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

Abstract

Despite the characteristic etiologies and phenotypes, different brain disorders rely on common pathogenic events. Glutamate-induced neurotoxicity is a pathogenic event shared by different brain disorders. Another event occurring in different brain pathological conditions is the increase of the extracellular ATP levels, which is now recognized as a danger and harmful signal in the brain, as heralded by the ability of P2 receptors (P2Rs) to affect a wide range of brain disorders. Yet, how ATP and P2R contribute to neurodegeneration remains poorly defined. For that purpose, we now examined the contribution of extracellular ATP and P2Rs to glutamate-induced neurodegeneration. We found both in vitro and in vivo that ATP/ADP through the activation of P2Y1R contributes to glutamate-induced neuronal death in the rat hippocampus. We found in cultured rat hippocampal neurons that the exposure to glutamate (100 µM) for 30 min triggers a sustained increase of extracellular ATP levels, which contributes to NMDA receptor (NMDAR)-mediated hippocampal neuronal death through the activation of P2Y1R. We also determined that P2Y1R is involved in excitotoxicity in vivo as the blockade of P2Y1R significantly attenuated rat hippocampal neuronal death upon the systemic administration of kainic acid or upon the intrahippocampal injection of quinolinic acid. This contribution of P2Y1R fades with increasing intensity of excitotoxic conditions, which indicates that P2Y1R is not contributing directly to neurodegeneration, rather behaving as a catalyst decreasing the threshold from which glutamate becomes neurotoxic. Moreover, we unraveled that such excitotoxicity process began with an early synaptotoxicity that was also prevented/attenuated by the antagonism of P2Y1R, both in vitro and in vivo. This should rely on the observed glutamate-induced calpain-mediated axonal cytoskeleton damage, most likely favored by a P2Y1R-driven increase of NMDAR-mediated Ca2+ entry selectively in axons. This may constitute a degenerative mechanism shared by different brain diseases, particularly relevant at initial pathogenic stages.

Update of P2Y receptor pharmacology: IUPHAR Review 27

“…Some P2Y receptors ‐ P2Y 1 , P2Y 2 , and P2Y 4 ‐ appear to be up‐regulated in pathological conditions such as brain injury, Alzheimer's disease, and epilepsy (Franke et al, 2012). P2Y 1 receptor antagonism is associated with cerebroprotection and might improve cognition in Alzheimer's disease (Reichenbach et al, 2018) and glutamate mediated hippocampal neurodegeneration (Simões et al, 2018). P2Y 1 receptors could also be novel candidates for the treatment of epilepsy (Alves et al, 2019).…”

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…Such [Ca 2+ ] i increase results in the activation of protein kinases and other downstream Ca 2+ -dependent enzymes that destroy important molecules and disintegrate the cell membrane, causing further Ca 2+ influx to the cells, release of free radicals from damaged mitochondria, and subsequent cell death (Chan, 2001;Kumagai et al, 2019; Figure 2). Additionally, after glutamate exposure, the concentration of the neurotransmitter ATP in the ECS increases, aggravating the NMDA receptor-mediated cell death (Simões et al, 2018). However, ATP also acts as a modulator, since glutamate released during neuronal activity can activate non-NMDA receptors on astrocytes, which triggers the release of ATP (Zhang et al, 2003).…”

Context-Specific Switch from Anti- to Pro-epileptogenic Function of the P2Y1 Receptor in Experimental Epilepsy

“…Recent studies, however, suggest a prominent role for P2Y receptors in ictogenesis and possibly epileptogenesis (Alves et al, 2017). Among the P2Y receptor family, P2Y 1 has received most attention as a potential drug target for epilepsy (Alves et al, 2017;Simões et al, 2018;Nikolic et al, 2018).…”