Characterisation of the neuroprotective effects of the new metabotropic glutamate receptor 3 positive allosteric modulator against dopaminergic degeneration in Parkinson’s disease models

Parkinson’s Disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the nigrostriatal circuit, and the development of motor and non-motor symptoms. Currently, no disease-modifying pharmacological treatments are available, and dopamine-based therapies help to mitigate symptoms but also cause side-effects. In this context, indirect evidence has suggested that activation of metabotropic Glutamate Receptor 3 (mGluR3) exerts neuroprotective effects in animal models of PD. However, the lack of selective agonists/ligands for this receptor has hindered more in-depth investigations. Recently, a new Positive Allosteric Modulator (PAM) selective for mGluR3 has been synthesized. In this study, we demonstrated through MTT assay that the novel mGluR3 PAM protects SH-SY5Y cells, a human neuroblastoma cell line, against death induced by 6-hydroxydopamine, a drug widely used to induce dopaminergic degeneration. The observed neuroprotection involves the modulation of mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K)-Akt pathways, as assessed through western blotting analysis. Furthermore, western blot assay shows that in vivo treatment with mGluR3 PAM up-regulates the expression of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), and modulates the activation of MAPK/ERK and PI3K-Akt pathways in mouse brain. Overall, though preliminary, our results suggest the therapeutic potential of the new mGluR3 PAM in the management of PD.