Huntington's disease (HD) is a genetic neurodegenerative disorder caused by CAG repeat expansion in the HTT gene, producing mutant huntingtin (mHTT) protein. This leads to neuronal damage through protein aggregation, transcriptional dysregulation, excitotoxicity, and mitochondrial dysfunction. mHTT impairs protein clearance and alters gene expression, energy metabolism, and synaptic function. Therapeutic strategies include enhancing mHTT degradation, gene silencing via antisense oligonucleotides and RNAi, promoting neuroprotection through BDNF signaling, and modulating neurotransmitters like glutamate and dopamine. Berberine, a natural isoquinoline alkaloid, has emerged as a promising therapeutic option for HD due to its multifaceted neuroprotective properties. Research indicates that berberine can mitigate the progression of neurodegenerative diseases, including HD, by targeting various molecular pathways. It exhibits antioxidant, anti-inflammatory, and autophagy-enhancing effects, which are crucial in reducing neuronal damage and apoptosis associated with HD. These properties make berberine a potential candidate for therapeutic intervention in HD, as demonstrated in both cellular and animal models. Berberine activates the PI3K/Akt pathway, which is vital for cell survival and neuroprotection. It reduces oxidative stress and neuroinflammation, both of which are implicated in HD pathology. Berberine enhances autophagic processes, promoting the degradation of mutant huntingtin protein, a key pathological feature of HD. In transgenic HD mouse models, berberine administration has been shown to alleviate motor dysfunction and prolong survival. It effectively reduces the accumulation of mutant huntingtin in cultured cells, suggesting a direct impact on the disease's molecular underpinnings. Berberine's safety profile, established through its use in treating other conditions, supports its potential for clinical trials in HD patients. Its ability to modulate neurotransmitter levels and engage multiple signaling pathways further underscores its therapeutic promise. While berberine shows significant potential as a therapeutic agent for HD, further research is necessary to fully elucidate its mechanisms and optimize its clinical application. The current evidence in the review paper, primarily from preclinical studies, provides a strong foundation for future investigations into berberine's efficacy and safety in human HD patients.
