Naringenin as a multi-target neuroprotective agent in neurodegenerative diseases

Neurodegenerative diseases (ND) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Multiple sclerosis (MS) are characterized by progressive neuronal loss driven by complex and multifactorial pathogenic mechanisms. Naringenin (NAR), a citrus-derived flavanone, has attracted considerable interest as a neuroprotective molecule due to its pleiotropic pharmacological activities such as antioxidant, anti-inflammatory and ability to modulate multiple cellular targets. This review provides a comprehensive overview of NAR pharmacokinetic profile, mechanistic actions, and therapeutic potential across major ND. We highlight how NAR's multi-target effects-including redox homeostasis maintenance, suppression of neuroinflammation, protein aggregation inhibition, and modulation of signaling pathways-contribute to neuroprotection in various experimental models of AD, PD, HD, ALS, and MS. Preclinical studies demonstrate that NAR can ameliorate cognitive and motor deficits in toxin and transgenic models of neurodegeneration, attenuate pathological hallmarks such as amyloid-beta toxicity, dopaminergic neuronal loss, and neuroinflammation, and induce cytoprotective pathways including Nrf2-mediated antioxidant response and autophagy. However, NAR's clinical translation is challenged by poor bioavailability; thus, novel delivery systems are being explored to enhance brain uptake. NAR emerges as a promising multi-functional neuroprotective agent that can simultaneously target diverse pathogenic processes in ND. Further research including advanced formulation development and well-designed clinical trials is warranted to fully establish NAR's therapeutic efficacy and safety in humans.