Polyphenols and microglial dynamics in neurodegenerative diseases: mechanistic advances and therapeutic perspectives

Neuroinflammation plays a central role in multiple neurological and neurodegenerative disorders, including ischemic brain injury, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Microglia, the principal immune cells with in the central nervous system (CNS) are pivotal mediators of neuroinflammatory responses via their dynamic transition across a spectrum of polarization states, broadly delineated by pro-inflammatory M1-like and anti-inflammatory M2-like phenotypic profiles. A pathological skew towards pro-inflammatory microglial activation drives and exacerbates disease progression, thereby rendering the modulation of microglial polarization states a promising therapeutic target for neuroprotective intervention. Natural polyphenols have garnered increasing interest owing to their capacity to traverse the blood-brain barrier (BBB), confer neuroprotective effects, and mitigate neuroinflammation. Despite challenges in clinical translation stemming from poor bioavailability and rapid in vivo metabolism, innovative delivery systems are being developed to address these limitations. This review consolidates current evidence regarding the mechanisms by which polyphenols modulate microglial phenotypic balance and polarization states and examines advanced delivery strategies designed to enhance their therapeutic efficacy in neuroinflammatory disorders. By synthesizing these perspectives, we offer novel insights into the potential application of polyphenols in neuroprotective therapies targeting pathological neuroinflammation.