Microglial modulation and therapeutic strategies in Parkinson's disease: a systematic review of neuroinflammatory mechanisms

Abstract

Background: Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-synuclein. Beyond neuronal degeneration, neuroinflammation plays a central role in the pathophysiology of the disease. Microglia, the primary immune cells of the central nervous system, exhibit high functional plasticity, allowing them to adopt either protective or pro-inflammatory profiles. This contributes to disease progression through the activation of inflammasomes, the release of cytokines, and interactions with other glial cells. Recent studies indicate that modulating the microglial phenotype represents a potential therapeutic target to mitigate disease progression. Objective: To evaluate the influence of microglia on therapeutic approaches for Parkinson's Disease, investigating their inflammatory mechanisms and their potential as a disease-modifying target. Methods: A systematic review was conducted according to PRISMA guidelines, based on a structured analysis of clinical studies published between 2016 and 2026 in the "PubMed" and "Science Direct" databases, using the descriptors "microglia" and "Parkinson's disease." After applying filters for language (Portuguese and English), open access, and full-text availability, 3,158 articles were initially analyzed. Of these, eight met the inclusion criteria, considering methodological quality and therapeutic relevance. Results: Of the eight included studies, most demonstrated a predominance of M1 microglial polarization in Parkinson’s Disease, with increased TNF-α, IL-1β, and activation of the NLRP3 inflammasome, associated with dopaminergic degeneration and clinical progression. It was observed that the TLR4/NF-κB pathway, potentiated by Peli1, intensifies the pro-inflammatory response and sustains chronic neuroinflammation. Conversely, Nrf2 activation reduced oxidative stress, inhibited NLRP3, modulated inflammatory cytokines, and promoted M2 polarization, being associated with neuroprotection and suggesting disease-modifying therapeutic potential. Conclusion: The studies highlight the functional modulation of microglia as a potential target for therapeutic interventions, since this approach is capable of reducing inflammation and preventing or delaying neurodegeneration. Its transcriptomic heterogeneity, influenced by brain region, aging, and genetic factors, determines distinct functional profiles that may favor either neuroprotective or neurotoxic processes.