Neuroprotective Effect of Morin Against Chemical‐Induced Neurotoxicities and Neurodegenerative Disease Models

Abstract

Morin (3,5,7,2′,4′‐pentahydroxyflavone) is a dietary flavonol with broad neuroprotective, anti‐inflammatory, and antioxidant actions across central and peripheral nervous system models. This synthesis consolidates evidence from in vitro and rodent studies—covering neurodegenerative proteinopathies (Alzheimer's, Parkinson's, and Huntington's), neuropathic pain, epilepsy, stress‐ and schizophrenia‐like phenotypes, and chemo‐/toxicant‐induced neurotoxicity—to evaluate morin's consistent benefits on survival, motor/cognitive performance, and biochemical normalization. Morin mitigated neurotoxicity induced by doxorubicin, ifosfamide, vincristine, acrylamide, heavy metals, and endocrine disruptors. Context‐specific effects included modulation of disease‐defining pathways (GSK3β/CDK5, mTORC1, PARP, and AMPK–ULK1–TFEB), microglial polarization, and normalization of neurotransmission (dopamine, GABA, 5‐HT, and reduced AChE). Core mechanisms included the following: restoration of redox and mitochondrial homeostasis via Nrf2/HO‐1 activation; replenishment of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH); decreased reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO); and preserved mitochondrial potential/fusion; suppression of innate immune and inflammasome signaling through downregulation of TLR4/NF‐κB and ERK–p65, reduced TNF‐α, IL‐1β/IL‐6, iNOS/COX‐2; inhibition of NLRP3/caspase‐1; and rebalancing of cell‐death programs (↓Bax/caspase‐3, ↑Bcl‐2; attenuation of RIPK1/RIPK3/MLKL‐mediated necroptosis). Formulation strategies (intranasal microemulsions, pluronic micelles, and more soluble derivatives) have enhanced brain exposure and efficacy, but translation now warrants optimized delivery, pharmacokinetic–pharmacodynamic mapping, target engagement biomarkers, and rigorously controlled trials to define dose, route, and indications as adjunctive to standard care in neurodegeneration, neuropathic pain, and toxicant‐related brain injury. Collectively, morin emerges as a multitarget neuroprotective scaffold with reproducible functional and mechanistic benefits.