Toll-like receptor signaling in Parkinson's disease: Focusing on TLR2 and TLR4 as therapeutic targets for natural compounds.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and the accumulation of α-synuclein-containing Lewy bodies. Growing evidence indicates that neuroinflammation, particularly through the activation of Toll-like receptors (TLRs), contributes significantly to PD pathogenesis. TLRs, particularly TLR2 and TLR4, detect endogenous damage-associated molecular patterns such as misfolded α-synuclein. This recognition initiates signaling pathways that drive microglial activation, pro-inflammatory cytokine release, and oxidative stress, ultimately leading to neuronal injury. This review synthesizes current insights into TLR involvement in PD, highlighting their roles in linking innate and adaptive immune responses, regulating neuroinflammatory cascades, and mediating interactions across the gut-brain axis. Furthermore, we examine the therapeutic potential of plant-derived bioactive compounds-including flavonoids, terpenoids, polyphenols, alkaloids, and lignans-as natural TLR modulators. These phytochemicals have demonstrated neuroprotective effects in preclinical studies by attenuating TLR-mediated inflammatory responses, reducing oxidative stress, and improving motor and cognitive outcomes. Challenges such as target specificity, bioavailability, and translational applicability are also discussed, along with future directions for advancing TLR-focused phytochemical therapies. This review provides a theoretical and mechanistic framework supporting natural TLR modulators as promising disease-modifying strategies in PD.