Effects of antioxidants on the blood-brain barrier and postischemic hyperemia

The role of free oxygen radicals in blood-brain barrier (BBB) disruption and postischemic hyperemia was evaluated in the rabbit model of focal cerebral ischemia-reperfusion. Six groups of rabbits underwent clipping of the anterior cerebral, middle cerebral, and intracranial internal carotid arteries. Cerebral blood flow (CBF) was measured by using radiolabeled microspheres, before, during, and 15 minutes after 1-hour occlusion of these arteries. After 50 minutes of ischemia, Group 1 animals (control) received a placebo. Animals in Groups 2-4 received one of three drugs: catalase at 10 mg/kg, methimazole at 5 mg/kg, or indomethacin at 10 mg/kg. A fifth group received a tungsten-supplemented diet for 14 days before ischemia was induced, and a sixth group was sham operated. Microvascular integrity within the brain was determined by the presence or absence of Evan's Blue (EB)-albumin dye leakage across the BBB and was measured by microspectrofluorometry. In the control group during ischemia, CBF dropped to 14%, 7%, and 11% of preischemic levels in rostral, middle, and caudal sections of the brain, respectively, as characterized by extensive EB-albumin dye leakage through the BBB into the ischemic hemisphere. During early reperfusion, postischemic hyperemia was associated with an increase in CBF of 128%, 123%, and 129% of control in the rostral, middle, and caudal sections of the brain, respectively. In all treated groups and in the group receiving a tungsten-supplemented diet, BBB integrity was protected during reperfusion without inhibition of postischemic hyperemia. This study suggests that early disruption of the BBB to large molecules is mediated by free oxygen radicals, which inhibit rather than cause postischemic hyperemia.