Abstract
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 growth-promoting 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.
Highlights
To elucidate if modulation of the G protein-coupled receptor 17 (GPR17) has any effects on neurite outgrowth in ororganotypic dopaminergic co-cultures the well-established neurite fibre quantification ganotypic dopaminergic the well-established fibre quantification method in our lab was usedco-cultures
The obtained data in the dopaminergic organotypic slice co-cultures indicate that (i) MTK, a non-selective GPR17 antagonist, can promote neurite outgrowth with effects comparable to those induced by the well-known neurotrophic factor glial cell line-derived neurotrophic factor (GDNF), (ii) treatment with MTK increases mRNAexpression of genes relevant to neuronal growth, (iii) a clear expression of GPR17 on NG2glia and in some NeuN-positive neurons, (iv) a time-dependent expression of GPR17 in untreated organotypic dopaminergic co-cultures
These results could be of special interest to patients with traumatic brain injury (TBI) and other neurological disorders, suggesting that MTK possibly attenuates damage, and promotes neuroregeneration and repair
Summary
The number of patients dying from and affected by neurological disorders has increased substantially between 1990 and 2015 [1]. Incidence and prevalence of traumatic brain injury (TBI) increased from 1990 to 2016 [2], as well as the prevalence of Parkinson’s disease [3] and dementia [4]. These disorders are the biggest health challenges of the century, posing a serious threat to social and healthcare systems as well as to the future of the global economy [5]. New strategies of treatments are pivotal to minimize patients’ disabilities promoting better life quality and to reduce costs for society
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