Neurotherapeutics

, Volume 14, Issue 1, pp 212–226

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

  • Song Cai
  • Chuwen Ling
  • Jun Lu
  • Songwei Duan
  • Yingzhao Wang
  • Huining Zhu
  • Ruibang Lin
  • Liang Chen
  • Xingchang Pan
  • Muyi Cai
  • Huaiyu Gu
Original Article

DOI: 10.1007/s13311-016-0489-4

Cite this article as:
Cai, S., Ling, C., Lu, J. et al. Neurotherapeutics (2017) 14: 212. doi:10.1007/s13311-016-0489-4
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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.

Keywords

Epilepsy Tetrapeptide AMPARs Drug Nervous systems 

Supplementary material

13311_2016_489_MOESM1_ESM.pdf (3.5 mb)
ESM 1(PDF 3598 kb)

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2016

Authors and Affiliations

  • Song Cai
    • 1
  • Chuwen Ling
    • 1
    • 2
  • Jun Lu
    • 3
  • Songwei Duan
    • 1
    • 4
  • Yingzhao Wang
    • 1
  • Huining Zhu
    • 1
  • Ruibang Lin
    • 1
    • 4
  • Liang Chen
    • 3
  • Xingchang Pan
    • 3
  • Muyi Cai
    • 3
  • Huaiyu Gu
    • 1
    • 5
  1. 1.Department of Anatomy, Zhongshan School of MedicineSun Yat-Sen UniversityGuangzhouChina
  2. 2.School of Public HealthSun Yat-Sen UniversityGuangzhouChina
  3. 3.Research Center of Protein and Functional PeptidesChina National Research Institute of Food and Fermentation IndustriesBeijingChina
  4. 4.Guanghua School of StomatologySun Yat-Sen UniversityGuangzhouChina
  5. 5.Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of MedicineSun Yat-sen UniversityGuangzhouChina