Altered expression of hypoxia-Inducible factor-1α participates in the epileptogenesis in animal models

• Published in: Synapse (New York, N.Y.) Vol. 68; no. 9; pp. 402 - 409
• Main Authors: Jie, Li, Guohui, Jiang, Chen, Yalan, Chen, Ling, Li, Zengyou, Wang, Zhihua, Wang, Xuefeng
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.09.2014
• Subjects: Acute Disease; Amino Acids, Dicarboxylic - pharmacology; Animals; Brain - drug effects; Brain - physiopathology; Central Nervous System Agents - pharmacology; Chronic Disease; Disease Models, Animal; Disulfides - pharmacology; epilepsy; Epilepsy - drug therapy; Epilepsy - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - agonists; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia-inducible factor-1α; Lithium Compounds; Male; Pentylenetetrazole; Pilocarpine; Random Allocation; Rats, Sprague-Dawley; Seizures - drug therapy; Seizures - physiopathology; spontaneous recurrent seizures; Status Epilepticus - drug therapy; Status Epilepticus - physiopathology; Sulfonamides - pharmacology; epilepsy; spontaneous recurrent seizures; hypoxia-inducible factor-1α
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.21752

ABSTRACT Although epilepsy is a common neurological disorder, its mechanism(s) are still not completely understood. Hypoxia can lead to neuronal cell death and angiogenesis, and the same mechanisms were also found in epilepsy. Hypoxia‐inducible factor‐1α (HIF‐1α) is an important transcription protein that regulates gene expression in the brain and other tissues in response to decreases in oxygen availability. However, little is known regarding the expression of HIF‐1α in the epileptic brain and whether HIF‐1α interventions affect the epileptic process. The aims of this study are to investigate the expression profile of HIF‐1α in rat models and to explore the role of HIF‐1α in epilepsy. We performed Western blots and immunofluorescence in a lithium‐pilocarpine rat epilepsy model. To determine the role of HIF‐1α in epilepsy, we used the HIF‐1α agonist DMOG and inhibitor KC7F2 to detect changes in the animal behavior in pentylenetetrazole (PTZ) and lithium‐pilocarpine epilepsy models. The expression of HIF‐1α was significantly increased after pilocarpine‐induced status epilepticus. DMOG significantly prolonged the latent period in the PTZ kindling model and decreased the rate of spontaneous recurrent seizures during the chronic stage in the lithium‐pilocarpine model. Conversely, the inhibitor KC7F2 produced an opposite behavioral change. Interestingly, both KC7F2 and DMOG had no effect on the acute stage of pilocarpine model and PTZ convulsive model. Our study suggests that upregulated HIF‐1α may be involved in the process of epileptogenesis but not in the acute stage of epilepsy. The modulation of HIF‐1α may offer a novel therapeutic target in epilepsy. Synapse, 2014. © 2014 Wiley Periodicals, Inc. Behavior changes showed that the spontaneous seizure times of HIF‐1α agonist DMOG‐treated group were significantly decreased compared with those of the control groups during the chronic period in the lithium‐pilocarpine epilepsy model. Conversely, its inhibitor KC7F2 produced an opposite behavioral change.