150 | New strategies to counteract dopaminergic degeneration: in vitro and in vivo neurotrophic properties of a tetrahydro-isoquinoline derivative as a novel mGlu2/3 agonist/positive allosteric modulator

Miriana Scordino¹, Giulia Urone¹, Monica Frinchi¹, Lucia Seidita¹, Alessandra Montalbano², Marilia Barreca², Paola Barraja², Maria Valeria Raimondi², Roberta Bivacqua², Fanny Malhaire³, Cyril Goudet³, Giuseppa Mudò¹, Virginia Spanò², Valentina Di Liberto¹ | ¹Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Italy; ²Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Italy; ³IGF, Université de Montpellier, CNRS, INSERM, France.

Parkinson's Disease (PD) is a neurodegenerative disorder marked by the progressive loss of dopaminergic neurons in the nigrostriatal circuit. Currently, available pharmacological treatments offer only symptomatic relief with adverse effects. Within this framework, indirect evidence has indicated that activating metabotropic Glutamate Receptor 3 (mGlu3) may exert neuroprotective effects in animal models of PD, but selective agonists for this receptor were lacking until now. Recently, a groundbreaking development has emerged in the form of a new Agonist/Positive Allosteric Modulator (Ago/PAM) that, although showing equal affinity for mGlu2 and mGlu3, displays greater efficacy at mGlu3 receptors in recombinant cells. Our study shows for the first time that the novel mGlu2/3 Ago/PAM protects the human neuroblastoma cell line SH-SY5Y against cell death induced by exposure to the dopaminergic toxin 6-hydroxydopamine (6-OHDA) through the modulation of key signaling pathways, such as mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K)-AKT pathways. Moreover, in vivo experiments revealed that administration of the original mGlu2/3 Ago/PAM upregulates the expression of crucial neurotrophins, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), while influencing MAPK/ERK and PI3K-AKT cascades in the brain of healthy mice. Finally, our results provide new insights into mGlu3 specific function and suggest the therapeutic potential of the new mGlu2/3 Ago/PAM in the management of PD.