Abstract
Diabetes mellitus is known to exacerbate cerebral ischemic injury. In the present study, we investigated antiapoptotic and anti-inflammatory effects of oral supplementation of ascorbic acid (AA) on cerebral injury caused by middle cerebral artery occlusion and reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. We also evaluated the effects of AA on expression of sodium-dependent vitamin C transporter 2 (SVCT2) and glucose transporter 1 (GLUT1) after MCAO/Re in the brain. The diabetic state markedly aggravated MCAO/Re-induced cerebral damage, as assessed by infarct volume and edema. Pretreatment with AA (100 mg/kg, p.o.) for two weeks significantly suppressed the exacerbation of damage in the brain of diabetic rats. AA also suppressed the production of superoxide radical, activation of caspase-3, and expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) in the ischemic penumbra. Immunohistochemical staining revealed that expression of SVCT2 was upregulated primarily in neurons and capillary endothelial cells after MCAO/Re in the nondiabetic cortex, accompanied by an increase in total AA (AA + dehydroascorbic acid) in the tissue, and that these responses were suppressed in the diabetic rats. AA supplementation to the diabetic rats restored these responses to the levels of the nondiabetic rats. Furthermore, AA markedly upregulated the basal expression of GLUT1 in endothelial cells of nondiabetic and diabetic cortex, which did not affect total AA levels in the cortex. These results suggest that daily intake of AA attenuates the exacerbation of cerebral ischemic injury in a diabetic state, which may be attributed to anti-apoptotic and anti-inflammatory effects via the improvement of augmented oxidative stress in the brain. AA supplementation may protect endothelial function against the exacerbated ischemic oxidative injury in the diabetic state and improve AA transport through SVCT2 in the cortex.
Highlights
Diabetes mellitus is a metabolic disorder associated with chronic hyperglycemia, which is known to enhance systemic oxidative stress, predisposing to diabetic complications
We demonstrated that chronic supplementation with ascorbic acid (AA) attenuates oxidative stress in both the plasma and the brain and alleviates cerebral injury induced by middle cerebral artery occlusion and reperfusion (MCAO/Re) in rats with streptozotocin (STZ)-induced diabetes [25]
This study indicates that the diabetic rats have low levels of AA in the plasma, and that chronic oral pretreatment with AA in diabetic rats decreases the cerebral O2− generation, apoptosis, and infarction induced by MCAO/Re; all of these effects could be a result of improved antioxidant status in the diabetic brain
Summary
Diabetes mellitus is a metabolic disorder associated with chronic hyperglycemia, which is known to enhance systemic oxidative stress, predisposing to diabetic complications. Diabetes is a major risk factor for atherosclerotic diseases such as acute brain ischemia [1,2]. It increases the risks of morbidity and mortality after stroke [3,4]. Reperfusion after a long period of vessel occlusion triggers the explosive generation of reactive oxygen species (ROS), such as superoxide radical (O2–), hydroxyl radical, hydrogen peroxide, etc., which causes apoptosis and delayed death of cells through oxidative damage to lipids, proteins, and DNA in the ischemic penumbral region [6,7,8,9]. In addition to apoptotic cell death, inflammatory neurodegeneration is another crucial process contributing to cerebral damage after ischemia and reperfusion [10]. ROS have been shown to activate nuclear factor-κB, which enhances the transcription of the genes encoding proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), leading to inflammatory responses [11]
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