Doxycycline Therapeutic Approach in Parkinsons Disease and L-DOPA-Induced Dyskinesia

DEL-BEL E.; BORTOLANZA, MARIZA; NASCIMENTO, GLAUCE C.; RAISMAN-VOZARI, RITA; DOS-SANTOS-PEREIRA, MAURICIO; GONZÁLEZ-LIZÁRRAGA, FLORENCIA; PARRALES V.; MICHEL, P.; PLOPER, DIEGO; AVILA C.; SOCIAS SB.; OUTEIRO T; CHEHIN R

Handbook of Neurotoxicity

Springer

Año: 2021; p. 1 - 900

Parkinson?s disease is a chronic neurodegenerative disorder associated with the lossof dopamine neurons in the substantia nigra, for which there is still no effectiveprotective treatment. Dyskinesia, or abnormal involuntary movements, is an unfortunateconsequence of long-term therapy with L-3,4-dihydroxyphenylalanine(L-DOPA), a gold standard treatment for Parkinson?s disease. Haplessly, the diseasecontinues to progress with aggravation of symptoms and debilitating long-term sideeffects. The contribution of this work was the discovery that the brain of L-DOPAtreateddyskinetic animals exhibited an increased striatal expression ofneuroinflammatory cellular constituents enrolled in the generation/maintenance ofdyskinesia. 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 affectL-DOPA?s action. L-DOPA-treated dyskinetic animals exhibited an increased striatalexpression of glial fibrillary acidic protein in reactive astrocytes, an increased numberof CD11b-positive microglial cells with activated morphology, and a rise of cellspositive for inducible nitric oxide synthase and cyclooxygenase 2 immunoreactivity.Besides, reactive oxygen species production and increased metalloproteinases activityare involved in the dyskinesia. The dramatic effect of doxycycline in preventingdyskinesia, the glial response, and the indicators of neuroinflammation componentsin the dopamine depleted striatum points once more to an involvement ofneuroinflammation in L-DOPA-induced dyskinesia. The observations indicate thetetracycline derivatives as a therapeutic strategy for dyskinesia at least in part viapreventing inflammatory components of dyskinesia pathogenesis in Parkinson?sdisease.