PMID- 26642806 OWN - NLM STAT- MEDLINE DCOM- 20161013 LR - 20180815 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 314 DP - 2016 Feb 9 TI - Role of adenosine A2A receptor in cerebral ischemia reperfusion injury: Signaling to phosphorylated extracellular signal-regulated protein kinase (pERK1/2). PG - 145-59 LID - S0306-4522(15)01058-1 [pii] LID - 10.1016/j.neuroscience.2015.11.059 [doi] AB - Following brain ischemia reperfusion (IR), the dramatic increase in adenosine activates A2AR to induce further neuronal damage. Noteworthy, A2A antagonists have proven efficacious in halting IR injury, however, the detailed downstream signaling remains elusive. To this end, the present study aimed to investigate the possible involvement of phospho-extracellular signal-regulated kinase (pERK1/2) pathway in mediating protection afforded by the central A2A blockade. Male Wistar rats (250-270 g) subjected to bilateral carotid occlusion for 45 min followed by a 24-h reperfusion period showed increased infarct size corroborating histopathological damage, memory impairment and motor incoordination as well as increased locomotor activity. Those events were mitigated by the unilateral intrahippocampal administration of the selective A2A antagonist SCH58261 via a decrease in pERK1/2 downstream from diacyl glycerol (DAG) signaling. Consequent to pERK1/2 inhibition, reduced hippocampal microglial activation, glial tumor necrosis factor-alpha (TNF-alpha) and brain-derived neurotropic factor (BDNF) expression, glutamate (Glu), inducible nitric oxide synthase (iNOS) and thiobarbituric acid reactive substances (TBARS) were evident in animals receiving SCH58261. Additionally, the anti-inflammatory cytokine interleukin-10 (IL-10) increased following nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Taken all together, these events suppressed apoptotic pathways via a reduction in cytochrome c (Cyt. c) as well as caspase-3 supporting a crucial role for pERK1/2 inhibition in consequent reduction of inflammatory and excitotoxic cascades as well as correction of the redox imbalance. CI - Copyright (c) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Mohamed, R A AU - Mohamed RA AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: reham.atef@pharma.cu.edu.eg. FAU - Agha, A M AU - Agha AM AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: azzaagha@yahoo.com. FAU - Abdel-Rahman, A A AU - Abdel-Rahman AA AD - Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, NC, USA. Electronic address: abdelrahmana@ecu.edu. FAU - Nassar, N N AU - Nassar NN AD - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: noha.nassar@pharma.cu.edu.eg. LA - eng PT - Journal Article DEP - 20151128 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine) RN - 0 (Adenosine A2 Receptor Antagonists) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Flavonoids) RN - 0 (Inflammation Mediators) RN - 0 (Pyrimidines) RN - 0 (Receptor, Adenosine A2A) RN - 0 (Triazoles) RN - E0399OZS9N (Cyclic AMP) RN - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) SB - IM MH - Adenosine A2 Receptor Antagonists/administration & dosage MH - Animals MH - Apoptosis/drug effects MH - Brain Ischemia/*metabolism MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cyclic AMP/metabolism MH - Flavonoids/administration & dosage MH - Hippocampus/drug effects/pathology MH - Inflammation Mediators/metabolism MH - *MAP Kinase Signaling System MH - Male MH - Maze Learning/drug effects/physiology MH - Microglia/drug effects/metabolism MH - Motor Activity/drug effects MH - Phosphorylation MH - Pyrimidines/administration & dosage MH - Rats MH - Rats, Wistar MH - Receptor, Adenosine A2A/*metabolism MH - Reperfusion Injury/metabolism MH - Triazoles/administration & dosage OTO - NOTNLM OT - A(2A) OT - apoptosis OT - ischemia reperfusion OT - microglia OT - oxidative stress OT - pERK1/2 EDAT- 2015/12/09 06:00 MHDA- 2016/10/14 06:00 CRDT- 2015/12/09 06:00 PHST- 2015/08/11 00:00 [received] PHST- 2015/11/02 00:00 [revised] PHST- 2015/11/25 00:00 [accepted] PHST- 2015/12/09 06:00 [entrez] PHST- 2015/12/09 06:00 [pubmed] PHST- 2016/10/14 06:00 [medline] AID - S0306-4522(15)01058-1 [pii] AID - 10.1016/j.neuroscience.2015.11.059 [doi] PST - ppublish SO - Neuroscience. 2016 Feb 9;314:145-59. doi: 10.1016/j.neuroscience.2015.11.059. Epub 2015 Nov 28.