Cytokine associated neuroinflammation in Parkinson’s disease: Molecular pathways, therapeutic targets, and translational insights

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which neuroinflammation plays a key role. An imbalance between pro- and anti-inflammatory cytokines has been observed in both experimental models and PD patients. The inflammatory mediators activate signaling pathways that lead to oxidative stress, excitotoxicity, blood-brain barrier (BBB) disruption, gut dysbiosis, and hypothalamic-pituitary-adrenal axis (HPA-axis) dysregulation. Increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and others, following PD, stimulate both glial and peripheral immune cells to migrate to injury sites, further promoting neuroinflammation. Cytokines can directly cause neuronal damage and death through various mechanisms. These pathological changes eventually contribute to α-synuclein aggregation and the loss of dopaminergic neurons. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which promotes IL-1β maturation and caspase-1-driven neurotoxicity, has become a critical molecular hub linking innate immune activation to disease progression. Preclinical and clinical studies support that drugs targeting cytokine signaling can reduce neurotoxicity and neurodegeneration. Therapeutic agents that modulate pathways such as ephrin, cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), Hippo, Receptor-Interacting Protein Kinase 1 (RIPK1), Leucine-rich repeat kinase 2 (LRRK2), and sirtuin pathways have shown anti-inflammatory effects in PD models. Combining approaches targeting immune and cytokine pathways offers a promising strategy for neuroprotection and disease modification in PD.