Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation

• DOI: 10.1038/s41419-018-0351-1
• Publication Date: 2018-02-20T16:50:20Z
• Authors: Ana P. Simões; Carla G. Silva; Joana M. Marques; Daniela Pochmann; Lisiane O. Porciú...; Sofia Ferreira; Jean P. Oses; Rui O. Beleza; Joana I. Real; Attila Köfalvi; Ben A. Bahr; Juan Lerma; Rodrigo A. Cunha; Ricardo J. Rodrigues
• Keywords: Excitotoxicity; Neurotoxicity

Abstract Despite the characteristic etiologies and phenotypes, different brain disorders rely on common pathogenic events. Glutamate-induced neurotoxicity is a event shared by disorders. Another occurring in pathological conditions increase of extracellular ATP levels, which now recognized as danger harmful signal brain, heralded ability P2 receptors (P2Rs) to affect wide range Yet, how P2R contribute neurodegeneration remains poorly defined. For that purpose, we examined contribution P2Rs glutamate-induced neurodegeneration. We found both vitro vivo ATP/ADP through activation P2Y1R contributes neuronal death rat hippocampus. cultured hippocampal neurons exposure glutamate (100 µM) for 30 min triggers sustained NMDA receptor (NMDAR)-mediated P2Y1R. also determined involved excitotoxicity blockade significantly attenuated upon systemic administration kainic acid or intrahippocampal injection quinolinic acid. This fades with increasing intensity excitotoxic conditions, indicates not contributing directly neurodegeneration, rather behaving catalyst decreasing threshold from becomes neurotoxic. Moreover, unraveled such process began an early synaptotoxicity was prevented/attenuated antagonism P2Y1R, vivo. should observed calpain-mediated axonal cytoskeleton damage, most likely favored P2Y1R-driven NMDAR-mediated Ca 2+ entry selectively axons. may constitute degenerative mechanism diseases, particularly relevant at initial stages.