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Doxycycline attenuates l -DOPA-induced dyskinesia through an anti-inflammatory effect in a hemiparkinsonian mouse model

Affiliation
Department of Basic and Oral Biology ,FORP ,Campus USP ,University of São Paulo ,Ribeirão Preto ,Brazil
dos Santos Pereira, Maurício;
Affiliation
Department of Basic and Oral Biology ,FORP ,Campus USP ,University of São Paulo ,Ribeirão Preto ,Brazil
Nascimento, Glauce Crivelaro do;
Affiliation
Department of Basic and Oral Biology ,FORP ,Campus USP ,University of São Paulo ,Ribeirão Preto ,Brazil
Bortolanza, Mariza;
Affiliation
Sorbonne Université ,Paris Brain Institute-ICM ,Inserm ,CNRS ,APHP ,Hôpital de La Pitié Salpêtrière ,Paris ,France
Michel, Patrick Pierre;
Affiliation
Sorbonne Université ,Paris Brain Institute-ICM ,Inserm ,CNRS ,APHP ,Hôpital de La Pitié Salpêtrière ,Paris ,France
Raisman-Vozari, Rita;
Affiliation
Department of Basic and Oral Biology ,FORP ,Campus USP ,University of São Paulo ,Ribeirão Preto ,Brazil
Del Bel, Elaine

The pharmacological manipulation of neuroinflammation appears to be a promising strategy to alleviate l -DOPA-induced dyskinesia (LID) in Parkinson’s disease (PD). Doxycycline (Doxy), a semisynthetic brain-penetrant tetracycline antibiotic having interesting anti-inflammatory properties, we addressed the possibility that this compound could resolve LID in l -DOPA-treated C57BL/6 mice presenting either moderate or intermediate lesions of the mesostriatal dopaminergic pathway generated by intrastriatal injections of 6-OHDA. Doxy, when given subcutaneously before l -DOPA at doses of 20 mg kg −1 and 40 mg kg −1 , led to significant LID reduction in mice with moderate and intermediate dopaminergic lesions, respectively. Importantly, Doxy did not reduce locomotor activity improved by l -DOPA. To address the molecular mechanism of Doxy, we sacrificed mice with mild lesions 1) to perform the immunodetection of tyrosine hydroxylase (TH) and Fos-B and 2) to evaluate a panel of inflammation markers in the striatum, such as cyclooxygenase-2 and its downstream product Prostaglandin E2 along with the cytokines TNF-α, IL-1β and IL-6. TH-immunodetection revealed that vehicle and Doxy-treated mice had similar striatal lesions, excluding that LID improvement by Doxy could result from neurorestorative effects. Importantly, LID inhibition by Doxy was associated with decreased Fos-B and COX-2 expression and reduced levels of PGE 2 , TNF-α, and IL-1β in the dorsolateral striatum of dyskinetic mice. We conclude 1) that Doxy has the potential to prevent LID regardless of the intensity of dopaminergic lesioning and 2) that the anti-inflammatory effects of Doxy probably account for LID attenuation. Overall, the present results further indicate that Doxy might represent an attractive and alternative treatment for LID in PD.

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License Holder: Copyright © 2022 dos Santos Pereira, Nascimento, Bortolanza, Michel, Raisman-Vozari and Del Bel.

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