EFFECTS OF PHARMACOLOGICAL GPR17 MODULATION IN THE SOD1G93A MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease that affects upper and lower motor neurons (MNs), resulting in muscle weakness, paralysis, and respiratory failure. Among the different pathological mechanisms, degeneration of oligodendrocyte (OL) and dysfunction of OL precursor cell (OPC) differentiation and maturation program contribute to ALS. In this contest, the membrane receptor G protein-coupled receptor 17 (GPR17) is a key player in OL differentiation. GPR17 is upregulated to trigger OPC maturation and then it is downregulated to complete the process. In several papers, GPR17 was demonstrated to be upregulated after brain injury as well as in many neurological disorders, and its modulation was shown to rescue OPC myelinating properties. The role of GPR17 in amyotrophic lateral sclerosis was studied for the first time in 2020 when Bonfanti and Coll demonstrated that GPR17 expression was abnormally increased in the lumbar spinal cord of SOD1G93A mice at both pre- and late symptomatic stages of the disease. Moreover, the GPR17 level was also abnormally expressed in SOD1G93A spinal cord OPCs, thus affecting cell differentiation and maturation. Of note, montelukast (MTK), a nonselective GPR17 antagonist, successfully rescued SOD1G93A OPC properties in vitro. On this basis, the main aim of this thesis was to test in vivo the translational potential of these in vitro promising data. A first preclinical trial was performed by chronically administering SOD1G93A mice with MTK (10mg/kg/day) or vehicle (water) by oral gavage. MTK treatment did not ameliorate survival nor disease progression and oligodendroglia markers. Thus, a second preclinical trial was planned by treating SOD1G93A and WT mice with MTK (30mg/kg/day) and vehicle. The higher dose of MTK extended survival, improved disease progression, and ameliorated motor performances, only in MTK-treated SOD1G93A females respect to vehicle ones. Of note, the behavioural ameliorations were paralleled by increased number of mature OL, reduced reactivity state of astrocytes and microglia and preserved MNs in spinal cord of MTK-treated SOD1G93A female mice. These results indicate that in vivo targeting GPR17 by the antagonist MTK dose- and genderdependently improves ALS progression and highlights GPR17 as a novel promising pharmacological target.