Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice

Kuroki, Takuma; Tanaka, Ryota; Shimada, Yoshiaki; Yamashiro, Kazuo; Ueno, Yoshio; Shimura, Hideki; Urabe, Takao; Hattori, Nobutaka

doi:10.1161/strokeaha.116.012934

Cited by 51 publications

(53 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…). Two drugs, exenatide and sitagliptin , both reduced production of the pro‐inflammatory cytokine, tumour necrosis factor alpha (TNF‐α). Sitagliptin also reduced interleukin‐6 (IL‐6) expression and enhanced production of the anti‐inflammatory cytokine, interleukin‐10 (IL‐10) .…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…Concerning vascular remodelling and inflammation, Kuroki et al [86] observed that a single administration of exendin-4, 60 min. after cerebral ischaemia, decreases vascular inflammation in hyperglycaemic mice when compared with vehicle and insulin administration.…”

Section: Diabetes Mellitus and Vascular Dysfunctionmentioning

confidence: 99%

Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis

Pereira

Carneiro

Matsumoto

et al. 2018

Basic Clin Pharma Tox

View full text Add to dashboard Cite

Diabetes currently affects more than 400 million people worldwide. This metabolic disorder causes various micro‐ and macrovascular complications that accelerate atherosclerosis and yet trigger other cardiovascular diseases. The characteristic frame of hyperglycaemia, hyperinsulinaemia and hyperlipidaemia in diabetes increases several inflammatory mediators leading to endothelial dysfunction and pro‐atherosclerotic processes. This MiniReview summarizes evidence that antidiabetic drugs have effects beyond lowering glycaemic levels. In experimental studies, antidiabetic drugs reduce the vascular production and release of pro‐inflammatory cytokines, the recruitment, infiltration and activation of immune cells and pro‐inflammatory mediators, thus decreasing vascular inflammatory responses; they also re‐establish vascular redox homeostasis by reducing oxidative stress and balancing the release of vasoconstrictor and vasodilator factors, hence contributing to the improvement of endothelial function. These effects are associated with a reduction in vascular remodelling due to decreased matrix metalloproteinases expression/activity, reduced inflammatory processes and vascular wall fibrosis. In clinical studies, antidiabetic drugs also reduce the production and release of pro‐inflammatory, pro‐atherosclerotic and pro‐oxidative mediators and improve flow‐mediated dilatation, indicating beneficial effects on endothelial function. These bonus effects of antidiabetic drugs may delay and/or reduce the installation and development of the atherosclerotic disease, decrease cardiovascular risk and possibly impact mortality risk, life expectancy and quality.

show abstract

“…We previously demonstrated that the GLP-1R agonists exenatide and liraglutide had neuroprotective and neurotrophic effects in cell and animal models of ischemic stroke, traumatic brain injury, Parkinson's disease (PD), Alzheimer's disease (AD) and ALS (Li et al, 2009, Li et al, 2010a, Li et al, 2012, Salcedo et al, 2012, Eakin et al, 2013, Greig et al, 2014). These data, together with findings by other groups (Bassil et al ., 2014; Holscher 2014; Darsalia et al, 2015; Athauda & Foltynie 2016 and Kuroki et al, 2016), suggest that incretin- based anti-diabetic drugs are neuroprotective and hold promise for repurposing as a treatment strategy for neurodegeneration. Positive pre-clinical data on these compounds has led to several ongoing clinical trials, such as a recent successful open label clinical trial of exenatide in Parkinson's disease patients (Aviles-Olmos et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke

et al. 2017

Experimental Neurology

View full text Add to dashboard Cite

Proglucagon-derived peptides, especially glucagon-like peptide-1 (GLP-1) and its long-acting mimetics, have exhibited neuroprotective effects in animal models of stroke. Several of these peptides are in clinical trials for stroke. Oxyntomodulin (OXM) is a proglucagon-derived peptide that co-activates the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR). The neuroprotective action of OXM, however, has not been thoroughly investigated. In this study, the neuroprotective effect of OXM was first examined in human neuroblastoma (SH-SY5Y) cells and rat primary cortical neurons. GLP-1R and GCGR antagonists, and inhibitors of various signaling pathways were used in cell culture to characterize the mechanisms of action of OXM. To evaluate translation in vivo, OXM-mediated neuroprotection was assessed in a 60-minute, transient middle cerebral artery occlusion (MCAo) rat model of stroke. We found that OXM dose- and time-dependently increased cell viability and protected cells from glutamate toxicity and oxidative stress. These neuroprotective actions of OXM were mainly mediated through the GLP-1R. OXM induced intracellular cAMP production and activated cAMP-response element-binding protein (CREB). Furthermore, inhibition of the PKA and MAPK pathways, but not inhibition of the PI3K pathway, significantly attenuated the OXM neuroprotective actions. Intracerebroventricular administration of OXM significantly reduced cerebral infarct size and improved locomotor activities in MCAo stroke rats. Therefore, we conclude that OXM is neuroprotective against ischemic brain injury. The mechanisms of action involve induction of intracellular cAMP, activation of PKA and MAPK pathways and phosphorylation of CREB.

show abstract

Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice

Cited by 51 publications

References 45 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

Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis

Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke

Contact Info

Product

Resources

About