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

British Journal of Pharmacology - Tập 178 Số 13 - Trang 2595-2616 - 2021
Mariza Bortolanza1, Glauce Crivelaro Nascimento1, Rita Raisman‐Vozari2, Elaine Del‐Bel1
1Dental School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
2Paris Brain Institute, Inserm U 1127, CNRS UMR 7225 Sorbonne Université Paris France

Tóm tắt

Background and Purposel‐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 ApproachWistar 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 ResultsA 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 ImplicationsThe 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.

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British Journal of Pharmacology

Tập 178 Số 13

2595-2616

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