Doxycycline Therapeutic Approach in Parkinson’s Disease and L-DOPA-Induced Dyskinesia

Abstract

Parkinson’s disease is a chronic neurodegenerative disorder associated with the loss of dopamine neurons in the substantia nigra, for which there is still no effective protective treatment. Dyskinesia, or abnormal involuntary movements, is an unfortunate consequence of long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), a gold standard treatment for Parkinson’s disease. Haplessly, the disease continues to progress with aggravation of symptoms and debilitating long-term side effects. The contribution of this work was the discovery that the brain of L-DOPA-treated dyskinetic animals exhibited an increased striatal expression of neuroinflammatory cellular constituents enrolled in the generation/maintenance of dyskinesia. Tetracycline antibiotic derivatives with anti-inflammatory activity, doxycycline, minocycline, and COL-3 (the former a derivative with no antibiotic activity), inhibited the development, reduced established dyskinesia, and did not affect L-DOPA’s action. L-DOPA-treated dyskinetic animals exhibited an increased striatal expression of glial fibrillary acidic protein in reactive astrocytes, an increased number of CD11b-positive microglial cells with activated morphology, and a rise of cells positive for inducible nitric oxide synthase and cyclooxygenase 2 immunoreactivity. Besides, reactive oxygen species production and increased metalloproteinases activity are involved in the dyskinesia. The dramatic effect of doxycycline in preventing dyskinesia, the glial response, and the indicators of neuroinflammation components in the dopamine depleted striatum points once more to an involvement of neuroinflammation in L-DOPA-induced dyskinesia. The observations indicate the tetracycline derivatives as a therapeutic strategy for dyskinesia at least in part via preventing inflammatory components of dyskinesia pathogenesis in Parkinson’s disease.