Characterization of new pharmacological targets is a promising approach in research of
neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as
an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established
ex vivo model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal
cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of
GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growthpromoting
effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist),
the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists
(PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase
in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17
agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced
elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling
showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of
untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion,
MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17,
highlighting GPR17 as an interesting therapeutic target in neuronal regeneration
