Pro-GLP-1, a Pro-drug of GLP-1, is neuroprotective in cerebral ischemia

Zhang, Huinan; Meng, Jingru; Li, Xubo; Zhou, Shimeng; Qu, Di; Wang, Ning; Jia, Min; Ma, Xue

doi:10.1016/j.ejps.2015.01.010

Cited by 21 publications

(30 citation statements)

References 44 publications

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“…The timing of drug administration varied between studies. Eight studies administered GLP‐1RAs pre‐ischaemia , eight post‐ischaemia and four both pre‐ and post‐ischaemia . For the seven studies involving DPP‐4Is, one study applied the drugs pre‐ischaemia , one post‐ischaemia and five studies both pre‐ and post‐ischaemia .…”

Section: Resultsmentioning

confidence: 99%

“…Mouse (C57BL/6), rat (Sprague Dawley/Wistar/Wistar albino) and gerbil (Mongolian) animal models were used (n = 1766). Fifteen studies tested non‐diabetic animals , six used diabetic/hyperglycaemic animals , and six studies included both non‐diabetic and diabetic . Diabetes was induced by streptozotocin , high‐fat diet or genetically modified animal strains including db/db mice , Goto‐Kakizaki rats and hyperglycaemia induced by infusion of 50% dextrose .…”

Section: Resultsmentioning

confidence: 99%

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Neuroprotective Mechanisms of Glucagon‐like Peptide‐1‐based Therapies in Ischaemic Stroke: A Systematic Review based on Pre‐Clinical Studies

Marlet

Ölmestig

Vilsbøll

et al. 2018

Basic Clin Pharma Tox

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Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) are widely used for the treatment of type 2 diabetes. Increasing evidence suggests that they may provide neuroprotection. The aim of this MiniReview was to systematically evaluate the proposed mechanism of action for GLP-1-based therapies in ischaemic brain damage in animals. We performed a literature search using MEDLINE, EMBASE and The Cochrane Library. GLP-1-based therapies administered before, during or after experimental stroke in diabetic and non-diabetic animals were evaluated. We reviewed 27 studies comprised of 20 involving GLP-1RAs and seven involving DPP-4Is. Both GLP-1RAs and DPP-4Is affected the acute inflammatory response secondary to ischaemia by reducing inflammation, endothelial leakage and excitotoxicity. Both treatments also reduced oxidative stress and apoptosis. GLP-1RAs significantly reduced infarct volume when administered acutely, but not later after stroke. The reported effects of DPP-4Is on infarct volume were inconsistent. GLP-1-RAs reliably improved functional outcome, but the effects on cerebral blood flow were inconclusive. These neuroprotective effects were often attributed to activation of the GLP-1 receptor, but non-GLP-1R-mediated effects have also been suggested. Both GLP-1RAs and DPP-4Is significantly affected inflammation, oxidative stress and apoptosis in animal stroke models; however, data from clinical trials only report therapeutic efficacy for GLP-1RAs. Thus, GLP-1RA administration is the most promising treatment to pursue for patients at risk of stroke or immediately after stroke. Future studies should address acute and prophylactic treatments in stroke patients with and without diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Neuroprotective Mechanisms of Glucagon‐like Peptide‐1‐based Therapies in Ischaemic Stroke: A Systematic Review based on Pre‐Clinical Studies

Marlet

Ölmestig

Vilsbøll

et al. 2018

Basic Clin Pharma Tox

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“…Both GLP-1 and Ex-4 have multiple physiologic functions, such as the induction of glucose-dependent insulin release, inhibition of glucagon secretion, stimulation of B cell replication, and antiapoptotic action [13]. Owing to their small molecule size, both GLP-1 and Ex-4 can diffuse across the BBB in the central nervous system and provide neuroprotection in cerebral ischemia [14, 15]. While it has been reported that Ex-4 can protect against oxidative products and neuronal cell death caused by ischemic brain damage, it is yet unknown whether Ex-4 is effective in preventing warfarin-associated HT after cerebral ischemia.…”

Section: Introductionmentioning

confidence: 99%

The glucagon-like peptide-1 receptor agonist exendin-4 ameliorates warfarin-associated hemorrhagic transformation after cerebral ischemia

Chen

Wang

Ding

et al. 2016

J Neuroinflammation

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BackgroundAs the number of patients with cardioembolic ischemic stroke is predicted to be double by 2030, increased burden of warfarin-associated hemorrhagic transformation (HT) after cerebral ischemia is an expected consequence. However, thus far, no effective treatment strategy is available for HT prevention in routine clinical practice. While the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is known to protect against oxidative stress and neuronal cell death caused by ischemic brain damage, its effect on preventing warfarin-associated HT after cerebral ischemia is yet unknown. Therefore, we hypothesized that Ex-4 would stabilize the blood-brain barrier (BBB) and suppress neuroinflammation through PI3K-Akt-induced inhibition of glycogen synthase kinase-3β (GSK-3β) after warfarin-associated HT post-cerebral ischemia.MethodsWe used male C57BL/6 mice for all experiments. A 5-mg warfarin sodium tablet was dissolved in animals’ drinking water (effective warfarin uptake 0.04 mg (2 mg/kg) per mouse). The mice were fed for 0, 6, 12, and 24 h with ad libitum access to the treated water. To study the effects of Ex-4, temporary middle cerebral artery occlusion (MCAO) was performed. Then, either Ex-4 (10 mg/kg) or saline was injected through the tail vein, and in the Ex-4 + wortmannin group, PI3K inhibitor wortmannin was intravenously injected, after reperfusion. The infarct volume, neurological deficits, and integrity of the BBB were assessed 72 h post MCAO. One- or two-way ANOVA was used to test the difference between means followed by Newman–Keuls post hoc testing for pair-wise comparison.ResultsWe observed that Ex-4 ameliorated warfarin-associated HT and preserved the integrity of the BBB after cerebral ischemia through the PI3K/Akt/GSK-3β pathway. Furthermore, Ex-4 suppressed oxidative DNA damage and lipid peroxidation, attenuated pro-inflammatory cytokine expression levels, and suppressed microglial activation and neutrophil infiltration in warfarin-associated HT post-cerebral ischemia. However, these effects were totally abolished in the mice treated with Ex-4 + the PI3K inhibitor—wortmannin. The PI3K/Akt-GSK-3β signaling pathway appeared to contribute to the protection afforded by Ex-4 in the warfarin-associated HT model.ConclusionsGLP-1 administration could reduce warfarin-associated HT in mice. This beneficial effect of GLP-1 is associated with attenuating neuroinflammation and BBB disruption by inactivating GSK-3β through the PI3K/Akt pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0661-0) contains supplementary material, which is available to authorized users.

