Purinergic system: involvement in brain injury and repair

Stroke is one of the main cause of death and adult disability in the world, but up to now only limited therapeutically strategies exist. In the last years several studies have been conducted to individuate new potential targets, but none of the trials of drugs can be recommended for use in the regular therapy of cerebral ischemia. In the central nervous system the metabolic stress related to hypoxia, ischemia and trauma elicits large increase in the concentration of nucleotides and adenosine, which has an important role in controlling subsequent tissue damage. In this work two therapeutic strategies for ischemic brain damage involving the purinergic system have been proposed. Considering the dangerous role of the activation of A3 adenosine receptor in ischemic damage, three classes of heterocyclic ligands were tested at human adenosine receptor subtypes and the best combination of substituentes was found to individuate the most affine and selective antagonists at human A3 adenosine receptor. The most interesting compound from the Pyrido[2,3-e]-1,2,4-triazolo[4,3-a]pyrazin-1-one derivatives was also tested in a rat in vitro model of cerebral ischemia showing an attractive effect on preventing the failure of synaptic activity induced by oxygen glucose deprivation. An emerging approach to treat the ischemic brain damage is the self brain repair. Given the difficulty to use exogenous stem cells for neuronal restoration, the best strategy could be to induce the self brain repair of damage acting on the activation of neural precursor or potentiating the action of neurotrophic factors. Nucleotides and leukotrienes are to unrelated class of ligands that are both released after a neuronal damage, and several studies have been carried out about the involvement of nucleotides as trophic agents in neuronal survival and neurotigenesis in regenerative conditions. In this work it has been demonstrated that uracil-sugar nucleotides and leukotrienes can improve the action of the nerve growth factors in a cell model of neuronal differentiation (PC12 cells) and so behave as neurotrophic agents. It has been suggested a possible mechanism of these effects, through the activation of the new P2Y- like receptor GPR17 which is a dualistic receptor activated by both uracil nucleotides and cysteinyl leukotrienes.