7 research outputs found

    GLP-1R activation by Ex-4 did not protect NSCs from hypoglycaemic <i>milieu</i>.

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    <p>NSCs were plated as single cells. Prior to 2.5mM glucose addition cells were incubated with Ex-4 (10 nM) or PACAP (100 nM) for 10 min. After 24 hours incubation intracellular ATP levels were measured. Data are shown as mean ±SEM (n = 17–25). Kruskal-Wallis followed by Dunn’s test was used. Differences were considered significant at P<0.05. * denotes P <0.05 compared with control, # denotes P<0.05 compared to 2.5mM glucose.</p

    A hypoglycaemic <i>milieu</i> decreases NCS viability in a dose-dependent manner.

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    <p>NSCs were plated as single cells and treated with 20 mM (control) 10, 5, 2.5, 0 mM glucose. To measure cell viability, intracellular ATP levels were measured after 24 hours. Values are shown as mean ±SEM (n = 14–25). Kruskal-Wallis followed by Dunn’s test was used. Differences were considered significant at P <0.05. * denotes P <0.05 compared with control, # denotes P<0.05 compared to 2.5mM glucose.</p

    PAC-1 activation counteracts impaired NSCs under hypoglycaemic <i>milieu via</i> the PKA-dependent pathway.

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    <p><b>(A, B)</b> NSCs were plated as single cells. Prior to 2.5mM glucose addition cells were incubated with PACAP (100 nM), Max-4 (30 nM), H89 (1 uM) and Gö6976 (1 uM) for 10 min. After 24 hours incubation, intracellular ATP levels were measured. Data are shown as mean ±SEM (A, n = 15–50; B, n = 16–28). Kruskal-Wallis followed by Dunn’s test was used. Differences were considered significant at P<0.05. * denotes P <0.05 compared with control, # denotes P<0.05 compared to 2.5mM glucose.</p

    PACAP increases NSC viability in response to hypoglycaemic <i>milieu</i> in correlation with a downward trend in apoptosis.

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    <p>NSCs were plated as single cells. Prior to 2.5mM glucose addition cells were incubated with PACAP (100 nM) for 10 min. After 24 hours incubation cells were harvested for Western blot experiments <b>(A, B)</b> or intracellular ATP determination <b>(C)</b> or NSC manual counting <b>(D)</b>. To obtain quantitative measurements Bcl-2 protein levels and cleaved caspase 3 were normalized against β-actin. Data are shown as mean ±SEM (A, n = 6–7; B, n = 5–8, C, n = 30–50; D, n = 3–4). Kruskal-Wallis followed by Dunn’s test or Fisher LSD test was used. Differences were considered significant at P<0.05. * denotes P <0.05 compared with control, # denotes P<0.05 compared to 2.5mM glucose.</p

    DPP-4 inhibitor and sulfonylurea differentially reverse type 2 diabetes-induced blood-brain barrier leakage and normalise capillary pericyte coverage

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    Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). While accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear.  Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitors (DPP-4i) linagliptin and the sulfonylurea glimepiride, restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before the sacrifice.  We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalised T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial-vascular interaction, and increased collagen IV density.  This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage which may contribute to the antidiabetic neurorestorative effects.  </p
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