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The selective A2A receptor antagonist SCH 58261 protects from neurological deficit, brain damage and activation of p38 MAPK in rat focal cerebral ischemia.

Abstract
We investigated the protective effect of subchronic treatment of the A2A receptor antagonist, SCH 58261 (0.01 mg/kg, i.p.), administered 5 min, 6 h and 15 h after permanent right middle cerebral artery occlusion (MCAo). Twenty-four hours after ischemia, an extensive pallid area, evaluated by cresyl violet staining, is evident in the vascular territories supplied by the MCA, the striatum and the sensory motor cortex. The pallid area reflects the extent of necrotic neurons. Soon after waking, rats showed a definite contralateral turning behavior which was significantly reduced by SCH 58261 treatment. Twenty-four hours after MCAo, SCH 58261 significantly improved the neurological deficit and reduced ischemic damage in the striatum and cortex. Phospho-p38 mitogen-activated protein kinase (MAPK), evaluated by Western Blot, increased by 500% in the ischemic striatum 24 h after MCAo. SCH 58261 treatment significantly reduced phospho-p38 MAPK by 70%. Microglia was immunostained using the OX-42 antibody. Phospho-p38 MAPK and OX-42-immunoreactive cells are localized in the ventral striatum and frontoparietal cortex. Furthermore, both OX-42 and phospho-p38 MAPK-immunoreactive cells have overlapping morphological features, typical of reactive microglia. SCH 58261 reduced phospho-p38 MAPK immunoreactivity in the striatum and in the cortex without changing the microglial cell morphology. These results indicate that the protective effect of the adenosine antagonist SCH 58261 during ischemia is not due to reduced microglial activation but involves inhibition of phospho-p38 MAPK and suggest that treatment with the A2A antagonist from the first hour to several hours after ischemia may be a useful therapeutic approach in cerebral ischemia.
AuthorsAlessia Melani, Marco Gianfriddo, Maria Giuliana Vannucchi, Sara Cipriani, Pier Giovanni Baraldi, Maria Grazia Giovannini, Felicita Pedata
JournalBrain research (Brain Res) Vol. 1073-1074 Pg. 470-80 (Feb 16 2006) ISSN: 0006-8993 [Print] Netherlands
PMID16443200 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
  • Neuroprotective Agents
  • Pyrimidines
  • Triazoles
  • p38 Mitogen-Activated Protein Kinases
Topics
  • Analysis of Variance
  • Animals
  • Blotting, Western (methods)
  • Brain (drug effects, metabolism, pathology)
  • Brain Injuries (etiology, pathology, prevention & control)
  • Brain Ischemia (complications, drug therapy)
  • Disease Models, Animal
  • Enzyme Activation (drug effects)
  • Functional Laterality (physiology)
  • Immunohistochemistry (methods)
  • Male
  • Microscopy, Confocal (methods)
  • Motor Activity (drug effects, physiology)
  • Nervous System Diseases (etiology, prevention & control)
  • Neurologic Examination (methods)
  • Neuroprotective Agents (administration & dosage)
  • Pyrimidines (administration & dosage)
  • Rats
  • Rats, Wistar
  • Triazoles (administration & dosage)
  • p38 Mitogen-Activated Protein Kinases (metabolism)

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