Abstract
Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disorder primarily caused by deficiency of the survival motor neurone (SMN) protein resulting in progressive degeneration of lower motor neurones, skeletal muscle atrophy, respiratory dysfunction, and premature mortality. Despite recent advances in treatment strategies targeting SMN gene replacement and RNA approaches, which have dramatically changed the disease landscape, significant challenges still persist such as incomplete restoration of function, restricted access, cost of treatment, and inability to halt progressive neurodegeneration. The search for safe and inexpensive adjunctive therapies that can act on several pathogenic pathways has therefore become a major area of investigation. Quercetin is a natural plant-derived flavonoid, which has been considered as a promising neuroprotective phytochemical for its potent antioxidant, anti-inflammatory, anti-apoptotic and mitochondrial protective effects. However, evidence regarding its potential therapeutic role in SMA is limited and has not been exhaustively synthesised. This review critically appraises the existing knowledge on quercetin in SMA by synthesising molecular mechanisms, pre-clinical data, pharmacological properties, formulation challenges and translational perspectives. Special emphasis is given to the modulation of oxidative stress, neuroinflammation, mitochondrial dysfunction, autophagy, apoptosis and crucial signalling pathways — including Nrf2/ARE, NF-κB, PI3K/Akt, MAPK and SIRT1 — that together contribute to motor neurone survival and disease progression. Moreover, the review highlights the major pharmaceutical problems of quercetin such as low aqueous solubility, poor oral bioavailability, rapid metabolism, and low blood-brain barrier permeability and emerging formulation strategies such as lipid-based delivery systems, polymeric nanoparticles, nanoemulsions, liposomes, and other nanocarrier platforms to enhance its therapeutic efficacy. The current evidence is critically reviewed to identify knowledge gaps, limitations of preclinical and barriers for clinical translation. Future perspectives on biomarker driven evaluation, advanced drug delivery systems, combination therapy with SMN-targeted treatments and well- designed clinical studies are also discussed. This review integrates mechanistic, pharmaceutical and translational perspectives to offer a comprehensive scientific rationale for the assessment of quercetinas a potential adjunct therapy for spinal muscular atrophy and highlights critical research needs for the future development of neuroprotective drugs.