ORIGINAL PAPER SCH58261 the Selective Adenosine A 2A Receptor Blocker Modulates Ischemia Reperfusion Injury Following Bilateral Carotid Occlusion: Role of Inflammatory Mediators R. A. Mohamed • A. M. Agha • N. N. Nassar Received: 22 June 2011 / Revised: 18 October 2011 / Accepted: 28 October 2011 / Published online: 10 November 2011 Ó Springer Science+Business Media, LLC 2011 Abstract In the present study, the effects of SCH58261, a selective adenosine A 2A receptor antagonist that crosses the blood brain barrier (BBB) and 8-(4-sulfophenyl) theophyl- line (8-SPT), a non-selective adenosine receptor antagonist that acts peripherally, were investigated on cerebral ische- mia reperfusion injury (IR). Male Wistar rats (200 - 250 g) were divided into four groups: (1) sham-operated (SO), IR pretreated with either (2) vehicle (DMSO); (3) SCH58261 (0.01 mg/kg); (4) 8-SPT (2.5 mg/kg). Animals were anes- thetized and submitted to occlusion of both carotid arteries for 45 min. All treatments were administered intraperito- neally (i.p.) post carotid occlusion prior to exposure to a 24 h reperfusion period. Ischemic rats showed increased infarct size compared to their control counterparts that corroborated with histopathological changes as well as increased lactate dehydrogenase (LDH) activity in the hippocampus. Moreover, ischemic animals showed habit- uation deficit, increased anxiety and locomotor activity. IR increased hippocampal glutamate (Glu), GABA, glycine (Gly) and aspartate (ASP). SCH58261 significantly reversed these effects while 8-SPT elicited minimal change. IR raised myeloperoxidase (MPO), tumor necrosis factor- alpha (TNF-a), nitric oxide (NO), prostaglandin E 2 (PGE 2 ) accompanied by a decrease in interleukin-10 (IL-10), effects that were again reversed by SCH58261, but 8-SPT elicited less changes. Results from the present study point towards the importance of central blockade of adenosine A 2A receptor in ameliorating hippocampal damage follow- ing IR injury by halting inflammatory cascades as well as modulating excitotoxicity. Keywords Adenosine Á Ischemia reperfusion injury Á Hippocampus Á Neurotransmitters Á NO Á TNF-a Abbreviations BBB Blood brain barrier DAG Diaceyl glycerol DMSO Dimethyl sulfoxide GABA c-aminobutyric acid Glu Glutamate Glycine Gly IL-10 Interleukin10 IP3 Inositol triphosphate IR Ischemia reperfusion MPO Myeloperoxidase NO Nitric oxide PGE 2 Prostaglandin E 2 TNF-a Tumor necrosis factor-alpha 8-SPT 8-(4-Sulfophenyl) theophylline SCH58261 7-(2-phenylethyl)-5-amino-2-(2-furyl)- pyrazolo-[4,3-e]-1,2,4-triazolo[1,5- c]pyrimidine SO Sham operated Introduction Adenosine acts at four receptor subtypes, A 1 ,A 2A–B and A 3 [1], where the A 2A receptor is considered as the main ‘‘inhibitory’’ signal of the immune response in the R. A. Mohamed Á A. M. Agha Á N. N. Nassar (&) Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt e-mail: nnagah@yahoo.com; nnassar@cu.edu.eg 123 Neurochem Res (2012) 37:538–547 DOI 10.1007/s11064-011-0640-x