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mGluR5 Allosteric Modulation Promotes Neurorecovery in a 6-OHDA-Toxicant Model of Parkinson’s Disease

  • Kyle Farmer
  • Khaled S. Abd-Elrahman
  • Alexa Derksen
  • Elyn M. Rowe
  • Ashley M. Thompson
  • Christopher A. Rudyk
  • Natalie A. Prowse
  • Zachary Dwyer
  • Samantha C. Bureau
  • Teresa Fortin
  • Stephen S.G. Ferguson
  • Shawn HayleyEmail author
Article

Abstract

Parkinson’s disease is a neurodegenerative disease characterized by a loss of dopaminergic substantia nigra neurons and depletion of dopamine. To date, current therapeutic approaches focus on managing motor symptoms and trying to slow neurodegeneration, with minimal capacity to promote neurorecovery. mGluR5 plays a key role in neuroplasticity, and altered mGluR5 signaling contributes to synucleinopathy and dyskinesia in patients with Parkinson’s disease. Here, we tested whether the mGluR5-negative allosteric modulator, (2-chloro-4-[2[2,5-dimethyl-1-[4-(trifluoromethoxy) phenyl] imidazol-4-yl] ethynyl] pyridine (CTEP), would be effective in improving motor deficits and promoting neural recovery in a 6-hydroxydopamine (6-OHDA) mouse model. Lesions were induced by 6-ODHA striatal infusion, and 30 days later treatment with CTEP (2 mg/kg) or vehicle commenced for either 1 or 12 weeks. Animals were subjected to behavioral, pathological, and molecular analyses. We also assessed how long the effects of CTEP persisted, and finally, using rapamycin, determined the role of the mTOR pathway. CTEP treatment induced a duration-dependent improvement in apomorphine-induced rotation and performance on rotarod in lesioned mice. Moreover, CTEP promoted a recovery of striatal tyrosine hydroxylase-positive fibers and normalized FosB levels in lesioned mice. The beneficial effects of CTEP were paralleled by an activation of mammalian target of rapamycin (mTOR) pathway and elevated brain-derived neurotrophic factor levels in the striatum of lesioned mice. The mTOR inhibitor, rapamycin (sirolimus), abolished CTEP-induced neurorecovery and rescue of motor deficits. Our findings indicate that mTOR pathway is a useful target to promote recovery and that mGluR5 allosteric regulators may potentially be repurposed to selectively target this pathway to enhance neuroplasticity in patients with Parkinson’s disease.

Keywords

Parkinson’s disease mGluR5 Therapeutic Recovery 6-OHDA 

Notes

Acknowledgments

S.H is a Canda Research Professor in neuroscience. S.S.G.F holds a Tier I Canada Research Chair in Brain and Mind. K.S.A. is a lecturer in the department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University and holds Clinician Postdoctoral Fellowships from the Alberta Innovates Health Solutions and Canadian Institutes of Health Research. KF is now a Postdoctoral associate in the Department of Neurology, Pittsburgh Institute of Neurodegenerative Diseases, at the University of Pittsburgh.

Funding

This study was funded by a Canadian Institutes of Health Research grant (61429) to S.H. and by the Engineering Research Council of Canada.

Compliance with ethical standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1818_Fig8_ESM.png (4.3 mb)
Fig. 8

Experimental timelines. Mice initially received an intra-SNc infusion of 6-OHDA then starting on Day day 30 began to receive the CTEP. Mice were also tested for 6-OHDA OHDA-induced apomorphine rotations at this time. In Experiment 1, mice were then further behaviorally tested between Days days 110-–114 and then sacrificedkilled. Experiment 2 was the same except mice were finally tested and sacrificed killed on Day 37. Experiment 3 again uses a similar paradigm with the addition of groups that receive the mTOR antagonist, rapamyacin, beginning one day (i.e., Day 29) prior to commencement of the CTEP administration period and continuing until endpoint at Day 37. (PNG 4383 kb)

12035_2019_1818_MOESM1_ESM.tif (36 mb)
High Resolution (TIF 36859 kb)
12035_2019_1818_MOESM2_ESM.jpg (668 kb)
ESM 1 Full Full-size striatal images from Figure Fig. 5. Representative images of TH+ fibers density showing the entire striatum of mice that received (Aa) vehicle and sham treatment, (Bb) 6-OHDA treatment, (Cc) 6-OHDA plus 1 week of CTEP (2 mg/kg), (Dd) 6-OHDA plus the mTORC1 inhibitor, rapamycin (6 mg/kg), or (Ee ) 6-OHDA plus CTEP and the rapamycin treatment. (JPG 668 kb)

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Authors and Affiliations

  1. 1.Department of NeuroscienceCarleton UniversityOttawaCanada
  2. 2.University of Ottawa Brain and Mind InstituteOttawaCanada
  3. 3.Department of Cellular and Molecular MedicineUniversity of OttawaOttawaCanada

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