Altered expression of histone and synaptic plasticity associated genes in the hippocampus of streptozotocin-induced diabetic mice

University of Newcastle, Callaghan, NSW, Australia.
Metabolic Brain Disease (Impact Factor: 2.64). 07/2013; 28(4). DOI: 10.1007/s11011-013-9418-y
Source: PubMed


Accumulating evidence indicates that hyper-glycaemia is deleterious to brain function, in particular to the hippocampus. It is thought this hippocampal dysfunction may contribute to hyperglycaemia related cognitive impairment, such as that which manifests with diabetes. In the present study, we investigated the effects of diabetes-related hyperglycaemia on hippocampal gene expression, in order to identify potential mechanisms that might be associated with the cognitive dysfunction that develops with diabetes mellitus. Genome-wide gene expression profiling was carried out on the hippocampi from streptozotocin (STZ)-induced diabetic mice, and from vehicle treated control mice. Genes of interest that satisfied expression fold-change and statistical criteria, and that were considered to be potentially associated with cognitive function, were further tested by real time, quantitative polymerase chain reaction (qPCR) analysis. We found that STZ-induced diabetes resulted in decreased hippocampal expression of genes involved in epigenetic regulation and synaptic plasticity, for example, histone deacetylases and glycogen synthase kinase 3 beta (HDACs and GSK3β). We also found increased expression of genes involved in signalling cascades related to cell growth, cell survival and energy metabolism, such as neurotropic tyrosine kinase receptor type 2, apolipoprotein E, and protein tyrosine phosphatase receptor type (Ntrk2, APOE, PTPRT). To our knowledge this is the first study to demonstrate a gene expression profile implicating epigenetic modifications and alterations of synaptic plasticity associated genes in diabetes mellitus. The present study will improve our understanding of the neural mechanisms that might underpin diabetes-related cognitive dysfunction.

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    • "Recently, it has been shown that diabetes has negative effects on brain functions. Enhancement in hippocampal astrocytic reactivity, impaired synaptic plasticity, vascular changes, decreased dendritic complexity and morphology, and disturbed neurotransmission have detrimental effects on diabetic brain tissues (Ceretta et al., 2012; Jing et al., 2013; Thomas et al., 2013). Such significant functional and morphological changes have been correlated well with the alterations in memory and learning abilities (El-Akabawy & El-Kholy, 2014). "
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    ABSTRACT: Context: Oxidative stress has been implicated in the progression of pathogenesis in diabetes mellitus and leads variety of deformations in central nervous system. Recent studies have provided several insights on therapeutic uses of resveratrol in diabetic complications. Objective: The present study reveals if resveratrol ameliorates oxidative stress and molecular changes in the brain frontal cortex of streptozotocin-induced diabetic rats. Materials and methods: Rats were divided into four groups; control, diabetic, resveratrol treated control, resveratrol treated diabetic. After diabetes induction, resveratrol (20 mg/kg) was given intraperitoneally once daily throughout 4 weeks. In addition to enzymatic activities, gene and protein expressions of brain antioxidant enzymes were utilized by qRT-PCR and Western blot, respectively. Results: The results indicated a significant elevation in total oxidant species (1.22-fold) and malonedialdehyde (1.38-fold) contents in diabetic rat brain cortex tissues. In addition, significant augmentation in the activities of catalase (1.38-fold) and superoxide dismutase (3-fold) was witnessed with the gene and protein expression levels reflecting a transcriptional regulation. Resveratrol treatment significantly normalized diabetic malonedialdehyde and oxidized glutathione levels and strengthens the action of all antioxidant enzymes. Recovery of the diabetes associated changes reflects the reduction of oxidative conditions by resveratrol and reveals the decrease in the requirement for the activation of antioxidant defense systems in the brain tissues of diabetic rats. Discussion and conclusion: Potent antioxidant and neuroprotective properties of resveratrol against diabetes-induced oxidative damage were demonstrated and the results would orient the new studies searching for molecular mechanism of diabetes-induced changes in brain tissues.
    No preview · Article · May 2015 · Pharmaceutical Biology
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    • "Results were considered statistically significant if the observed significance level was 0.05. As we have previously reported findings for the control and diabetic conditions [14], comparisons in the present study are between the diabetes plus DHA group and the previous diabetes group [14]. "
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    ABSTRACT: A body of evidence has accumulated indicating diabetes is associated with cognitive impairments. Effective strategies are therefore needed that will delay or prevent the onset of these diabetes-related deficits. In this regard, dietary modification with the naturally occurring compound, docosahexaenoic acid (DHA), holds significant promise as it has been shown to have anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The hippocampus, a limbic structure involved in cognitive functions such as memory formation, is particularly vulnerable to the neurotoxic effects related to diabetes, and we have previously shown that streptozotocin-induced diabetes alters hippocampal gene expression, including genes involved in synaptic plasticity and neurogenesis. In the present study, we explored the effects of dietary supplementation with DHA on hippocampal gene expression in C57Bl/6 diabetic mice. Diabetes was established using streptozotocin (STZ) and once stable, the dietary intervention group received AIN93G diet supplemented with DHA (50 mg/kg/day) for 6 weeks. Microarray based genome-wide expression analysis was carried out on the hippocampus of DHA supplemented diabetic mice and confirmed by real time polymerase chain reaction (RT-qPCR). Genome-wide analysis identified 353 differentially expressed genes compared to non-supplemented diabetic mice. For example, six weeks of dietary DHA supplementation resulted in increased hippocampal expression of Igf II and Sirt1 and decreased expression of Tnf-α, Il6, Mapkapk2 and ApoE, compared to non-supplemented diabetic mice. Overall, DHA supplementation appears to alter hippocampal gene expression in a way that is consistent with it being neuroprotective in the context of the metabolic and inflammatory insults associated with diabetes.
    Full-text · Article · May 2015
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    ABSTRACT: Diabetes is associated with cognitive impairment and brain aging, with alterations in hippocampal neurogenesis and synaptic plasticity implicated in these changes. As the prevalence of diabetes continues to rise, readily implemented strategies are increasingly needed in order to protect the brain’s cognitive functions. One possibility is resveratrol (RES) (3,5,4- trihydroxystilbene), a polyphenol of the phytoalexin family that has been shown to be protective in a number of neuropathology paradigms. In the present study, we sought to determine whether dietary supplementation with RES has potential for the protection of cognitive functions in diabetes. Diabetes was induced using streptozotocin, and once stable, animals received AIN93G rodent diet supplemented with RES for 6 weeks. Genome–wide expression analysis was conducted on the hippocampus and genes of interest were confirmed by quantitative, real-time PCR. Genome-wide gene expression analysis of the hippocampus revealed that RES supplementation of the diabetic group resulted in 481differentially expressed genes compared to non-supplemented diabetic mice. Intriguingly, gene expression that was previously found significantly altered in the hippocampus of diabetic mice, and that is implicated in neurogenesis and synaptic plasticity (Hdac4, Hat1, Wnt7a, ApoE), was normalised following RES supplementation. In addition, pathway analysis revealed Jak-Stat signalling was the most significantly enriched pathway. The Jak-Stat pathway induces a pro-inflammatory signalling cascade, and we found most genes involved in this cascade (e.g. Il15, Il22, Socs2, Socs5) had significantly lower expression following RES supplementation. These data indicate RES could be neuroprotective and beneficial for the maintenance of cognitive function in diabetes.
    No preview · Article · Jan 2013 · The Journal of nutritional biochemistry
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