title: ATP P2Y1 receptors control cognitive deficits and neurotoxicity but not glial modifications induced by brain ischemia in mice.
abstract: ATP is a pleiotropic cell-to-cell signaling molecule in the brain that functions through activation of the P2 receptors (P2R), encompassing ionotropic P2XR or metabotropic P2YR. Noxious brain insults increase the extracellular levels of ATP and previous studies have implicated different P2R, namely P2Y1R, in the control of ischemic brain damage, but it remains to be defined if P2Y1R antagonists also alleviate the behavioral impairments associated with brain ischemia. Furthermore, as P2Y1R can control neuronal and glial functions, we explored if P2Y1R antagonist-mediated protection would mainly involve neuronal and/or glial processes. Adult male mice subject to permanent middle cerebral artery occlusion (pMCAO) displayed an infarcted cortical area (2,3,5-triphenyltetrazolium chloride staining), decreased neurological score with decreased working and reference memory performance (Y-maze, object recognition and aversive memory), accompanied by neuronal damage (FluoroJade C), astrogliosis (glial fibrillary acidic protein) and microgliosis (CD11b). All of these changes were attenuated by intracerebroventricular pre-treatment (10 min before pMCAO) with the generic P2R antagonist 4-[(E)-{4-formyl-5-hydroxy-6-methyl-3-[(phosphono-oxy)methyl]pyridin-2-yl}diazenyl]benzene-1,3-disulfonic acid (PPADS, 0.5-1.0 nmol/μL). In contrast, the selective P2Y1R antagonist (1R*,2S*)-4-[2-Iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphono-oxy)bicycle[3.1.0] hexane-1-methanol dihydrogen phosphate ester (MRS2500, 1.0-2.0 nmol/μL) afforded equivalent behavioral benefits but only prevented neuronal damage but not astrogliosis or microgliosis upon pMCAO. These results indicated that P2Y1R-associated neuroprotection mainly occurred through neuronal mechanisms, whereas other P2R were also involved in the control of astrocytic reactivity upon brain injury.
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: Marta R S
authors.initials: MR
authors.lastname: Carmo
authors.forename: Ana Patrícia
authors.initials: AP
authors.lastname: Simões
authors.forename: Analu A
authors.initials: AA
authors.lastname: Fonteles
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Souza
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.forename: Geanne M
authors.initials: GM
authors.lastname: Andrade
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003071:Cognition; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D018782:Maze Learning; D008568:Memory; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*
chemical_list: C495475:2-iodo-N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphate; D003838:Deoxyadenine Nucleotides; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate
keywords: ATP; P2 receptor; P2Y1 receptor; astrogliosis; ischemia; neurodegeneration