Treadmill Exercise Attenuates l-DOPA-Induced Dyskinesia and Increases Striatal Levels of Glial Cell-Derived Neurotrophic Factor (GDNF) in Hemiparkinsonian Mice
- 199 Downloads
Exercise can act as a disease-modifying agent in Parkinson’s disease (PD), and we have previously demonstrated that voluntary exercise in running wheels during 2 weeks normalizes striatopallidal dopaminergic signaling and prevents the development of l-DOPA-induced dyskinesia (LID) in C57BL/6 mice. We now tested whether LID in Swiss albino mice could be attenuated by treadmill-controlled exercise alone or in combination with the reference antidyskinetic drug amantadine. The daily intraperitoneal (i.p.) treatment with three different doses of l-DOPA/benserazide (30/12.5, 50/25, or 70/35 mg/kg) during 3 weeks induced increasing levels of LID scores in hemiparkinsonian Swiss albino mice previously lesioned with a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA, 10 μg). Then, we addressed the antidyskinetic effects of treadmill-controlled exercise by comparing LID, induced by l-DOPA/benserazide (50/25 mg/kg, i.p.) during 4 weeks, in sedentary and daily exercised mice. Exercise reduced LID and improved motor skills of dyskinetic mice, as indicated by decreased contralateral bias, increase in maximal load test, and latency to fall in rotarod. The antidyskinetic effect of amantadine (60 mg/kg, i.p.) was only observed in sedentary mice, indicating the absence of synergistic antidyskinetic effect of the combination of treadmill exercise plus amantadine. Finally, Western blot analysis unraveled an ability of exercise to increase the striatal immunocontent of glial cell-derived neurotrophic factor (GDNF), apart from normalizing striatal levels of tyrosine hydroxylase. These findings show that controlled treadmill exercise attenuates LID and provide the first indication that the antidyskinetic effects of treadmill exercise may involve increased striatal GDNF levels.
KeywordsExercise Treadmill Dyskinesia l-DOPA GDNF Parkinson’s disease 6-OHDA
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Universal 408676/2016-7), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-FCT), Programa de Apoio aos Núcleos de Excelência (PRONEX-Project NENASC), and Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC). MS received scholarships from CNPq, and AES received scholarship from FAPESC/CAPES. ASA and RDP are supported by research fellowships from CNPq.
Compliance with Ethical Standards
All experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of UFSC (protocol PP00357).
Conflict of Interest
The authors declare that they have no conflict of interest.
- 6.Toy WA, Petzinger GM, Leyshon BJ, Akopian GK, Walsh JP, Hoffman MV, Vučković MG, Jakowec MW (2014) Treadmill exercise reverses dendritic spine loss in direct and indirect striatal medium spiny neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. Neurobiol Dis 63:201–209CrossRefGoogle Scholar
- 13.da Conceição FSL, Ngo-Abdalla S, Houzel J-C, Rehen SK (2010) Murine model for Parkinson’s disease: from 6-OH dopamine lesion to behavioral test. J Vis Exp 35:1376Google Scholar
- 14.Nishimura F, Yoshikawa M, Kanda S, Nonaka M, Yokota H, Shiroi A, Nakase H, Hirabayashi H et al (2003) Potential use of embryonic stem cells for the treatment of mouse parkinsonian models: improved behavior by transplantation of in vitro differentiated dopaminergic neurons from embryonic stem cells. Stem Cells 21:171–180CrossRefGoogle Scholar
- 21.Frazzitta G, Morelli M, Bertotti G et al (2012) Intensive rehabilitation treatment in parkinsonian patients with dyskinesias: a preliminary study with 6-month followup. Parkinsons Dis 2012:4–7Google Scholar
- 25.Petzinger GM, Walsh JP, Akopian G, Hogg E, Abernathy A, Arevalo P, Turnquist P, Vuckovic M et al (2007) Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J Neurosci 27:5291–5300CrossRefGoogle Scholar