A novel dual-glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist is neuroprotective in transient focal cerebral ischemia in the rat

4区 · 医学

Article

作者: Xue, Guo-Fang ; Li, Guanglai ; Li, Dongfang ; Hoelscher, Christian ; Han, Ling

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to be neuroprotective in previous studies in animal models of Alzheimer's or Parkinson's disease. Recently, novel dual-GLP-1/GIP receptor agonists that activate both receptors (DA) were developed to treat diabetes. We tested the protective effects of a novel potent DA against middle cerebral artery occlusion injury in rats and compared it with a potent GLP-1 analog, Val(8)-GLP-1(glu-PAL). Animals were evaluated for neurologic deficit score, infarct volume, and immunohistochemical analyses of the brain at several time points after ischemia. The Val(8)-GLP-1(glu-PAL)-treated and DA-treated groups showed significantly reduced scores of neurological dysfunction, cerebral infarction size, and percentage of TUNEL-positive apoptotic neurons. Furthermore, the expression of the apoptosis marker Bax, the inflammation marker iNOS, and the survival marker Bcl-2 was significantly increased. The DA-treated group was better protected against neurodegeneration than the Val(8)-GLP-1(glu-PAL) group, and the scores of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were higher, whereas the percentage of TUNEL-positive neurons and the levels of Bax and iNOS were lower in the DA group. DA treatment reduced the infarct volume and improved the functional deficit. It also suppressed the inflammatory response and cell apoptosis after reperfusion. In conclusion, the novel GIP and GLP-1 dual-receptor agonist is more neuroprotective than a GLP-1 receptor agonist in key biomarkers of neuronal degeneration.

2012-09-01·Brain Research4区 · 医学

Effects of the glucagon-like polypeptide-1 analogue (Val8)GLP-1 on learning, progenitor cell proliferation and neurogenesis in the C57B/16 mouse brain

4区 · 医学

Article

作者: Hoelscher, Christian ; Hunter, Kerry ; McGovern, Stephen F. J.

Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer's disease. Here, we tested the properties of the glucagon-like polypetide-1 (GLP-1) analogue (Val8)GLP-1, a drug originally developed as a treatment for T2DM at a range of doses (2.5 nmol; 25 nmol; 100 nmol; or 250 nmol/kg bw ip.) in an acute memory study in wild type C57B/l6 mice. We also tested (Val8)GLP-1 and the GLP-1 receptor antagonist exendin (9-39) in a chronic study (3 weeks at 25 nmol/kg bw ip. once-daily). We found that (Val8)GLP-1 crossed the blood brain barrier readily and that peripheral injection increased levels in the brain 30 min post-injection ip. but not 2h post-injection in rats. In the acute study, the low dose of 2.5 nmol/kg ip. enhanced motor activity in the open field task, while total distance travelled, exploratory behaviour and anxiety was not affected at any dose. Learning an object recognition task was not affected either. In the chronic study, no effect was observed in the open field assessment. The antagonist exendin (9-39) impaired object recognition learning and spatial learning in a water maze task, demonstrating the importance of GLP-1 signalling in memory formation. Locomotor activity was also affected in some cases. Blood sugar levels and insulin sensitivity was not affected in chronically treated mice. Neuronal stem cells and neurogenesis was enhanced by (Val8)GLP-1 in the dentate gyrus of wild type mice. The results demonstrate that (Val8)GLP-1 is safe in a range of doses, crosses the BBB and has potentially beneficial effects in the CNS by enhancing neurogenesis.

2010-03-01·European Journal of Pharmacology3区 · 医学

Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: A link between diabetes and Alzheimer's disease

3区 · 医学

Article

作者: Christian Hölscher ; Victor A. Gault ; Paula L. McClean ; Patrick Harriott

Type 2 diabetes has been identified as a risk factor for patients with Alzheimer's disease. Insulin signalling is often impaired in Alzheimer's disease, contributing to the neurodegenerative process. One potential strategy to help prevent this is the normalisation of insulin signalling in the brain. Therefore, the present study was designed to test the effects of novel enzyme-resistant analogues of the insulin-releasing incretin hormone, glucagon-like peptide 1 (GLP-1). The effects of Liraglutide (Victoza) and other novel GLP-1 analogues were tested on synaptic plasticity (LTP) in area CA1 of the hippocampus. At a dose of 15nmol in 5microl i.c.v., Liraglutide (P<0.005), Asp(7)GLP-1 (P<0.001), N-glyc-GLP-1 (P<0.01), and Pro(9)GLP-1 (P<0.001). In contrast, the GLP-1 receptor antagonist exendin(9-39)amide impaired LTP (P<0.001). Co-injection of exendin(9-39) and Liraglutide showed no effect on LTP. These results clearly demonstrate that Liraglutide and other GLP-1 analogues elicit effects on neurotransmission in the brain. Furthermore, GLP-1 peptides are not only effective in modulating insulin-release and achieving glycaemic control in type 2 diabetes, but are also effective in modulating synaptic plasticity. These findings are consistent with our previous observations that the novel analogue (Val(8))GLP-1 enhances LTP and reverses the impairments of LTP induced by beta-amyoid fragments. Therefore, the drug effects seen here could potentially ameliorate the impairments in neuronal communication and cognitive processes observed in Alzheimer's disease.

100 项与 (Val8)GLP-1(Ulster University) 相关的药物交易

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