Anales RANF

S13-01 ATP AS A DANGER SIGNAL IN THE BRAIN R.A. Cunha 1,2,3 1 . CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; 2 . Faculty of Medicine, University of Coimbra, Portugal; 3 . MIA-Portugal, University of Coimbra, Portugal. Brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as a danger signal in the brain. Indeed, the exposure of rat hippocampal neurons to glutamate (100 μM) for 30 min, to mimic glutamate -induced neurotoxicity present in all neurodegenerative disorders, triggered a sustained increase of the extracellular levels of ATP that started prior to neuronal degeneration; glutamate exposure triggered neuronal death 24 h later, which was fully abrogated upon removal of extracellular ATP/ADP by apyrase (5 U/mL) or upon selective pharmacological or genetic blockade of P2Y1 receptors (P2Y1R). In vivo, the blockade of P2Y1R attenuated rat hippocampal neuron death upon systemic administration of kainic acid or upon intrahippocampal injection of quinolinic acid. This glutamate-induced excitotoxic process began with an early synaptotoxicity that was also prevented/attenuated by the antagonism of P2Y1R, both in vitro and in vivo. Notably, the inhibition with α , β -methylene ADP of the extracellular catabolism of ATP into adenosine through the action of ecto-5’-nucleotidase or CD73, also abrogated the behavioral, electrophysiological and neurochemical modifications present either in a rat model of Parkinson’s disease based on the intra-striatal administration of 6- hydroxydopamine, or in a mouse model of epilepsy triggered by intra-hippocampal injection of kainate or in a mouse model of Alzheimer’s disease based on the intracerebral administration of β -amyloid peptides, these two later effects also mimicked by genetic elimination of CD73. This CD73-mediated neuroprotection was phenocopied by blocking adenosine A 2A receptors (A 2A R), in particular neuronal A 2A R, in the animal models of brain diseases. Overall, these results re-enforce the role of ATP as a danger signal in noxious brain conditions and unravel a dual ability of ATP to promote synaptotoxicity that initiates neurodegeneration: directly through P2Y1R and indirectly through A 2A R upon CD73- mediated extracellular catabolism. However, the spatio-temporal interplay between these two parallel pathways remains to be determined. Supported by Fundacion LaCaixa, FCT (POCI-01-0145-FEDER-031274) and Centro 2020 (CENTRO-01-0246-FEDER-000010).