incretins and Infarction--Middle-Cerebral-Artery

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist exendin-4 (Ex-4), a drug that has been used in the clinical treatment of type 2 diabetes mellitus, also confers a neuroprotective effect against stroke. Although GLP-1 analogs were reported to induce sustained insulin secretion and glucose tolerance improved after cessation of treatment, no study has revealed whether Ex-4 exerts sustained neuroprotection against stroke and the underlying mechanism after treatment cessation. In this study, mice were pretreated with Ex-4 for 7 days, and middle cerebral artery occlusion (MCAO) was performed on different days after cessation of Ex-4 treatment. Ex-4 ameliorated neurological dysfunction and reduced the infarct volume induced by MCAO. These protective effects lasted for 6 days after the cessation of Ex-4 treatment and were associated with sustained upregulation of PI3K, AKT, mTOR, and HIF-1α levels, as well as HIF-1α downstream genes. Knockdown of GLP-1R or HIF-1α in the brain by short hairpin RNA abolished Ex-4 treatment-mediated neuroprotection. In normal mice, Ex-4 treatment led to instant upregulation of p-PI3K, p-AKT, p-mTOR, and HIF-1α expression levels, which quickly returned to normal after cessation of Ex-4 treatment, while the expression levels of insulin growth factor-1 receptor (IGF-1R) remained high for 6 days after Ex-4 cessation. Additionally, Ex-4 did not directly induce IGF-1 production, which was only induced by MCAO. Ex-4 induces extended cerebral ischemic tolerance. This neuroprotective effect is associated with activation of GLP-1R and upregulation of IGF-1R in the brain, and the latter then activates the PI3K/AKT/mTOR/HIF-1 signaling pathway via binding to IGF-1 secreted from the ischemic brain.

Topics: Animals; Blood Glucose; Brain; Exenatide; Hypoxia-Inducible Factor 1, alpha Subunit; Incretins; Infarction, Middle Cerebral Artery; Insulin; Male; Mice; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Signal Transduction; TOR Serine-Threonine Kinases

Diabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury.. 72 Sprague-Dawley (SD) male rats were randomly divided into 4 groups: ① blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly.. DA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Brain; Diabetes Mellitus, Experimental; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Infarction, Middle Cerebral Artery; Liraglutide; Neurons; Peptides; Rats, Sprague-Dawley; Receptors, Gastrointestinal Hormone; Reperfusion Injury; Signal Transduction; Streptozocin

Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9-39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO

Topics: Animals; Arterioles; Cerebrovascular Circulation; Disease Models, Animal; Glucagon-Like Peptide-1 Receptor; Hindlimb; Incretins; Infarction, Middle Cerebral Artery; Ischemic Preconditioning; Ischemic Stroke; Male; Neuroprotective Agents; Peptide Fragments; Rats, Sprague-Dawley; Regional Blood Flow; Vasodilation; Vasodilator Agents

A substantial number of ischaemic stroke patients who receive reperfusion therapy in the acute phase do not ever fully recover. This reveals the urgent need to develop new adjunctive neuroprotective treatment strategies alongside reperfusion therapy. Previous experimental studies demonstrated the potential of glucagon-like peptide-1 (GLP-1) to reduce acute ischaemic damage in the brain. Here, we examined the neuroprotective effects of two GLP-1 analogues, liraglutide and semaglutide.. A non-diabetic rat model of acute ischaemic stroke involved 90, 120 or 180 min of middle cerebral artery occlusion (MCAO). Liraglutide or semaglutide was administered either i.v. at the onset of reperfusion or s.c. 5 min before the onset of reperfusion. Infarct size and functional status were evaluated after 24 h or 72 h of reperfusion.. Liraglutide, administered as a bolus at the onset of reperfusion, reduced infarct size by up to 90% and improved neuroscore at 24 h in a dose-dependent manner, following 90-min, but not 120-min or 180-min ischaemia. Semaglutide and liraglutide administered s.c. reduced infarct size by 63% and 48%, respectively, and improved neuroscore at 72 h following 90-min MCAO. Neuroprotection by semaglutide was abolished by GLP1-R antagonist exendin(9-39).. Infarct-limiting and functional neuroprotective effects of liraglutide are dose-dependent. Neuroprotection by semaglutide is at least as strong as by liraglutide and is mediated by GLP-1Rs.

Topics: Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Incretins; Infarction, Middle Cerebral Artery; Liraglutide; Male; Neuroprotective Agents; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Time Factors

Preclinical Research & Development The purpose of the present study is to evaluate the neuroprotective effect of recombinant human glucagon-like peptide-1 (rhGLP-1) as well as to explore corresponding mechanisms in diabetic rats with cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion (MCAO). Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. The rats were pretreated with rhGLP-1 (20 μg/kg intraperitoneally, thrice a day) for 14 days. Thereafter, the rats were subjected to MCAO 90 min/reperfusion 24 hr. At 2 and 24 hr of reperfusion, the rats were assessed for neurological deficits and subsequently executed for the evaluation of cerebral infarct volume, oxidative stress parameters, and the expression of excitatory amino acid transporter 2 (EAAT2) and apoptotic markers. Results indicate that rhGLP-1 significantly ameliorated neurological deficits and reduced cerebral infarct volume in diabetic MCAO rats. In addition, oxidative stress parameters in ischemic penumbra were significantly alleviated in rhGLP-1-pretreated diabetic MCAO rats. rhGLP-1 significantly upregulated the ratio of Bcl-2/Bax and EAAT2 expression and downregulated cleaved caspase-3 expression in ischemic penumbra of diabetic MCAO rats. Our results suggest that rhGLP-1 could significantly ameliorate neurological deficits and reduce cerebral infarct volume in diabetic MCAO rats, which may be due to the inhibition of oxidative stress and apoptosis and the promotion of EAAT2 expression.

Topics: Animals; Apoptosis; Brain Ischemia; Diabetes Complications; Diabetes Mellitus; Excitatory Amino Acid Transporter 2; Glucagon-Like Peptide 1; Humans; Incretins; Infarction, Middle Cerebral Artery; Neuroprotective Agents; Oxidative Stress; Rats; Recombinant Proteins; Reperfusion Injury