Abstract
Diabetes mellitus is known to exacerbate acute cerebral ischemic injury. Previous studies have demonstrated that infarction volumes caused by transient cerebral ischemia were greater in diabetic rats than in nondiabetic rats. Tumor necrosis factor-α (TNF-α) is a proinflammatory protein produced in the brain in response to cerebral ischemia that promotes apoptosis. Etanercept (ETN), a recombinant TNF receptor (p75)-Fc fusion protein, competitively inhibits TNF-α. Therefore, we evaluated the neuroprotective effects of chronic or acute treatment with ETN on cerebral injury caused by middle cerebral artery occlusion/reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. Furthermore, we evaluated the effects of ETN against the apoptosis and myeloperoxidase activity. Single administration of ETN before MCAO significantly suppressed exacerbation of cerebral damage in nondiabetic rats, as assessed by infarct volume. In contrast, the diabetic state markedly aggravated MCAO/Re-induced cerebral damage despite ETN treatment within 24 h before MCAO. However, the damage was improved by repeated administration of ETN at 900 μg/kg/daily in rats in an induced diabetic state. These results suggested that repeated administration of ETN can prevent exacerbation of cerebral ischemic injury in the diabetic state and is mainly attributed to anti-inflammatory effects.
Highlights
Diabetes mellitus (DM) is a metabolic disorder associated with chronic hyperglycemia, which is known to enhance systemic oxidative stress, predisposing patients to diabetic complications
The rats subjected to MCAO were divided into six treatment groups: Treatment 1, where non-DM rats were treated with ETN (300, 450, and 900 μg/kg, i.p.) within 24 h before MCAO, Treatment 2, where non-DM rats were treated with ETN (300, 450, and 900 μg/kg, i.v.) immediately after MCAO, Treatment 3, where non-DM rats were treated with ETN (300, 450, and 900 μg/kg, i.v.) immediately after middle cerebral artery occlusion/reperfusion (MCAO/Re), Treatment 4, where DM rats were treated with ETN (450 and 900 μg/kg, i.v.) within 24 h before MCAO, Treatment 5, where DM rats were treated with ETN (450 and 900 μg/kg, i.v.) immediately after MCAO, and Treatment 6, where ETN (450 or 900 μg/kg, twice/week, i.p.) was repeatedly administered after the onset of diabetes for 5 weeks
The plasma levels of tumor necrosis factor-α (TNF-α) in the non-DM and DM groups were measured by Enzyme-linked immunosorbent assay (ELISA) (Figure 1)
Summary
Diabetes mellitus (DM) is a metabolic disorder associated with chronic hyperglycemia, which is known to enhance systemic oxidative stress, predisposing patients to diabetic complications. World Health Organization data show that approximately 386 million people worldwide are currently suffering from diabetes, which is a major risk factor for atherosclerotic diseases, such as acute brain ischemia [1, 2]. Previous studies have demonstrated that diabetes increased oxidative stress and inflammation in the brain [5] and aggravated cerebral ischemic injury in animal models [6,7,8]. Brain injury induced by focal ischemia is characterized by significant and rapid upregulation of cytokines, such as tumor necrosis factor-α (TNF-α). It is well known that inflammation has an essential role in the pathogenesis of transient cerebral ischemic injury [9]
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