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

Shereen Nizari,Frank Reimann,Alexander V Gourine,Alla Korsak,Sean M Davidson,Derek M Yellon,Philippa Chapman,Isabel N Christie,Nils Korte,Shefeeq M Theparambil,Marina Basalay,Stefan Trapp

doi: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.

Highlights

Stroke remains one of the most common causes of death and disability worldwide [42]
remote ischaemic conditioning (RIC) induced by 4 episodes of unilateral femoral ischaemia/reperfusion markedly reduced the cerebral infarct size (8.2 ± 3.4%; p = 0.019) (Fig. 1b) and improved the neurological score (Fig. 1c)
Powerful innate mechanisms of inter-organ protection are activated by remote ischaemic conditioning which can be established by cycles of ischaemia/reperfusion applied to an organ/tissue distant from the organ being protected [13]

Summary

Introduction

Stroke remains one of the most common causes of death and disability worldwide [42]. Interventions to restore cerebral blood flow to the viable tissue surrounding the infarct core, called the penumbra, are efficient if applied within hours after the stroke onset and limited to a large artery clot removal by intravenous thrombolysis or invasive mechanical thrombectomy [74]. Remain constricted and contribute to the noreflow phenomenon after stroke This highlights the need for the development of novel therapies that can effectively. Our body is capable of recruiting powerful innate mechanisms of inter-organ protection against ischaemia/ reperfusion injury These mechanisms effectively protect the heart and the brain and can be activated by cycles of ischaemia/reperfusion applied to an organ or tissue remote to the organ being protected. This well-characterized phenomenon is called remote ischaemic conditioning (RIC) [23, 31, 33, 39, 47]. The mechanisms of RIC-induced neuroprotection are not fully understood and have been proposed to include reduction of astrogliosis, maintenance of blood–brain barrier integrity, the opening of KATP channels, prevention of let7a and miR-43 overexpression, and other mechanisms [15, 20, 48, 69, 70, 77, 82]

Methods

Results

Conclusion