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 90min 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.

Neuroprotection by remote ischemic conditioning in the setting of acute ischemic stroke: a preclinical two-centre study

“…The extent of the in-vivo ischemic lesions in a rat model with 90-min ischemia is known to maximize at 48 h 48 . However, based on our previous experience 49 , extending the time of reperfusion beyond 24 h is accompanied by an increased mortality in the control group, as well as by an increased occurrence of visible hemorrhagic transformation of stroke in the survived animals. Either the death of animals, observed normally with the largest infarct volumes, or exclusion of animals because of the hemorrhages could end up with the smaller recorded IS than the real one is.…”

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

“…Several studies reported the neuroprotective effects of GLP-1 and GLP-1R agonists in preclinical models of stroke [ 9 , 21 , 45 ]. Yet, the mechanisms underlying the GLP-1R-mediated neuroprotection are not fully understood.…”

“…Twenty four hours after MCAO, all animals underwent behavioural neurological assessment using the 0–22 scale, as described in detail previously [ 9 , 79 ]. The principal points of the functional status evaluation were spontaneous activity, gait, postural signs, lateral resistance, limb placing, and parachute reflex.…”

“…GLP-1 is released by the enteroendocrine cells in the gut and also by the groups of specialized CNS neurons located in the brainstem [ 35 , 66 ]. Experimental studies conducted in gerbils, mice and rats demonstrated that GLP-1 receptor (GLP-1R) agonists Exendin 4 (Ex4), liraglutide or semaglutide, administered either systemically or centrally, are highly effective in protecting the brain against ischaemic stroke induced by bilateral carotid artery occlusion or middle cerebral artery occlusion [ 9 , 21 , 50 , 59 , 78 ]. In at-risk diabetic patients, semaglutide was shown to significantly decrease the incidences of non-fatal strokes [ 60 , 61 ].…”

Neuroprotective Effects of Diabetes Drugs for the Treatment of Neonatal Hypoxia-Ischemia Encephalopathy

“…A PD trial is already completed and has reported that patients on exendin-4 show a statistically significant improvement in clinical motor and cognitive measures compared to the control group (Athauda et al, 2017). Numerous experimental studies also demonstrated the potential of glucagon-like peptide-1 (GLP1) and analog, such as liraglutide or semaglutide, to reduce acute ischaemic damage in the brain Zhu et al, 2016;Basalay et al, 2019;Yang et al, 2019). Exendin-4, liraglutide and quinoxaline 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB, an agonist and allosteric modulator of the GLP-1R) have been shown to increase neuron survival under OGD in vitro by reducing reactive oxygen species (ROS), apoptotic and necrotic mechanisms Zhang et al, 2016;Zhu et al, 2016).…”