exenatide and Hemorrhage

Tissue plasminogen activator (tPA) is recommended by the FDA to dissolve intravascular clots after acute ischemic stroke (AIS). However, it may contribute to hemorrhagic transformation (HT). The Wnt/β-catenin signaling pathway plays an important role in regulating the blood-brain barrier (BBB) formation in the central nervous system. We explored whether glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4) reduces the risk of HT after rtPA treatment via the Wnt/β-catenin pathway by using a rat transient middle cerebral artery occlusion (MCAO) model in vivo and an oxygen-glucose deprivation plus reoxygenation (OGD/R) model in vitro. Our results showed that EX-4 attenuated neurological deficits, brain edema, infarct volume, BBB disruption, and rtPA-induced HT in ischemic stroke. EX-4 suppressed the production of ROS and the activation of MMP-9 to protect the integrity of the BBB by activating the Wnt/β-catenin signaling pathway. PRI-724, a selective inhibitor of β-catenin, was able to reverse the therapeutic effect of EX-4 in vivo and in vitro. Therefore, our results indicate that the GLP-1R agonist may be a potential therapeutic agent to decrease the risk of rtPA-induced HT after ischemic stroke via the Wnt/β-catenin signaling pathway.

Topics: Animals; beta Catenin; Exenatide; Hemorrhage; Ischemic Stroke; Rats; Stroke; Tissue Plasminogen Activator; Wnt Signaling Pathway

Diabetes mellitus is an endemic disease of the current era. It is important to treat it properly. All antidiabetic medications have side effects and various safety profiles.. Fifty-two years old patient with type II diabetes mellitus, who had spontaneous cutaneous and intra muscular bleeding after starting treatment with Exenatide. The patient's history did not include any kind of spontaneous bleeding. Investigations did not reveal abnormal platelets count and function or coagulation profile. The use of the Exenatide was discontinued and during one year of follow-up, the patient did not experience an additional occurrence of spontaneous bleeding.. To the best of our knowledge, this is the first report of spontaneous bleeding probably caused by Exenatide. The exact pathophysiology, by which the drug can cause spontaneous bleeding, is still not clear and has to be revealed.

Topics: Aged; Diabetes Mellitus, Type 2; Exenatide; Hemorrhage; Humans; Hypoglycemic Agents; Male; Middle Aged; Muscle, Skeletal; Skin

As 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.. We 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.. We 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.. GLP-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.

Topics: Animals; Anticoagulants; Blood-Brain Barrier; Brain; Brain Infarction; Brain Ischemia; Cytokines; Disease Models, Animal; Exenatide; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Hemorrhage; Hypoglycemic Agents; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Microglia; Nervous System Diseases; Peptides; Signal Transduction; Venoms; Warfarin