EFFECTS OF THEOPHYLLINE AND CYCLOHEXYLADENOSINE ON BRAIN INJURY FOLLOWING NORMOGLYCEMIC AND HYPERGLYCEMIC ISCHEMIA - A HISTOPATHOLOGIC STUDY IN THE RAT

The present study was designed to determine the effects of theophyllin e, an adenosine receptor antagonist, and cyclohexyladenosine (CHA), an adenosine receptor agonist, on ischemic brain injury following normo- and hyperglycemic ischemia and reperfusion in fasted male Wistar rats . Moderate hyperglycemia was achieved by administering 17% D-glucose ( 3 g/kg i.p.), whereas normoglycemic animals received an equal volume o f saline. The animals were further divided into two groups: One group was pretreated with either theophylline (0.20 mu mol/g i.p.) or an equ al volume of saline; the second group received either intraventricular CHA (6.25 nmol) or mock CSF prior to the onset of ischemia. During is chemia, pericranial temperature was maintained at 36 degrees C and EEG was monitored. Cerebral ischemia was induced for 15 min, after which flow was restored and the animals were allowed to recover completely. There were no significant differences in physiologic parameters among the groups studied. Five days following the ischemic episode, the rats were perfused with formalin and the brains subserially sectioned (8 m u m) in the coronal plane and stained with celestine blue/acid fuchsin . Histopathologic analysis was performed in a blinded fashion to deter mine percentage of dead neurons. Hyperglycemic animals had significant ly greater ischemic injury in CA(1) cortex, and caudate than the normo glycemic group (p < 0.01). Moreover, rats pretreated with theophylline had a significantly (p < 0.01) higher percentage of dead neurons in C A(1) cortex, and caudate than corresponding controls. On the other han d, rats treated with CHA exhibited significantly (p < 0.01) less cereb ral ischemic injury than corresponding controls, in either normo- or h yperglycemic conditions. These data confirm previous studies showing t he deleterious effects of hyperglycemia on cerebral ischemia-reperfusi on injury. Moreover, our results illustrate a protective effect of ade nosine on both normo- and hyperglycemic ischemia-reperfusion injury an d thus support the hypothesis that attenuated cerebral ischemic produc tion of adenosine contributes to increased tissue injury observed unde r hyperglycemic conditions.