Rosiglitazone Attenuates Memory Impairment in Aged Rat with Diabetes by Inhibiting NF-kappa B Signal Pathway Activation

Abstract

Although the cognitive impairment in geriatric diabetes is common, its mechanisms remain unclear and therapies are limited. The present study investigated the effects of rosiglitazone on memory impairment in aged rats with diabetes. Diabetes was induced by streptozotocin in aged Wistar rats of 20–22 months. Then, the diabetic rats were divided randomly into the diabetic model group and rosiglitazone treatment group for assessment of cognitive function and cerebral injury at 8 weeks using Morris water maze (MWM) paradigm, real-time PCR and western blot analysis. Wistar rats of the same age were also assessed as control. In vitro, the therapeutic effect of rosiglitazone was investigated using rat chromaffin cell line PC12 cultured with high glucose and/or C-reactive protein (CRP). 8 weeks after diabetes induction aged rats exhibited marked and persistent hyperglycemia, weight loss, higher level of serum CRP and learning impairments. Enhanced cerebral inflammation in aged rats with diabetes was associated with over-activation of the nuclear factor κB (NF-κB) signalling pathway and upregulation of inflammatory cytokines (IL-6, TNFα) in the hippocampus. Compared with the diabetic group, level of serum CRP, inflammatory cytokines and over-activation of NF-κB signalling pathway in the hippocampus were restored partially concomitant with attenuation of cognitive dysfunction indicated as markedly decreased escape latency and distance during MWM test in the rosiglitazone treatment group. In vitro, high glucose significantly activated NF-κB signalling pathway and upregulated inflammatory cytokines. CRP synergistically promoted high glucose-mediated effects. Rosiglitazone significantly ameliorated the effects mediated by high glucose and CRP.These effects were significantly reversed by co-treatment with the PPARγ antagonist T0070907. These results suggest that rosiglitazone can improve cognitive function in aged rats with diabetes by inhibiting the NF-κB signal activation and decreasing the expressions of inflammatory cytokines in the hippocampus.

Key words

geriatric diabetes - rosiglitazone - cognitive impairment - C-reactive protein - nuclear factor -κB

^* Liu Fei and Huang Yong-Jun contributed equally to this study.

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