Abstract
Ibudilast, phosphodiesterase-4 inhibitor, is widely used in Japan for treating dizziness in the chronic stage of cerebral infarction. We investigated that neuroprotective effects of ibudilast on ischemic injury following permanent focal cerebral ischemia in the rat. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). An oral suspension of ibudilast (30 mg/kg/day) or vehicle was given for 7 days before ischemia. Magnetic resonance imaging of cerebral blood flow (CBF) was measured 30 minutes and 24 hours after ischemia. Infarct volume, brain edema, neurological outcome, and immunohistological assessments were performed 24 hours after ischemia. Although, there were no differences in the area of decreased CBF 30 minutes after ischemia between vehicle-treated and ibudilast-treated groups, ibudilast treatment significantly reduced the area of decreased CBF, infarct volume, and brain edema 24 hours after ischemia. Ibudilast treatment significantly improved neurological deficit scores accompanied by decreasing lipid peroxidation, oxidative DNA damage, microglial activation, expression of tumor necrosis factor-alpha in the cortical ischemic boundary area compared with the vehicle. Our findings suggest that pre-ischemic oral administration of ibudilast may ameliorate the extent of post-ischemic brain damage and neurological deficits by increasing the CBF and inhibiting oxidative stress and inflammation. Since ibudilast is a well-established drug for a long-term clinical therapy, it may be promising as a candidate therapy for human stroke.
