Persistent COX-2 upregulation in L-DOPA-induced dyskinesia is unaffected by inhibition with celecoxib

Neuroinflammation is a major contributor to L-DOPA-induced dyskinesia (LID), a common complication in Parkinson's disease (PD) therapy. Cyclooxygenase-2 (COX-2), a key proinflammatory enzyme, is elevated in the lesioned striatum of dyskinetic models, though its role as a causal factor or consequence remains unclear. This study addresses two aims: 1 - to explore COX-2 expression patterns in hemiparkinsonian dyskinetic mice with partial nigrostriatal lesion, correlating these patterns with the severity of abnormal involuntary movements (AIMs) and FosB/ΔFosB expression; 2- to evaluate the efficacy of COX-2 inhibitors in alleviating the established LID or preventing its development. In the first part, C57Bl/6 male mice had their AIMs intensity scored and were euthanized at 1, 7, 14, or 21 days after L-DOPA administration for molecular analysis. In the second part, mice with previously established LID were treated with either vehicle, the selective COX-2 inhibitor Celecoxib, or a non-selective COX inhibitor, Indomethacin for 5 days. An additional group received Celecoxib alongside L-DOPA for 21 days during LID development. COX-2 expression was associated with LID development after 14 days of L-DOPA treatment, correlating with AIMs severity and FosB/ΔFosB expression. COX-2 was found in striatal regions lacking tyrosine hydroxylase fibers and co-localized with neuronal markers. Although COX-2 inhibition did not reduce AIMs or COX-2 and FosB/ΔFosB expression, it significantly lowered PGE₂ levels, a downstream product of the COX-2 pathway. These results suggest that COX-2 upregulation may contribute to LID persistence through mechanisms beyond classical PGE₂-mediated neuroinflammation.