Orally Administrated Ascorbic Acid Suppresses Neuronal Damage and Modifies Expression of SVCT2 and GLUT1 in the Brain of Diabetic Rats with Cerebral Ischemia-Reperfusion

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.

Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of Tissue Plasminogen Activator in a Rat Stroke Model

“…Hence, it appears that AA may suppress oxidative stress and the accumulation of free radicals and thereby inhibit the side effects of r-tPA. Recently, Iwata et al (2014) [15] found that chronic AA supplementation inhibits apoptotic and pro-inflammatory changes and attenuates brain injury and neurological deficits in STZ-induced diabetic rats. Our results showed that the levels of MMP-9 and brain oedema increased after the induction of permanent MCAO and also after therapy with r-tPA.…”

“…It has been shown that antioxidant treatment with AA significantly reduces lipid peroxidation and increases superoxide dismutase and catalase activities after seizures induced by pilocarpine [14]. Moreover, AA is an essential antioxidant for scavenging free radicals in the brain and may protect endothelial function against the exacerbated ischaemic oxidative injury in diabetes [15]. Furthermore, oxidative stress is an early trigger for the up-regulation of MMP-9 which in turn contributes to BBB damage after cerebral ischaemia reperfusion [16,17].…”

Vitamin C Inhibits Aggravated Eryptosis by Hydrogen Peroxide in Glucose-6-Phosphated Dehydrogenase Deficiency

“…AA mainly relies on Na + -dependent transporter, while DHA was mediated by glucose transporter (GLTU) [35,36]. Besides, DHA has been reported to be reduced to AA at first inside the cell, and it is AA that played key anti-oxidant roles [37,38]. It was indicated in Fig.…”

Diabetic aggravation of stroke and animal models

“…Moreover, hyperglycemia per se causes decrease in reperfusion blood flow by facilitating vasoconstriction (Martini and Kent, 2007). Further, various research groups have used the endovascular MCAO model to assess the benefit of different therapeutic strategies proposed to treat the enhanced neurodegeneration associated with stroke among diabetics (Briyal et al, 2012; Cui et al, 2012; Darsalia et al, 2014; Iwata et al, 2014; Simard et al, 2009; Song et al, 2014; Yan et al, 2013). The endovascular MCAO model has been used to study diabetic aggravation of ischemic brain damage in db/db diabetic mice (Chen et al, 2012; Chen et al, 2011) and SHR rats (Slivka, 1991).…”