Anales RANF

CPL-01 Lecture in Honour Prof Geoff. Burnstock PURINERGIC MODULATION OF MYELIN, A NEW TARGET FOR NEUROREGENERATIVE THERAPIES Mariapia Abbracchio. University of Milano, Italy Oligodendrocytes (OLs), the myelin-forming cells, have emerged as new targets to implement CNS recovery not only in classical demyelinating diseases like multiple sclerosis, but also in Alzheimer’s, trauma, stroke and Amyotrophic Lateral Sclerosis. Important, clinical studies have confirmed that implementation of myelin repair does correlate with neuronal recovery, thus validating myelin protection and reconstruction as a new neuroreparative approach. Quiescent Oligodendrocyte Precursor Cells (OPCs) are present in brain’s parenchyma and spinal cord throughout life. Upon damage, OPCs proliferate and migrate to lesioned areas to start differentiating into fully mature myelin- producing cells. Unfortunately, this reaction is often insufficient to complete repair, likely due to the inflammatory local milieu that markedly blocks OPCs at immature stages. In recent years, we have shown that OPCs express various types of purinoceptors regulating their quiescence, reaction to injury and maturation. Among these receptors, the P2Y-like GPR17 receptor is needed to start OPC differentiation but, after the immature OL stage, has to be downregulated to allow cells’ terminal maturation. Here, we utilized the first in house developed fluorescent GPR17 reporter mouse for fate mapping studies to follow the final destiny of GPR17-expressing OPCs (GPR17 + cells) in different models of disease. In models characterized by high acute inflammation levels, like stroke and Experimental Autoimmune encephalomyelitis (EAE), GPR17 + cells proliferate and are attracted to demyelinating lesions, but only a small number of these cells can enter the lesion area to generate new myelin producing OLs. Conversely, in the cuprizone demyelination model, which is characterized by milder inflammation, many of the recruited GPR17 + cells do express terminal myelination markers suggesting progression to more mature phenotypes. In line with these findings, the first synthetic GPR17 selective ligand significantly retarded EAE development in vivo , supporting the validity of the GPR17-based neuroreparative approach. Supported by ERANET Neuron EC project and Italian FISM.