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

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.

Hematopoietic cytokines as therapeutic players in early stages Parkinson's disease.

Parkinson's disease (PD) is a devastating age related neurodegenerative disease that is believed to have a lengthy prodromal state. It is critical to find methods to harness compensatory recovery processes in order to slow or prevent the eventual progression of clinical symptoms. The current perspective paper argues that immune system signaling molecules represent such a promising therapeutic approach. Two cytokines of interest are granulocyte macrophage-colony stimulating factor (GM-CSF) and erythropoietin (EPO). These hematopoietic cytokines have been protective in models of stroke, neuronal injury, and more recently PD. It is our belief that these trophic cytokines can be used not only for cell protection but also regeneration. However, success is likely dependent on early intervention. This paper will outline our perspective on the development of novel trophic recovery treatments for PD. In particular, we present new data from our lab suggesting that EPO and GM-CSF can foster neural re-innervation in a "mild" or partial lesion PD model that could be envisioned as reflecting the early stages of the disease.