Plant-Derived Phytochemicals as Multi-Target Neuroprotective Strategies for Huntington’s Disease: Molecular Mechanisms, Therapeutic Potential and Translational Challenges

Abstract

Huntington's disease is an inherited progressive neurodegenerative disorder that is caused by expansion of the CAG trinucleotide in the HTT gene, leading to the production of the abnormal huntingtin (mHTT) protein that accumulates and causes the death of neurons. Although numerous efforts have been made for the symptomatic treatment, and new molecular therapies emerge, a disease-modifying treatment is not yet available. The medicinal plants and their bioactive phytochemicals may be useful for HD therapy, the promising therapeutic opportunities given their multi-target activities against key pathological mechanisms implicated in HD. In this review, the molecular basis of HD pathogenesis has been summarized and the neuroprotective potential of the plant-derived compounds namely curcumin, resveratrol, epigallocatechin-3-gallate (EGCG) withanolides, ginsenosides and quercetin has been critically evaluated. These phytochemicals have antioxidant, anti-inflammatory, mitochondrial protective, anti-apoptotic and autophagy-regulating activity, which involves the regulation of pathways like Nrf2/ARE, NFκB, SIRT1/PGC-1α, AMPK/mTOR and protein clearance mechanisms. Experimental models suggest that these molecules have anti-oxidative, pro-mitocondrial, anti-neuro-inflammatory and pro-neuronal survival effects. However, poor bioavailability, limited penetration of the blood–brain barrier (BBB), variability of plant preparations and the lack of human studies are limiting the clinical translation. The therapeutic potential of plant derived compounds could be improved by future developments in the field of nanotechnology based drug delivery systems, artificial intelligence, computational drug discovery, precision medicine and standardized clinical evaluation. Medicinal phytochemicals are potential complementary candidates for multi-target approaches against HD, but need to be extensively validated in clinically relevant models and humans.