Abstract
Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that protects against brain injury. However, little is known about the effect of Ex-4 on kainic acid (KA)-induced seizures and hippocampal cell death. Therefore, this study evaluated the neuroprotective effects of Ex-4 pretreatment in a mouse model of KA-induced seizures. Three days before KA treatment, mice were intraperitoneally injected with Ex-4. We found that Ex-4 pretreatment reversed KA-induced reduction of GLP-1R expression in the hippocampus and attenuated KA-induced seizure score, hippocampal neuronal death, and neuroinflammation. Ex-4 pretreatment also dramatically reduced hippocampal lipocalin-2 protein in KA-treated mice. Furthermore, immunohistochemical studies showed that Ex-4 pretreatment significantly alleviated blood–brain barrier leakage. Finally, Ex-4 pretreatment stimulated hippocampal expression of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), a known target of GLP-1/GLP-1R signaling. These findings indicate that Ex-4 pretreatment may protect against KA-induced neuronal damage by regulating GLP-1R/CREB-mediated signaling pathways.
Highlights
The kainic acid (KA) mouse model of seizures and epilepsy has been proven to be an important system for understanding seizure pathology and developing therapeutic agents
We explored the effects of Ex-4 pretreatment on hippocampal neuronal death, neuroinflammation, and blood–brain barrier (BBB) breakdown in KA-induced seizure mice
Our findings suggest that activation of glucagon-like peptide-1 receptor (GLP-1R) by Ex-4 pretreatment protected against hippocampal damage via upregulation of the p-CREB signaling pathway
Summary
The kainic acid (KA) mouse model of seizures and epilepsy has been proven to be an important system for understanding seizure pathology and developing therapeutic agents. Several studies have shown that activation of GLP-1/GLP-1 receptor (GLP-1R) signaling leads to protection against memory loss, neuroinflammation, and neurotoxicity [12,13,14,15]. Already used as a treatment for type 2 diabetes mellitus, Ex-4 has been shown by several studies to exert neuroprotective effects in brain injury models, such as subarachnoid hemorrhage, hyperthermia-induced seizures, and cerebral ischemia [9,12,16,20]. We explored the effects of Ex-4 pretreatment on hippocampal neuronal death, neuroinflammation, and BBB breakdown in KA-induced seizure mice. Our findings suggest that activation of GLP-1R by Ex-4 pretreatment protected against hippocampal damage via upregulation of the p-CREB signaling pathway
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