Shifting from Neurotoxic to Neuroprotective States: Exploring Therapeutic Approaches to Modulate Microglial Polarization M1/M2 in Parkinson’s Disease

Abstract

Parkinson's disease (PD) is a rapidly growing neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons and neuroinflammation, particularly mediated by microglial activation. The transition between pro-inflammatory M1 and anti-inflammatory M2 microglial phenotypes plays a crucial role in PD pathogenesis. This paper explores therapeutic strategies aimed at modulating microglial polarization, focusing on the potential of Apilarnil (API), a bee-derived compound, and Rho-associated protein kinase (ROCK) inhibitors. We examine how these therapies influence key molecular pathways, such as AKT/mTOR, NF-κB, and PPAR-γ, which regulate microglial function and contribute to neuroinflammation in PD. Studies reveal that API, through its dose-dependent effects, improves motor function, restores dopamine (DA) metabolism, reduces α-synuclein aggregation, and shifts microglial polarization towards the neuroprotective M2 phenotype. Similarly, ROCK inhibitors, such as Fasudil and Y-27632, modulate microglial activity and promote neuroprotection by targeting inflammatory pathways. These findings highlight the potential of API and ROCK inhibition as therapeutic approaches for PD, with a focus on reducing neuroinflammation and promoting neuronal survival. However, further clinical research is required to assess their safety and efficacy in human PD treatment.