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

2017; Volume: 26; Issue: 4 Linguagem: Inglês

10.5607/en.2017.26.4.227

2093-8144

Soojin Kim, Jae Won Jeong, Hye-Seon Jung, Bo-Kyung Kim, Ye-Eun Kim, Da-Sol Lim, Sodam Kim, Yun Seon Song,

Adenosine and Purinergic Signaling

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 E 2 after MCAO.C-Jun NH 2 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.