Doxycycline and its derivative, COL-3, decrease dyskinesia induced by l-DOPA in hemiparkinsonian rats

Abstract

Background and Purpose: l-DOPA-induced dyskinesia is a debilitating effect of treating Parkinson's disease with this drug. New therapeutic approaches that prevent or attenuate this side effect are needed. Experimental Approach: Wistar adult male rats submitted to 6-hydroxydopamine-induced unilateral medial forebrain bundle lesion were treated with l-DOPA (p.o. 20 mg·kg−1 or s.c. 10 mg·kg−1) once a day for 14 days. After this period, we tested if doxycycline (40 mg·kg−1, i.p.) and COL-3 (50 and 100 nmol, i.c.v.) could reverse l-DOPA-induced dyskinesia. In an additional experiment, doxycycline was administered together with l-DOPA to verify if it would prevent l-DOPA-induced dyskinesia development. Key Results: A single injection of doxycycline or COL-3 attenuated l-DOPA-induced dyskinesia. Co-treatment with doxycycline from the first day of l-DOPA suppressed the onset of dyskinesia. The improved motor response after l-DOPA was not affected by doxycycline or COL-3. Doxycycline treatment was associated with decreased immunoreactivity of FosB, COX-2, the astroglial protein GFAP and the microglial protein OX-42, which were elevated in the basal ganglia of rats exhibiting dyskinesia. Doxycycline decreased metalloproteinase-2/-9 activity, metalloproteinase-3 expression and ROS production. Metalloproteinase-2/-9 activity and production of ROS in the basal ganglia of dyskinetic rats showed a significant correlation with the intensity of dyskinesia. Conclusion and Implications: The present study demonstrates the anti-dyskinetic potential of doxycycline and its analogue compound COL-3 in hemiparkinsonian rats. Given the long-established and safe clinical use of doxycycline, this study suggests that these drugs might be tested to reduce or prevent l-DOPA-induced dyskinesia in Parkinson's patients.