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

Abstract

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.

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues—Liraglutide and Semaglutide

“…Previously, it had been demonstrated that GLP-1R agonist exendin-4 ameliorates warfarin-associated haemorrhagic transformation after cerebral ischaemia [34]. Importantly, semaglutide has recently been shown in the SUSTAIN-6 trial to have clinical benefit in terms of reducing the rate of non-fatal stroke [34], although studies assessing functional outcome after stroke are still needed [35]. In this regard, our experimental study demonstrated improved functional recovery in rats treated with either liraglutide or semaglutide.…”

“…Although this latter observation still needs to be confirmed by further studies, this possible characteristic of semaglutide can be valuable for the patients with acute ischaemic stroke, especially those undergoing thrombolytic therapy [31][32][33]. Previously, it had been demonstrated that GLP-1R agonist exendin-4 ameliorates warfarin-associated haemorrhagic transformation after cerebral ischaemia [34]. Importantly, semaglutide has recently been shown in the SUSTAIN-6 trial to have clinical benefit in terms of reducing the rate of non-fatal stroke [34], although studies assessing functional outcome after stroke are still needed [35].…”

Neuroprotective exendin-4 enhances hypothermia therapy in a model of hypoxic-ischaemic encephalopathy

“…Several studies have demonstrated a multitude of neuroprotective actions, with exendin-4-mediated PI3K surge in different areas of the CNS, leading to increase in phosphorylation of AKT via PI3K signalling pathway. This mechanism of action is thought to increase the anti- versus pro-apoptotic bcl-2 family protein balance ( Brywe et al , 2005 ; Athauda and Foltynie, 2016 ), attenuate neuroinflammation and stabilize the blood–brain barrier post-transient middle cerebral artery occlusion in non- ( Chen et al , 2016 ) and diabetic mice ( Li et al , 2016 ). Intracellular cAMP levels are also raised in exendin-4-treated post-transient middle cerebral artery occlusion as a result of increased GLP1R expression ( Teramoto et al , 2011 ; Kim et al , 2017 ).…”

Glucagon-like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

“…37,50,55 GLP-1RA administration following stroke induction has been associated with an anti-inflammatory effect. 26 Tumor necrosis factor alpha (TNF-) is a cytokine synthesised by many cell linesbut particularly by macrophages and microglia. 56 TNF- is involved with the inflammatory response following stroke onset.…”