Dataset Information

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues-Liraglutide and Semaglutide.

ABSTRACT:

Purpose

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.

Methods

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.

Results

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).

Conclusion

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.

SUBMITTER: Basalay MV

PROVIDER: S-EPMC6994526 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues-Liraglutide and Semaglutide.

Basalay Maryna V MV Davidson Sean M SM Yellon Derek M DM

Cardiovascular drugs and therapy 20191201 6

<h4>Purpose</h4>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 semaglut ...[more]

PMID: 31721014

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Project description:The circadian clock is closely related to the development of diabetes mellitus and cardiovascular disease, and disruption of the circadian clock exacerbates myocardial ischaemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop that controls the expression pattern of the circadian nuclear receptor Rev-erbα to maintain the stability of circadian genes such as BMAL1. However, the mechanism by which the HDAC3-orchestrated Rev-erbα/BMAL1 pathway increases MI/RI in diabetes and its relationship with mitophagy have yet to be elucidated. Here, we observed that the clock genes Rev-erbα, BMAL1, and C/EBPβ oscillations were altered in the hearts of rats with streptozotocin (STZ)-induced diabetes, with upregulated HDAC3 expression. Oscillations of Rev-erbα and BMAL1 were rapidly attenuated in diabetic MI/R hearts versus non-diabetic I/RI hearts, in accordance with impaired and rhythm-disordered circadian-dependent mitophagy that increased injury. Genetic knockdown of HDAC3 significantly attenuated diabetic MI/RI by mediating the Rev-erbα/BMAL1 circadian pathway to recover mitophagy. Primary cardiomyocytes with or without HDAC3 siRNA and Rev-erbα siRNA were exposed to hypoxia/reoxygenation (H/R) in vitro. The expression of HDAC3 and Rev-erbα in cardiomyocytes was increased under high-glucose conditions compared with low-glucose conditions, with decreased BMAL1 expression and mitophagy levels. After H/R stimulation, high glucose aggravated H/R injury, with upregulated HDAC3 and Rev-erbα expression and decreased BMAL1 and mitophagy levels. HDAC3 and Rev-erbα siRNA can alleviate high glucose-induced and H/R-induced injury by upregulating BMAL1 to increase mitophagy. Collectively, these findings suggest that disruption of HDAC3-mediated circadian gene expression oscillations induces mitophagy dysfunction, aggravating diabetic MI/RI. Cardiac-specific HDAC3 knockdown could alleviate diabetic MI/RI by regulating the Rev-erbα/BMAL1 pathway to restore the activation of mitophagy.

Dataset Information

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues-Liraglutide and Semaglutide.

Purpose

Methods

Results

Conclusion

Publications

Neuroprotection in Rats Following Ischaemia-Reperfusion Injury by GLP-1 Analogues-Liraglutide and Semaglutide.

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