Molecular mechanisms underlying Parkinson's disease and role of phytochemicals, α-synuclein, sirtuins, and incretin mimetics in potential therapy.

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by dopaminergic neuronal loss in the substantia nigra and intracellular accumulation of misfolded α-synuclein aggregates. Despite being extensively studied, current pharmacological and surgical interventions remain mostly symptomatic, leaving limited efficacy in halting or reversing disease progression. The complicated pathogenesis of PD involves oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy, and proteostasis imbalance, altogether contributing to neuronal vulnerability. In addition to established drugs such as levodopa, other medications affecting dopamine pathways and incretin mimetics, numerous studies have highlighted the therapeutic potential of phytomolecules to target these processes. This includes resveratrol, curcumin, quercetin, baicalein, berberine and epigallocatechin gallate (EGCG), which have demonstrated pleiotropic neuroprotective effects by mitigating oxidative and inflammatory cascades, improving mitochondrial biogenesis, preventing proteostasis imbalance, and/or blocking α-synuclein aggregation. Some phytomolecules may also act through the sirtuin and PI3K/Akt signaling pathways, linking neuroprotection with metabolic regulation. Some phytomolecules may additionally alleviate insulin resistance and stimulate incretin (GLP-1/GIP) secretion, potentially enhancing their neuroprotective. The exact relationship between αS, sirtuins, insulin signaling and phytomolecules is not yet fully understood. Nevertheless, increasing evidence suggests that phytomolecules can modulate brain insulin resistance and enhance incretin signaling, which contribute to their neuroprotective effects in PD. This review highlights the interconnected metabolic and neuronal mechanisms in Parkinson's disease encompassing α-synuclein pathology, sirtuin imbalance, and disrupted insulin signaling role in PD and explores incretin and phytomolecules molecule based therapies, often utilized for type 2 diabetes management as complementary multi-target neuroprotective strategies.