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.