Abstract WP109: Glucagon-Like Peptide-1 Has Anti-Inflammatory Effects Through Increasing IB1, A Scaffold Regulator Of JNK, In Cerebral Ischemia

Background and Purpose: Hyperglycemia is frequently observed in patients with acute ischemic stroke, and conversely, diabetic patients showed a high frequency of stroke. This correlation indicates shared mechanisms in pathology. Glucagon like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion and is used to treat type 2 diabetes mellitus. Recently, beyond the glucose-lowering effect, GLP-1 has been reported to possess neuroprotective effects. We therefore investigated the neuroprotective mechanism of GLP-1 receptor (GLP-1R) agonist exendin-4 (ex-4) after cerebral ischemia-reperfusion injury. Methods: Male Sprague-Dawley rats were subjected to 60 min of middle cerebral artery occlusion (MCAO) with intracerebroventricular (i.c.v) pretreatment of ex-4. Oxygen glucose deprivation was induced to primary neuron cultures in an anaerobic chamber. Changes of genes were further confirmed by QPCR and Western blot, and siRNA was used to ascertain the mechanism. Results: Ischemia-reperfusion injury reduced the expressions of GLP-1R by 46.3% (p<0.01) ; higher oxidative stress in SOD2 KO mice induced lower expression of GLP-1R, but higher in SOD1 Tg mice. Down regulated GLP-1R by ischemic injury was 70% restored by GLP-1R agonist, ex-4 (p<0.01), which resulted in significant reduction of infarct volume. Intracellular cyclic AMP levels, a second messenger of GLP-1R, were also increased by 2.7 fold according to a high GLP-1R expression (p<0.01). Moreover, our results showed that ex-4 attenuated pro-inflammatory Cyclooxygenase-2 (Cox-2) by 85% (p<0.001) and prostaglandin E2 by 27% (p<0.01) after MCAO. The c-Jun NH 2 terminal kinase (JNK) signaling that stimulates activation of Cox-2 was 36% inhibited by the i.c.v injection of ex-4 at 24 h (p<0.05). Islet-brain 1 (IB1), a scaffold regulator of JNK, was 1.7 fold increased by ex-4 at 24 h. Suppression of IB1 levels with the use of siRNA impaired the anti-inflammatory effects of ex-4 against ischemic injury. Conclusions: GLP-1R activation by ex-4 resulted in reduction of Cox-2 through increasing IB1, which led to anti-inflammatory neuroprotection in stroke. Our study suggests that anti-inflammatory action of GLP-1 could be a new strategy for the treatment of stroke accompanied by hyperglycemia.