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“…Geniposide, an extract of Gardenia jasminoides J. Ellis and a novel agonist for glucagon-like peptide-1 receptor (GLP-1R), has been shown to exert antinociception effects [15], promote β-cell regeneration, attenuate β-cell apoptosis [16,17], regulate insulin secretion in INS-1 cells [18], and prevent oxidative stress of PC12 cell [19]. Accumulating evidences has revealed that glucagon-like peptide 1 (GLP-1) and GLP-1 analogues exert anti-apoptotic effects by activating GLP-1R via the phosphatidylinositol 3 kinase (PI3K)/ AKT signaling pathway [3,[20][21][22]. Geniposide can also activate GLP-1R in response to oxidative stress in PC12 cells via the PI3K/AKT pathway [23], inhibit PC12 cell death by the mitochondrial pathway [24], and attenuate memory deficits in amyloid precursor protein (APP)/ presenilin 1(PS1) transgenic mice by improving mitochondrial dysfunction [25].…”

Section: Introductionmentioning

confidence: 99%

Geniposide Prevents Hypoxia/Reoxygenation-Induced Apoptosis in H9c2 Cells: Improvement of Mitochondrial Dysfunction and Activation of GLP-1R and the PI3K/AKT Signaling Pathway

Jiang

Chang²,

Wang³

et al. 2016

Cell Physiol Biochem

104

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Background/Aims: Myocardial ischemia/reperfusion injury is a major cause of morbidity and mortality associated with coronary heart disease. Many studies have demonstrated that natural products are promising chemotherapeutic drugs counteracting the loss of cardiomyocytes. Thus, the purpose of the present study was to investigate the effects of geniposide, a traditional Chinese herb extract from Gardenia jasminoides J. Ellis, on cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) in H9c2 cells, and their underlying mechanisms. Methods: Cell viability and apoptosis ratio were assessed using the cell counting kit-8 assay and Annexin V/propidium iodide (PI) staining. The concentrations of lactate dehydrogenase (LDH), intracellular total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were detected by microplate reader. The production of reactive oxygen species/reactive nitrogen species (ROS/RNS), the level of mitochondrial calcium, and mitochondrial membrane potential depolarization were measured by confocal laser scanning microscopy. Mitochondrial morphology was visualized using transmission electron microscopy. The expressions of Bcl-2 mRNA and Caspase-3 mRNA were measured by reverse transcription-polymerase chain reaction (RT-PCR). The protein levels of cleaved caspase-3, Bcl-2, Bax, AKT, p-AKT^serine473, cytochrome-c were detected by western bloting. Results: Geniposide pretreatment increased cell viability, decreased LDH levels in the supernatant, and inhibited cardiomyocyte apoptosis caused by H/R. Furthermore, geniposide reversed mitochondrial dysfunction by decreasing oxidative stress products (ROS/RNS and MDA), increasing anti-oxidative enzyme (T-SOD) level, improving mitochondrial morphology, attenuating mitochondrial calcium overload and blunting depolarization of mitochondrial membrane. Moreover, geniposide pretreatment increased Bcl-2 level and decreased Bax level, thus enhancing the Bcl-2/Bax ratio. Consistent with the above result, Bcl-2 mRNA expression was upregulated and caspase-3 mRNA expression was downregulated by geniposide. In addition, geniposide decreased the protein expression of cleaved caspase-3 and cytochrome-c and increased the level p-AKT^serine473. The protective effects of geniposide were partially reversed by glucagon-like pepitide-1 receptor antagonist exendin-(9-39) and the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002. Conclusions: Our results suggest that geniposide pretreatment inhibits H/R-induced myocardial apoptosis by reversing mitochondrial dysfunction, an effect in part due to activation of GLP-1R and PI3K/AKT signaling pathway.

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Pro-GLP-1, a Pro-drug of GLP-1, is neuroprotective in cerebral ischemia

Cited by 21 publications

References 44 publications

Neuroprotective Mechanisms of Glucagon‐like Peptide‐1‐based Therapies in Ischaemic Stroke: A Systematic Review based on Pre‐Clinical Studies

Neuroprotective Mechanisms of Glucagon‐like Peptide‐1‐based Therapies in Ischaemic Stroke: A Systematic Review based on Pre‐Clinical Studies

The glucagon-like peptide-1 receptor agonist exendin-4 ameliorates warfarin-associated hemorrhagic transformation after cerebral ischemia

Geniposide Prevents Hypoxia/Reoxygenation-Induced Apoptosis in H9c2 Cells: Improvement of Mitochondrial Dysfunction and Activation of GLP-1R and the PI3K/AKT Signaling Pathway

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