Xu L, Li B, Cheng M, Zhang W, Pan J, Zhang C, Gao H
Department of Geriatrics, Qi Lu Hospital of Shandong University, Jinan, China.
Exp Clin Endocrinol Diabetes. 2008 Apr;116(4):215-24. doi: 10.1055/s-2007-993188. Epub 2008 Feb 2.
Chronic degenerative brain disease in diabetes, known as 'diabetic encephalopathy', is a recognized complication that can occur due to long-standing diabetes in patients. It is defined by chronic cognitive disturbance and it is thought to relate to regional tissue pathological changes in the brain. Furthermore, hyperglycemia induced activation of the AGE (S)/RAGE/NF-kappaB pathway may play an important role in the pathogenesis of the degenerative changes seen in the diabetic hippocampus. To help prevent the development of and to potentially treat this brain disease, effective interventions directed toward key molecular target(s) are required. Grape seed proanthocyanidin extracts (GSPE), which are the anti-oxidants derived from grape seeds, have been reported to possess a variety of potent properties. As a consequence, they may have therapeutic effects in the prevention and treatment of complications in patients with diabetes. In this study, we firstly examined whether GSPE could attenuate the structural degenerative changes in the diabetic hippocampus in a rodent model of diabetes. Secondly, we addressed if such effects of GSPE may be occurring through modulation of the receptor for advanced glycation end products (RAGE) and/or nuclear factor-kappa BP65 (NF-kappaBP65). Hippocampi from GSPE treated STZ induced diabetic rats were immunohistochemically stained for glial fibrillary acidic protein, RAGE and NF-kappaBP65 and for morphological observations. Western blot was used to detect the proteins of RAGE and NF-kappaBP65. Real time, reverse transcriptase coupled to polymerase chain reaction was used for quantitative determination of mRNA for RAGE and NF-kappaBP65. Analysis of data showed that long term chronic hyperglycemia caused the overexpression of AGE (S)/RAGE and NF-kappaBp65 in the CA region of hippocampus in STZ induced diabetic rats. GSPE decreased the expression of RAGE and NF-kappaBP65 at a daily oral dosage of 250 mg/kg. This study provides indication that GSPE can prevent structural changes of diabetes in the rat brain and it suggests that GSPE might be a useful remedy in the treatment of diabetic encephalopathy. In addition, it implicates the potential pathological role of RAGE and NF-kappaBP65 in diabetic encephalopathy.
糖尿病中的慢性退行性脑疾病，即“糖尿病性脑病”，是一种公认的并发症，可发生于长期患糖尿病的患者。它由慢性认知障碍所定义，并且被认为与大脑局部组织的病理变化有关。此外，高血糖诱导的晚期糖基化终产物（AGEs）/晚期糖基化终产物受体（RAGE）/核因子κB（NF-κB）信号通路的激活，可能在糖尿病海马体中所见的退行性变化的发病机制中起重要作用。为了帮助预防和潜在治疗这种脑部疾病，需要针对关键分子靶点进行有效的干预。葡萄籽原花青素提取物（GSPE）是从葡萄籽中提取的抗氧化剂，据报道具有多种强大特性。因此，它们可能对预防和治疗糖尿病患者的并发症具有治疗作用。在本研究中，我们首先检测了GSPE是否能减轻糖尿病啮齿动物模型中海马体的结构退行性变化。其次，我们探讨了GSPE的这种作用是否可能通过调节晚期糖基化终产物受体（RAGE）和/或核因子κB p65（NF-κBp65）而发生。对经GSPE处理的链脲佐菌素诱导的糖尿病大鼠的海马体进行免疫组织化学染色，以检测胶质纤维酸性蛋白、RAGE和NF-κBp65，并进行形态学观察。采用蛋白质印迹法检测RAGE和NF-κBp65的蛋白表达。实时逆转录聚合酶链反应用于定量测定RAGE和NF-κBp65的mRNA。数据分析表明，长期慢性高血糖导致链脲佐菌素诱导的糖尿病大鼠海马体CA区AGEs/RAGE和NF-κBp65的过度表达。GSPE以每日口服250mg/kg的剂量可降低RAGE和NF-κBp65的表达。本研究表明，GSPE可预防大鼠脑部的糖尿病结构变化，提示GSPE可能是治疗糖尿病性脑病的有效药物。此外，它还提示了RAGE和NF-κBp65在糖尿病性脑病中的潜在病理作用。
