Oral Administration of Grape Seed Proanthocyanidin Extracts Downregulate RAGE Dependant Nuclear Factor- Kappa BP65 Expression in the Hippocampus of Streptozotocin Induced Diabetic Rats

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.

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