Anti-inflammatory Effect of Glucagon Like Peptide-1 Receptor Agonist, Exendin-4, through Modulation of IB1/JIP1 Expression and JNK Signaling in Stroke

Abstract

Glucagon like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors, which block inactivation of GLP-1, are currently in clinical use for type 2 diabetes mellitus. Recently, GLP-1 has also been reported to have neuroprotective effects in cases of cerebral ischemia. We therefore investigated the neuroprotective effects of GLP-1 receptor (GLP-1R) agonist, exendin-4 (ex-4), after cerebral ischemia-reperfusion injury. Transient middle cerebral artery occlusion (tMCAO) was induced in rats by intracerebroventricular (i.c.v.) administration of ex-4 or ex9-39. Oxygen-glucose deprivation was also induced in primary neurons, bEnd.3 cells, and BV-2. Ischemia-reperfusion injury reduced expression of GLP-1R. Additionally, higher oxidative stress in SOD2 KO mice decreased expression of GLP-1R. Downregulation of GLP-1R by ischemic injury was 70% restored by GLP-1R agonist, ex-4, which resulted in significant reduction of infarct volume. Levels of intracellular cyclic AMP, a second messenger of GLP-1R, were also increased by 2.7-fold as a result of high GLP-1R expression. Moreover, our results showed that ex-4 attenuated pro-inflammatory cyclooxygenase-2 (COX-2) and prostaglandin E2 after MCAO. C-Jun NH2 terminal kinase (JNK) signaling, which stimulates activation of COX-2, was 36% inhibited by i.c.v. injection of ex-4 at 24 h. Islet-brain 1 (IB1), a scaffold regulator of JNK, was 1.7-fold increased by ex-4. GLP-1R activation by ex-4 resulted in reduction of COX-2 through increasing IB1 expression, resulting in anti-inflammatory neuroprotection during stroke. Our study suggests that the anti-inflammatory action of GLP-1 could be used as a new strategy for the treatment of neuroinflammation after stroke accompanied by hyperglycemia.

Inflammatory cell populations in early neuroinflammation in the core and peri-ischemic lesions of rat brain after transient focal cerebral ischemia: A morphometric study

“…COX-2 expression in ischemic tissue is quickly up-regulated after tMCAO together with MMP-2 and MMP-9 activity. Increased levels of COX-2 increase the level of prostaglandin E, with tissue destruction and early development of oedema (Kim et al, 2017). In our study, we found significantly higher COX-2-positive surface area in the penumbra than in the core.…”

Preventive Effects of Dulaglutide on Disuse Muscle Atrophy Through Inhibition of Inflammation and Apoptosis by Induction of Hsp72 Expression

“…Disuse-induced skeletal muscle atrophy is closely related to inflammatory process (Hunter et al, 2002). In addition, GLP-1based therapies have been shown to exert anti-inflammatory effects in chronic inflammatory diseases (Kim et al, 2017). We evaluated the expression of inflammatory cytokines and found that the mRNA levels of TNF-a, IL-1b, and IL-6 in the GA muscle were upregulated following 10 days from immobilization and that dulaglutide treatment inhibited this increase ( Figure 4A).…”

The impact of exenatide (a GLP‑1 agonist) on markers of inflammation and oxidative stress in normal human astrocytes subjected to various glycemic conditions

“…Excessive oxidative stress was also abolished by exenatide in the ischemic model of cardiac muscle injury (46). Noteworthy, it was also noted that excessive oxidative stress that occurred in rat model of cerebral stroke led to a significant reduction in the level of GLP-1 receptors (47). This loss might be at least partly compensated by the exogenously administered exenatide.…”