title: Role of adenosine A2A receptor in cerebral ischemia reperfusion injury: Signaling to phosphorylated extracellular signal-regulated protein kinase (pERK1/2).
abstract: 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-α) 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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: reham.atef@pharma.cu.edu.eg.
authors.forename: R A
authors.initials: RA
authors.lastname: Mohamed
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: azzaagha@yahoo.com.
authors.forename: A M
authors.initials: AM
authors.lastname: Agha
authors.affiliation: Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, NC, USA. Electronic address: abdelrahmana@ecu.edu.
authors.forename: A A
authors.initials: AA
authors.lastname: Abdel-Rahman
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: noha.nassar@pharma.cu.edu.eg.
authors.forename: N N
authors.initials: NN
authors.lastname: Nassar
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005419:Flavonoids / Q000008:administration & dosage; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D010766:Phosphorylation; D011743:Pyrimidines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D019208:Brain-Derived Neurotrophic Factor; D005419:Flavonoids; D018836:Inflammation Mediators; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D000242:Cyclic AMP; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: A(2A); apoptosis; ischemia reperfusion; microglia; oxidative stress; pERK1/2