Background Huntington’s disease (HD) is caused by mutant huntingtin (mHtt) and presents increased oxidative stress biomarkers, suggesting that aberrant redox signaling is associated with HD pathogenesis. Treatment with MitoQ, a mitochondria-targeted antioxidant, was neuroprotective in other models of neurodegenerative disorders, including ALS, Parkinson’s and Alzheimer’s diseases.
Aims Evaluate the efficacy of MitoQ in rescuing HD phenotypes in vivo.
Methods MitoQ (500 µM) or vehicle were administered in drinking water to wild-type and R6/2 HD mice (that expresses mHtt exon 1) from 5 weeks. Animal welfare and weight were monitored 2x/week and behaviour assessed at 5–6 and 10–11 weeks. Animals were euthanized at 11 weeks and tissues collected for MitoQ quantification by LC-MS/MS and protein analysis by Western-Blot.
Results MitoQ was detected in brain, heart, liver and muscle. R6/2 mice differed from wild-type by presenting paw clasping, reduced body weight gain, decreased grasping strength, open-field rearings, and latency to fall from an accelerating rotarod. In the pole test, R6/2 mice required more time to descend a vertical pole than controls, and MitoQ rescued this phenotype. The R6/2 mouse cortex presented increased levels of NMDAR1 and inducible Hsp70, and decreased levels of TFAM, mGLUR2, Hsp40 and mitochondrial Hsp70. The R6/2 mouse liver presented decreased NRF2 and increased SOD2 and protein carbonyls. Treatment with MitoQ reduced NMDAR1 levels in the R6/2 mouse cortex. Conclusions: These results in the accelerated HD R6/2 mouse model suggest that MitoQ has some protective potential (fine motor tasks – pole test), possibly by attenuating excitotoxicity (NMDAR1). Further studies with a slower, more progressive HD model, expressing full-length mHtt, should help clarify the protective potential of MitoQ. Acknowledgements: FCT: P2020-PTDC/NEU-NMC/0412/2014; POCI-01-0145-FEDER-016577; 3599-PPCDT; UID/QUI/50006/2013; SFRH/BPD/102259/2014.
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