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.
Subject(s)
Dopaminergic Neurons/metabolism , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Receptor, Metabotropic Glutamate 5/metabolism , Animals , Apomorphine/pharmacology , Disease Models, Animal , Male , Mice , Neurodegenerative Diseases/metabolism , Oxidopamine/pharmacologyABSTRACT
PURPOSE: To examine the effectiveness of a modified form of constraint-induced movement therapy (mCIMT) in the context of a day camp model in 6 children aged 5-9 years with spastic hemiplegic cerebral palsy. METHODS: Before, 1 week after, and 3 months after 9 consecutive days of mCIMT, participants were assessed using the Quality of Upper Extremity Skills Test (QUEST) and assessments of range of motion and grip strength. Caregiver perceptions were assessed using the Pediatric Evaluation of Disability Inventory (PEDI) and a parent questionnaire. RESULTS: Significant improvements were observed on the "grasps" and "protective extension" subsections of the QUEST after the intervention. Increased social function was also observed as measured by the PEDI. All improvements were maintained at the 3-month follow-up assessment. Analysis of individual participants yielded additional information on clinically significant improvements as a result of the mCIMT intervention. CONCLUSIONS: The day camp model of mCIMT was effective in inducing lasting and meaningful changes in the children with hemiplegic cerebral palsy.
