Background and Purpose-Minocycline, a semisynthetic tetracycline antibiotic, has been reported to ameliorate brain injury and inhibit microglial activation after focal cerebral ischemia. However, the cerebroprotective mechanism of minocycline remains unclear. In the present study, we investigated that mechanism of minocycline in a murine model of 4-hour middle cerebral artery (MCA) occlusion. Methods-One day after 4-hour MCA occlusion, minocycline was administered intraperitoneally for 14 days. Neurologic scores were measured 1, 7, and 14 days after cerebral ischemia. Motor coordination was evaluated at 14 days by the rota-rod test at 10 rpm. Activated microglia and high-mobility group box1 (HMGB1), a cytokine-like mediator, were also evaluated by immunostaining and Western blotting. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling immunostaining was carried out 14 days after cerebral ischemia. Results-Repeated treatment with minocycline (1, 5, and 10 mg/kg) for 14 days improved neurologic score, motor coordination on the rota-rod test, and survival in a dose-dependent manner. Minocycline decreased the expression of Iba1, a marker of activated microglia, as assessed by both immunostaining and Western blotting. Moreover, minocycline decreased the activation of microglia expressing HMGB1 within the brain and also decreased both brain and plasma HMGB1 levels. Additionally, minocycline significantly decreased the number of terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling-positive cells and prevented ischemic brain atrophy 14 days after cerebral ischemia. Conclusions-Our

We examined the neuroprotective mechanism of cannabidiol, non-psychoactive component of marijuana, on the infarction in a 4 h mouse middle cerebral artery (MCA) occlusion model in comparison with D 9 -tetrahydrocannabinol (D 9 -THC). Release of glutamate in the cortex was measured at 2 h after MCA occlusion. Myeloperoxidase (MPO) and cerebral blood flow were measured at 1 h after reperfusion. In addition, infarct size and MPO were determined at 24 and 72 h after MCA occlusion. The neuroprotective effect of cannabidiol was not inhibited by either SR141716 or AM630. Both pre-and postischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection, whereas only pre-ischemic treatment with D 9 -THC reduced the infarction. Unlike D 9 -THC, cannabidiol did not affect the excess release of glutamate in the cortex after occlusion. Cannabidiol suppressed the decrease in cerebral blood flow by the failure of cerebral microcirculation after reperfusion and inhibited MPO activity in neutrophils. Furthermore, the number of MPO-immunopositive cells was reduced in the ipsilateral hemisphere in cannabidioltreated group. Cannbidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB 1 receptorindependent mechanism, suggesting that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders. Keywords: cannabidiol, cannabinoid, cerebral blood flow, cerebral ischemia, glutamate, myeloperoxidase. Cannabis contains about 60 different cannabinoids, including the psychoactive component D 9 -tetrahydrocannabinol (D 9 -THC) and other major non-psychoactive components such as cannabidiol, cannabinol, and cannabigerol. D 9 -THC has been demonstrated to produce hypothermia, neuroprotection, and tolerance (Hampson et al. 2000;Rubino et al. 2000;Wiley and Martin 2002;Braida et al. 2003;Leker et al. 2003;Hayakawa et al. 2004;Mishima et al. 2005). These effects are, at least in part, related to binding to the CB 1 receptor. On the other hand, cannabidiol has a very low affinity (in the micromolar range) for CB 1 and CB 2 receptors and has been found to act as an anticonvulsant in animal models of epilepsy and in humans with epilepsy. Moreover, cannabidiol has been shown to have antispasmodic, anxiolytic, anti-nausea, and anti-rheumatoid properties

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Cilostazol, an antiplatelet drug, and probucol, a cholesterol-lowering drug, are reported to ameliorate atherosclerosis in animal models. However, their combined effect on atherosclerosis is unclear. We therefore evaluated their combined effect on atherosclerotic lesions in LDL receptor-deficient mice. Male LDL receptor-deficient mice were fed a high fat diet with or without cilostazol alone, probucol alone, or with cilostazol and probucol in combination, for 8 weeks. Body weight and plasma lipid levels were measured before and during treatment. At the end of treatment, the size distribution of plasma lipoproteins was analyzed by HPLC and then plasma HDL cholesterol levels and en face aortic atherosclerotic lesion areas were measured. Probucol alone significantly decreased both total cholesterol and HDL cholesterol, while cilostazol alone did not decrease total cholesterol, but significantly increased HDL cholesterol. Both cilostazol alone and probucol alone significantly decreased atherosclerotic lesion areas, and their combined administration showed more significant decreases than when each drug was administered singly. The combination of cilostazol and probucol was more effective in preventing atherosclerotic lesion formation than the administration of each drug alone; this may provide us with a new strategy for treating atherosclerosis.

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