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Doxycycline, an anti-inflammatory agent, alleviates dyskinesia induced by L-DOPA in Parkinsonian rats
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  • Mariza Bortolanza,
  • Glauce Nascimento,
  • Rita Raisman-Vozari,
  • Elaine Del Bel
Mariza Bortolanza
Department of Basic and Oral Biology, Faculty of Odontology of Ribeirao Preto, University of Sao Paulo (USP), Av do Café s/n; Brazil
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Glauce Nascimento
Faculty of Odontology of Ribeirao Preto, University of Sao Paulo (USP), Av do Café s/n; Brazil; Tel: +55 16 3315 4050
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Rita Raisman-Vozari
2Sorbonne Universite, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France
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Elaine Del Bel
University of Sao Paulo Faculty of Dentistry of Ribeirao Preto
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Abstract

Background and Purpose L-DOPA induced dyskinesia is a debilitating side effect of treating Parkinson’s disease with L-DOPA. There is a need to discover a treatment that has the same benefits as L-DOPA treatment without the associated side effects. Here, we demonstrate the anti-dyskinetic potential of doxycycline and the analog compound COL-3 (without antimicrobial activity) in hemiparkinsonian rats presenting L-DOPA-induced dyskinesia. Experimental Approach Wistar adult male rats received a unilateral medial forebrain bundle injection of 6-hydroxydopamine and were then orally administered L-DOPA once a day for 14 days. This resulted in dyskinetic-like behavior. Key Results A single injection of doxycycline (intraperitoneal) or COL-3 (intracerebroventricular) together with L-DOPA attenuated the dyskinesia. Co-treatment with doxycycline from the first day of L-DOPA suppressed the onset of dyskinesia. The improved motor responses to L-DOPA remained intact in the presence of doxycycline or COL-3, indicating the preservation of the L-DOPA benefits. Doxycycline treatment was associated with decreased expression of FosB, cyclooxygenase-2, astrocytes, and microglia, which had previously been found to be elevated in the basal ganglia of rats exhibiting dyskinesia. In addition, metalloproteinase-2/-9 activity, metalloproteinase-3 expression, and production of reactive oxygen species in the basal ganglia of dyskinetic rats showed a significant positive correlation with the intensity of dyskinesia, which was decreased with the doxycycline treatment. Conclusion and Implications Given the long-established and safe use of doxycycline and the similar effect of COL-3 (without antimicrobial activity), this study indicates that both drugs should undergo testing for their ability to reduce signs of dyskinesia induced by L-DOPA in patients with Parkinson’s disease.

Peer review status:ACCEPTED

17 Jun 2020Submitted to British Journal of Pharmacology
19 Jun 2020Submission Checks Completed
19 Jun 2020Assigned to Editor
02 Jul 2020Reviewer(s) Assigned
30 Jul 2020Review(s) Completed, Editorial Evaluation Pending
31 Jul 2020Editorial Decision: Revise Minor
01 Oct 20201st Revision Received
05 Oct 2020Assigned to Editor
05 Oct 2020Submission Checks Completed
05 Oct 2020Reviewer(s) Assigned
16 Oct 2020Review(s) Completed, Editorial Evaluation Pending
29 Oct 2020Editorial Decision: Revise Minor
03 Dec 20202nd Revision Received
06 Dec 2020Submission Checks Completed
06 Dec 2020Assigned to Editor
16 Dec 2020Reviewer(s) Assigned
09 Feb 2021Review(s) Completed, Editorial Evaluation Pending
16 Feb 2021Editorial Decision: Accept