Raloxifene Beyond Osteoporosis: Unlocking Neurorestoration Through Remyelination, Inflammatory Regulation, and Neuroimmune Modulation in CNS Pathologies.

Raloxifene, a selective estrogen receptor modulator (SERM), has emerged as a promising candidate for repurposing in neurodegenerative and neuropsychiatric disorders. Traditionally approved for osteoporosis and breast cancer prevention, its tissue-selective estrogen receptor modulation underpins its potential therapeutic applications. This review critically examines the pharmacological, preclinical, and clinical evidence supporting raloxifene's neuroprotective and neuropsychiatric effects, as well as its mechanisms of action, safety profile, and clinical limitations. Raloxifene exerts neuroprotective effects by targeting estrogen receptors, including ERα, ERβ, and GPER, modulating genomic and non-genomic pathways. These pathways regulate oxidative stress, mitochondrial stability, neuroinflammation, and apoptosis-core features of neurological disorders such as Alzheimer's (AD), Parkinson's (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Preclinical studies demonstrate raloxifene's ability to reduce amyloid-β aggregation in AD, protect dopaminergic neurons in PD, mitigate demyelination in MS, and decrease protein aggregation in ALS. Additionally, raloxifene exhibits positive effects on memory, attention, and negative symptoms in schizophrenia, alongside antidepressant and anxiolytic properties. Although promising, raloxifene's clinical translation faces challenges. Existing trials are limited by small sample sizes, heterogeneous designs, and a lack of long-term data. Most studies focus on postmenopausal women, leaving gaps regarding effects in men, premenopausal women, and younger populations. Furthermore, discrepancies between preclinical and clinical dosing complicate its therapeutic optimization. Future research should explore sex-specific effects, optimize CNS-targeted dosing strategies, and employ biomarkers for neuroprotection and inflammation. Long-term trials are essential to evaluate its disease-modifying potential. Raloxifene represents a promising repurposing candidate for CNS disorders, however, its therapeutic role remains to be established through robust clinical validation.