title: EGAR, A Food Protein-Derived Tetrapeptide, Reduces Seizure Activity in Pentylenetetrazole-Induced Epilepsy Models Through α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate Receptors.
abstract: A primary pathogeny of epilepsy is excessive activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs). To find potential molecules to inhibit AMPARs, high-throughput screening was performed in a library of tetrapeptides in silico. Computational results suggest that some tetrapeptides bind stably to the AMPAR. We aligned these sequences of tetrapeptide candidates with those from in vitro digestion of the trout skin protein. Among salmon-derived products, Glu-Gly-Ala-Arg (EGAR) showed a high biological affinity toward AMPAR when tested in silico. Accordingly, natural EGAR was hypothesized to have anticonvulsant activity, and in vitro experiments showed that EGAR selectively inhibited AMPAR-mediated synaptic transmission without affecting the electrophysiological properties of hippocampal pyramidal neurons. In addition, EGAR reduced neuronal spiking in an in vitro seizure model. Moreover, the ability of EGAR to reduce seizures was evaluated in a rodent epilepsy model. Briefer and less severe seizures versus controls were shown after mice were treated with EGAR. In conclusion, the promising experimental results suggest that EGAR inhibitor against AMPARs may be a target for antiepilepsy pharmaceuticals. Epilepsy is a common brain disorder characterized by the occurrence of recurring, unprovoked seizures. Twenty to 30 % of persons with epilepsy do not achieve adequate seizure control with any drug. Here we provide a possibility in which a natural and edible tetrapeptide, EGAR, can act as an antiepileptic agent. We have combined computation with in vitro experiments to show how EGAR modulates epilepsy. We also used an animal model of epilepsy to prove that EGAR can inhibit seizures in vivo. This study suggests EGAR as a potential pharmaceutical for the treatment of epilepsy.
authors: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
authors: Song
authors: S
authors: Cai
authors: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.|School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
authors: Chuwen
authors: C
authors: Ling
authors: Research Center of Protein and Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China.
authors: Jun
authors: J
authors: Lu
authors: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.|Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
authors: Songwei
authors: S
authors: Duan
authors: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
authors: Yingzhao
authors: Y
authors: Wang
authors: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
authors: Huining
authors: H
authors: Zhu
authors: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.|Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
authors: Ruibang
authors: R
authors: Lin
authors: Research Center of Protein and Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China.
authors: Liang
authors: L
authors: Chen
authors: Research Center of Protein and Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China.
authors: Xingchang
authors: X
authors: Pan
authors: Research Center of Protein and Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China. caimuyi@vip.sina.com.
authors: Muyi
authors: M
authors: Cai
authors: Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China. 471071491@qq.com.|Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China. 471071491@qq.com.
authors: Huaiyu
authors: H
authors: Gu
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000302:isolation & purification / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D029941:Fish Proteins / Q000008:administration & dosage* / Q000302:isolation & purification / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010433:Pentylenetetrazole; D017434:Protein Structure, Tertiary; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012474:Salmon; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D012867:Skin / Q000737:chemistry
chemical_list: D000927:Anticonvulsants; D029941:Fish Proteins; D018091:Receptors, AMPA; D010433:Pentylenetetrazole
keywords: AMPARs; Drug; Epilepsy; Nervous systems; Tetrapeptide