Does Bosentan Protect Diabetic Brain Alterations in Rats? The Role of Endothelin‐1 in the Diabetic Brain

Abstract

Diabetes mellitus (DM) is a major problem all over the world, affecting more people in recent years. Individuals with diabetes are more prone to disease than non-diabetics, especially vascular complications. The aim of this study was to examine the roles of the endothelin (ET)-1 in brain damage formed in a streptozocin (STZ)-induced diabetes model, and the effect of bosentan, which is the non-specific ET1 receptor blocker in the prevention of the diabetes-induced brain damage. To examine the effects of bosentan (50 mg/kg and 100 mg/kg) in this study, the rats were given the drug for 3 months. The rats were divided into four groups: the sham group (n = 10), the diabetic control group (n = 10), the group of diabetic rats given bosentan 50 mg/ kg (n = 10) and the group of diabetic rats given bosentan 100 mg/kg (n = 10). Diabetes was induced in the rats by STZ (60 mg/kg i.p.). On day 91, all rats were killed. Brain tissues of the rats were measured by molecular, biochemical and histopathological methods. Antioxidant levels in the therapy groups were observed as quite near to the values in the healthy group. In this study, while the brain eNOS levels in the diabetic groups decreased, the ET1 and iNOS levels were found to be increased. However, in the diabetes group, hippocampus and cerebellum, pericellular oedema and a number of neuronal cytoretraction were increased in neuropiles, whereas these results were decreased in the therapy group. Based on all of these results, ET1 will not be ignored in diabetes-induced cerebral complications.Diabetes mellitus (DM) is a severe disease which eventually results in death. During diabetes mellitus, tissues cannot uptake glucose and very severe complications such as nephropathy, retinopathy, neuropathy and peripheral vascular complications occur [1]. Many new mechanisms have been suggested during the formation and progress of these complications. There are studies in many areas, from inflammation to cellular membrane disorders, of the mechanisms of diabetesinduced complications [1][2][3]. There are also many studies on the receptors which are responsible for the formation of diabetes and diabetes-induced complications in relation to our topic: angiotensin receptors, urotensin receptors, glucagon-like peptide 1 receptors and peroxisome proliferator-activated receptora [4,5].Previous studies have shown the importance of angiotensin in diabetes-induced liver damage [6,7], and there are many recent studies showing that endothelin-1 receptors play important roles in diabetes. One study showed that cell proliferation and, at the same time, ET1 production increased in type 2 diabetes [8,9]. Diabetes-related, clinical and experimental studies showed that ET1 plasma levels increased [10,11]. A study by Mastumoto et al. showed that the expression of both ET1 and the receptors increased in the streptozotocin (STZ)-induced diabetes model [12]. In another study, giving endothelin-1 to individuals with insulin resistance reduced endothelin-1-induced vasodilatation [13]. ET1 levels w...

Modelling of the Effect of End‐Tidal Carbon Dioxide on Cerebral Oxygen Saturation in Beach Chair Position under General Anaesthesia

“…It has been reported that one reason for reduced cerebrovascular reactivity in patients with DM is endothelial dysfunction caused by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances [25]. Hyperglycaemia-induced reactive oxygen overproduction directly reduces endothelial nitric oxide synthase that leads to decrease in the production of vasodilator nitric oxide, while the production and the plasma level of vasoconstrictor endothelin-1 are elevated in DM [25,26].…”

Role of endothelin receptors and relationship with nitric oxide synthase in impaired erectile response in diabetic rats

“…A literature review of experimental and clinical studies has shown that ET receptors have different physiologic effects, which also changes according to the receptor sites and conditions (Bell et al ., ; Zygalaki et al ., ). Complications in the vascular system and in different organs may occur in diabetes (Cayir et al ., ; Demir et al ., ). ET‐RA has up‐regulated to correlate with ET‐1 level in both diabetes and its complications (Bell et al ., ), ET‐RA has been shown to be down‐regulated in diabetic coronary artery disease and gestational diabetes (Zygalaki et al ., ; Dieber‐Rotheneder et al ., ).…”

“…iNOS is elaborated after inflammation and results in an exaggerated increase in NO. Previous studies have shown that iNOS levels are increased in diabetes (Demir et al ., ). In conditions where ET‐1 levels are increased, NO excretion decreases, and in response to this decrease iNOS expression is increased (Granado et al ., ).…”

“…In our study, treated groups were exposed to BOS for 60 days at 50 and 100 mg kg −1 day −1 dissolved in 1 ml distilled water + 1 ml PBS (Phosphate buffered saline) (drug administered orally 2 ml rat −1 day −1 ). The dose of BOS was chosen on the basis of published data (Cayir et al ., ; Demir et al ., ). Likewise, a 2 ml vehicle (1 ml saline + 1 ml distilled water) was administered to healthy (control) rats for 60 days.…”

“…Bosentan (BOS) is an oral nonselective endothelin receptor antagonist used for the treatment of pulmonary hypertension (PAH) and HIV‐related PAH (Sitbon et al ., ). In experimental studies, researchers showed that ET‐1 antagonists may prove beneficial in the treatment of diabetic complications (Cayir et al ., ; Demir et al ., ). However, there are no experimental or clinical studies about the protective effect of BOS on diabetic ED.…”