Protective effect of anthocyanins in middle cerebral artery occlusion and reperfusion model of cerebral ischemia in rats
Introduction
Cerebral ischemia results from a reduction of cerebral blood flow that is caused by the occlusion of a cerebral artery. During cerebral ischemia and reperfusion, damage in the core region leads to slow cell death and growth of the infarction in the surrounding region, termed the ‘ischemic penumbra’. The multiple pathophysiological mechanisms (excitotoxicity, oxygen free-radicals, periinfarct depolarization, inflammation and apoptosis) are involved in post-ischemic neuronal progressive cell death in the penumbra (Dirnagl et al., 1999, Lipton, 1999, Mergenthaler et al., 2004).
Especially, oxidative stress is a major factor in cerebral ischemic damage because the brain consumes a large quantity of oxygen. The reactive oxygen and nitrogen species can lead to lipid peroxidation, protein oxidation, and DNA damage in brain ischemia/reperfusion injury (Warner et al., 2004). Moreover, oxidative damage due to reactive oxygen radicals has complex interactions with excitotoxicity, apoptosis, and inflammation (Andrabi et al., 2004).
Anthocyanins are natural pigments belonging to the flavonoid family and widely distributed in the human diet such as beans, fruits, vegetables, and red wine. It has been reported that anthocyanins have positive effects as a potent antioxidant. Cyanidin-3-O-glucoside (C3G), a large part of anthocyanin fractions, has protective effects as a scavenger of active oxygen species in hepatic ischemia/reperfusion model (Tsuda et al., 1999). In myocardial ischemia/reperfusion damage, C3G reduced lipid peroxidation and malondialdehyde generation (Amorini et al., 2003). Moreover, anthocyanins have been shown to reduce the level of inflammatory mediators in the inflammatory disease models (Rossi et al., 2003, Tsuda et al., 2002). These results demonstrated that anthocyanins have potent protective effects in the inflammation and oxidative stress-mediated disease models. However, the effects of anthocyanins have not yet been reported in an experimental model of cerebral ischemia. In the present study, we examined whether anthocyanins have any protective effects on focal cerebral ischemia. We also investigated the molecular mechanisms underlying neuro-protective effects of anthocyanins.
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Animals and treatment
Male Sprague–Dawley rats (250–300 g) were used in this study. The animals were kept in a storage room under the conditions of constant temperature (23 ± 3 °C), relative humidity (50 ± 10%), and illumination (12 h light/dark cycles) until the initiation of the experiment. All animals were fed with standard animal chow daily and had access to drinking water ad libitum. The animals treated with Medox-75 mg anthocyanin/capsule (300 mg/kg, p.o.; Medpalett Pharmaceuticals AS, Sandnes, Norway) twice: at
Anthocyanins reduced size of cerebral infarction
We examined whether anthocyanins could reduce size of infarct volume by using TTC staining. In the vehicle-treated group, the cerebral infarction was found on most of the cerebral cortex. The 300 mg/kg dose of anthocyanins considerably reduced the cerebral infarction size as compared with the vehicle controls, (Fig. 1A). When the relative percent of the cerebral infarction was compared between the groups, the 300 mg/kg anthocyanins-treated group (14.3 ± 2.2%) exhibited a significant reduction of
Discussion
Despite numerous therapeutic trials, stroke is still the leading cause of death in the world. It has been known that oxidative stress and inflammation are responsible for neuronal damage in ischemia. In pathological condition, such as ischemic stroke, the overproduction of superoxide and nitric oxide can trigger brain damage (Warner et al., 2004, White et al., 2000). Another major mechanism of ischemic damage is an inflammation. Further tissue and cellular damages are produced by induction of
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These authors contributed equally to this work.