The Roles of Neuroinflammation in l-DOPA-Induced Dyskinesia: Dissecting the Roles of NF-κB and TNF-α for Novel Pharmacological Therapeutic Approaches

Abstract

Levodopa-induced dyskinesia (LID) is a common and debilitating complication of long-term Parkinson's disease treatment. This review explores the roles of NF-κB and TNF-α signalling pathways in LID pathophysiology and potential therapeutic approaches targeting these mechanisms. Chronic levodopa treatment leads to aberrant neuroplasticity and neuroinflammation, involving activation of NF-κB and increased production of pro-inflammatory cytokines like TNF-α. NF-κB activation in glial cells contributes to sustained neuroinflammation and exacerbates dopaminergic neuron loss. TNF-α levels are elevated in brain regions affected by LID and correlate with dyskinesia severity. Several compounds are involved in mitigating LID by modulating these pathways. Agmatine reduces NF-κB activation and NMDA receptor expression while protecting dopaminergic neurons. Resveratrol and doxycycline demonstrate antidyskinetic effects by attenuating neuroinflammation and TNF-α production. The Rho-kinase (ROCK) inhibitor fasudil and cannabinoid receptor 2 (CB2) receptor agonists also show efficacy in reducing LID severity and neuroinflammation. Hydrogen gas inhalation decreases pro-inflammatory cytokine levels associated with LID. These findings highlight the complex interplay between NF-κB, TNF-α and other neurotransmitter systems in LID pathogenesis. Targeting neuroinflammation and glial activation through these pathways represents a promising strategy for developing novel LID treatments. Further research is needed to fully elucidate the mechanisms and optimize therapeutic approaches targeting NF-κB and TNF-α signalling in LID.