Neuroinflammation plays a crucial role in the progression of age-related and chronic neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. This review examines the mechanisms of neuroinflammation by focusing on microglial and astrocyte activation, key signaling pathways such as NFκB and JAK/STAT, and metabolic disturbances that modulate inflammatory processes. Pharmacological treatments, including NSAIDs, minocycline, and statins, have demonstrated some efficacy; however, their therapeutic potential is often limited by suboptimal drug delivery to the target regions and variability in patient response. The review further highlights innovative pharmacologic strategies that modulate microglial function, moving beyond the outdated M1/M2 polarization models and embracing a more dynamic view of microglial plasticity, where activation depends on the local environment and disease context. Furthermore, state-of-the-art computational and experimental drug discovery techniques are leveraged to explore novel therapies. Additionally, natural compounds such as curcumin, resveratrol, and nootropics have shown potential in modulating neuroinflammation through diverse molecular pathways. Compounds were selected based on their demonstrated clinical relevance and ability to modulate neuroinflammation through well-defined molecular mechanisms. Excluded compounds like melatonin and cannabidiol were omitted due to limited clinical data on their efficacy and concerns about off-target effects.
Despite these promising advances, significant challenges remain, particularly in crossing the blood-brain barrier (BBB), which hinders drug bioavailability. Novel strategies, including nanoparticle-based delivery systems, receptor-mediated transcytosis, and focused ultrasound, are being explored to enhance drug bioavailability and cross the blood-brain barrier. Furthermore, the development of reliable biomarkers is essential for tracking treatment response in neurodegenerative diseases. Integrating biomarker-driven therapeutic strategies with emerging drug delivery technologies can lead to more precise, personalized treatment approaches tailored to individual patient needs. These efforts are particularly crucial, as neurodegenerative diseases are heterogeneous in their pathogenesis and progression. Future research should focus on these multidisciplinary approaches to bridge existing gaps in treatment and improve patient outcomes.