Berberine's paradox in Neurodegeneration: Therapeutic promise and safety challenges in Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). α-Synuclein (α-Syn) is a key protein implicated in PD pathogenesis, with its structural and biophysical properties widely investigated due to their role in disease mechanisms. The presence of Lewy bodies and Lewy neurites, pathological hallmarks of PD primarily composed of aggregated α-Syn, further underscores its critical involvement. This correlation has led to the hypothesis that α-Syn aggregation actively contributes to PD development. Recent studies have implicated oligomers formed during the initial phases of protein aggregation as the primary neurotoxic agents driving cellular degeneration in PD. This pathological process worsens mitochondrial dysfunction, oxidative stress, and microglial activation, ultimately contributing to SNpc degeneration and PD progression. Currently, available PD medications only provide symptomatic relief and do not address underlying neuropathological mechanisms such as oxidative stress, mitochondrial impairment, α-syn aggregation, or SNpc degeneration. Moreover, long-term use of anti-PD drugs like L-DOPA can lead to motor complications and systemic side effects. As a result, repurposing traditional herbal medicines with antioxidant and anti-inflammatory properties presents a promising therapeutic approach. Studies suggest that berberine (BBR) may mitigate PD-related neuropathology. However, the exact mechanisms by which BBR exerts its neuroprotective effects remain unclear. This review explores the potential molecular pathways through which BBR could alleviate PD pathology.