Exp Neurobiol.  2017 Aug;26(4):227-239. 10.5607/en.2017.26.4.227.

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

• Kim S
• Jeong J
• Jung HS
• Kim B
• Kim YE
• Lim DS
• Kim SD
• Song YS

• KMID: 2389009
• DOI: http://doi.org/10.5607/en.2017.26.4.227

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 Eâ‚‚ after MCAO. C-Jun NHâ‚‚ 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.

Keyword

Neuroinflammation; Cerebral ischemia; Glucagon like peptide-1 receptor; Exendine-4; Islet-brain 1; c-Jun NHâ‚‚ terminal kinase

MeSH Terms

Animals
Brain Ischemia
Cyclic AMP
Cyclooxygenase 2
Diabetes Mellitus, Type 2
Down-Regulation
Glucagon*
Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor
Hyperglycemia
Infarction, Middle Cerebral Artery
Insulin
Mice
Neurons
Neuroprotection
Neuroprotective Agents
Oxidative Stress
Phosphotransferases
Rats
Reperfusion Injury
Second Messenger Systems
Stroke*
Cyclic AMP
Cyclooxygenase 2
Glucagon
Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor
Insulin
Neuroprotective Agents
Phosphotransferases