clinical success has been limited due to pharmacokinetic constraints, inadequate blood-brain barrier (BBB) penetration, methodological deficiencies, and a lack of objective biomarkers. Key mechanistic targets include mitochondrial stabilization, modulation of glutamate-induced calcium overload, suppression of proinflammatory glial activation, and inhibition of specific RCD pathways such as necroptosis (RIPK1/RIPK3/MLKL) and ferroptosis (GPX4/ALOX-15). Advanced in vitro platforms—including iPSC-derived organoids and co-culture systems—and rigorously designed in vivo models are essential for mechanistic validation and prediction of clinical efficacy. Translational success further relies on achieving therapeutically relevant unbound drug concentrations in the CNS (Cu,br) and integrating clinically validated biomarkers (e.g., plasma NfL, GFAP) into preclinical endpoints. Emerging therapeutic strategies encompass CNS-penetrant small molecules, biologics, cell-derived extracellular vesicles, and phytochemicals delivered via advanced formulations. This review emphasizes the necessity of mechanism-specific, biomarker-driven, and rigorously validated approaches to overcome historical translational failures and realize clinically effective neuroprotective interventions.