Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke.
Authors
Nizari, Shereen
Basalay, Marina
Chapman, Philippa
Korte, Nils
Korsak, Alla
Christie, Isabel N
Theparambil, Shefeeq M
Davidson, Sean M
Reimann, Frank
Trapp, Stefan
Yellon, Derek M
Publication Date
2021-05-03Journal Title
Basic Res Cardiol
ISSN
0300-8428
Publisher
Springer Science and Business Media LLC
Volume
116
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Nizari, S., Basalay, M., Chapman, P., Korte, N., Korsak, A., Christie, I. N., Theparambil, S. M., et al. (2021). Glucagon-like peptide-1 (GLP-1) receptor activation dilates cerebral arterioles, increases cerebral blood flow, and mediates remote (pre)conditioning neuroprotection against ischaemic stroke.. Basic Res Cardiol, 116 (1) https://doi.org/10.1007/s00395-021-00873-9
Abstract
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 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.
Keywords
Original Contribution, Brain arterioles, Brain capillaries, Cerebral blood flow, Glucagon-like peptide-1, Ischaemic stroke, Middle cerebral artery occlusion, Neuroprotection, Remote ischaemic preconditioning
Sponsorship
MRC (MC_UU_00014/3)
Identifiers
s00395-021-00873-9, 873
External DOI: https://doi.org/10.1007/s00395-021-00873-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333194
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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