scholarly journals Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Shereen Nizari ◽  
Marina Basalay ◽  
Philippa Chapman ◽  
Nils Korte ◽  
Alla Korsak ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Cortex ◽  
Cerebral Blood Flow ◽  
Ischaemic Stroke ◽  
Receptor Activation ◽  
Remote Ischaemic Conditioning ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Ischaemic Conditioning ◽  
Dilatory Effect

AbstractStroke 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 PO2, indicative of increased cerebral blood flow. These results demonstrate that neuroprotection against ischaemic stroke established by remote ischaemic conditioning is mediated by a mechanism involving GLP-1R signalling. Potent dilatory effect of GLP-1R activation on cortical arterioles suggests that the neuroprotection in this model is mediated via modulation of cerebral blood flow and improved brain perfusion.

scholarly journals Glucagon-like peptide-1 (GLP-1) mediates cardioprotection by remote ischaemic conditioning

2016 ◽  
Vol 112 (3) ◽  
pp. 669-676 ◽  
Author(s):  
Marina V. Basalay ◽  
Svetlana Mastitskaya ◽  
Aleksander Mrochek ◽  
Gareth L. Ackland ◽  
Ana Gutierrez del Arroyo ◽  
...  
Keyword(s):  
Remote Ischaemic Conditioning ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Ischaemic Conditioning

scholarly journals Reply: Glucagon-like peptide-1 mediates cardioprotection by remote ischaemic conditioning

2017 ◽  
Vol 113 (1) ◽  
pp. 13.2-14 ◽  
Author(s):  
Marina Basalay ◽  
Svetlana Mastitskaya ◽  
Aleksander Mrochek ◽  
Gareth L. Ackland ◽  
Ana Gutierrez del Arroyo ◽  
...  
Keyword(s):  
Remote Ischaemic Conditioning ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Ischaemic Conditioning

scholarly journals Residues within the Transmembrane Domain of the Glucagon-Like Peptide-1 Receptor Involved in Ligand Binding and Receptor Activation: Modelling the Ligand-Bound Receptor

2011 ◽  
Vol 25 (10) ◽  
pp. 1804-1818 ◽  
Author(s):  
K. Coopman ◽  
R. Wallis ◽  
G. Robb ◽  
A. J. H. Brown ◽  
G. F. Wilkinson ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Structural Model ◽  
Transmembrane Domain ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Agonist Affinity ◽  
Camp Generation ◽  
N Terminus ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The C-terminal regions of glucagon-like peptide-1 (GLP-1) bind to the N terminus of the GLP-1 receptor (GLP-1R), facilitating interaction of the ligand N terminus with the receptor transmembrane domain. In contrast, the agonist exendin-4 relies less on the transmembrane domain, and truncated antagonist analogs (e.g. exendin 9–39) may interact solely with the receptor N terminus. Here we used mutagenesis to explore the role of residues highly conserved in the predicted transmembrane helices of mammalian GLP-1Rs and conserved in family B G protein coupled receptors in ligand binding and GLP-1R activation. By iteration using information from the mutagenesis, along with the available crystal structure of the receptor N terminus and a model of the active opsin transmembrane domain, we developed a structural receptor model with GLP-1 bound and used this to better understand consequences of mutations. Mutation at Y152 [transmembrane helix (TM) 1], R190 (TM2), Y235 (TM3), H363 (TM6), and E364 (TM6) produced similar reductions in affinity for GLP-1 and exendin 9–39. In contrast, other mutations either preferentially [K197 (TM2), Q234 (TM3), and W284 (extracellular loop 2)] or solely [D198 (TM2) and R310 (TM5)] reduced GLP-1 affinity. Reduced agonist affinity was always associated with reduced potency. However, reductions in potency exceeded reductions in agonist affinity for K197A, W284A, and R310A, while H363A was uncoupled from cAMP generation, highlighting critical roles of these residues in translating binding to activation. Data show important roles in ligand binding and receptor activation of conserved residues within the transmembrane domain of the GLP-1R. The receptor structural model provides insight into the roles of these residues.

The Study of Electroacupuncture on Cerebral Blood Flow in Rats With and Without Cerebral Ischemia

2006 ◽  
Vol 34 (02) ◽  
pp. 351-361 ◽  
Author(s):  
Ching-Liang Hsieh ◽  
Qwang-Yuen Chang ◽  
I-hsin Lin ◽  
Jaung-Geng Lin ◽  
Chung-Hsiang Liu ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Cortex ◽  
Cerebral Blood Flow ◽  
Cerebral Ischemia ◽  
Peripheral Blood ◽  
Sprague Dawley ◽  
Calcitonin Gene ◽  
Cerebral Ischemic ◽  
Induced Changes ◽  
Common Carotid Arteries

Electroacupuncture (EA) is widely used to treat disorders of the nervous system, such as stroke. The aim of the present study was to investigate the effect of EA on cerebral blood flow (CBF) in cerebral ischemic rats. We developed an animal model of cerebral ischemia (CI) by occluding the blood flow of both common carotid arteries in Sprague-Dawley (SD) rats; 2 or 15 Hz EA was applied to both Zusanli acupoints. The levels of nitric oxide (NO) in the peripheral blood and amounts of calcitonin gene-related peptide (CGRP) in the cerebral cortex and thalamus were measured. In addition, L-N (G)-nitro arginine methyl ester (L-NAME) was used to measure the changes in CBF induced by EA in rats with and without CI. The results indicated that both 2 and 15 Hz EA increase the mean CBF in rats with and without CI. However, neither 2 nor 15 Hz EA induced changes in levels of NO in peripheral blood or changes in CGRP levels in cerebral cortex and thalamus. In addition, L-NAME did not change the increase in CBF. We concluded that both 2 and 15 Hz EA at both Zusanli acupoints induced the increase of CBF in rats with and without CI. Whether the effect of EA is related to NO or CGRP will be investigated in a future study.

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