title: Cortical spreading depression releases ATP into the extracellular space and purinergic receptor activation contributes to the induction of ischemic tolerance.
abstract: Cortical Spreading Depression (CSD) is a well-studied model of preconditioning that provides a high degree of tolerance to a subsequent ischemic event in the brain. The present study was undertaken in order to determine whether the release of ATP during CSD could contribute to the induction of ischemic tolerance. Direct measurement of ATP levels during CSD indicates that with each CSD wave ATP is released into the extracellular space at levels exceeding 100 microM. Cultures of rat primary cortical neurons exposed to low levels of extracellular ATP developed tolerance to subsequent oxygen-glucose deprivation (OGD) or metabolic hypoxia. The preconditioning effect requires new protein synthesis and develops with time, suggesting that a complex genomic response is required for the induction of tolerance. Multiple purinergic receptors are involved in mediating tolerance, with P2Y receptor activation having the greatest effect. Although extracellular adenosine or glutamate may make a small contribution, most of the tolerance was found to be induced independently of adenosine or glutamate receptor activation. Multiple signal transduction pathways mediate the response to extracellular ATP with the protein kinase A pathway and activation of phospholipase C contributing the most. The results are consistent with the proposal that CSD releases ATP into the extracellular space and the subsequent activation of P2Y receptors makes a major contribution to the induction of ischemic tolerance in the brain.
authors: Department of Cellular and Molecular Medicine, University of Ottawa, ON, Canada K1H 8M5.
authors: Sarah C
authors: SC
authors: Schock
authors: Nzau
authors: N
authors: Munyao
authors: Yury
authors: Y
authors: Yakubchyk
authors: Luc A
authors: LA
authors: Sabourin
authors: Antoine M
authors: AM
authors: Hakim
authors: Enrique C G
authors: EC
authors: Ventureyra
authors: Charlie S
authors: CS
authors: Thompson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D013181:Cortical Spreading Depression; D003485:Cyanates / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000172:deficiency; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D019194:Ischemic Preconditioning; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011983:Receptors, Purinergic / Q000378:metabolism*; D013997:Time Factors
chemical_list: D003485:Cyanates; D004791:Enzyme Inhibitors; D011983:Receptors, Purinergic; D000255:Adenosine Triphosphate; C024835:potassium cyanate; D005947:Glucose