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.

Bioactive Peptides

“…More than a single proteolytic enzyme (whether purified or crude) can be used to hydrolyze the protein to produce the hydrolysate containing short peptide sequences. However, addition of the enzymes (whether simultaneously or sequentially) would depend on the optimal pH and temperature of the enzymes [ 14 , 15 , 16 , 17 ]. Though no specific proteolytic enzymes are known to produce specific bioactive peptides in foods, subtilisin hydrolysis tends to yield low molecular weight peptides some of which are bioactive.…”

Olfactomedin-3 Enhances Seizure Activity by Interacting With AMPA Receptors in Epilepsy Models

“…By mediating excitatory synaptic transmission and enhancing the excitatory postsynaptic current, AMPARs ultimately participate in the onset of epilepsy and development ( Jaremko et al, 2017 ; Widagdo et al, 2017 ; Joshi et al, 2018 ). Thus it can be seen AMPAR complexes play a major role in the pathogenesis and development of epilepsy ( Mayer, 2016 ; Adotevi and Leitch, 2017 ; Cai et al, 2017 ). Proteomics and mass spectrometry analysis had been revealed that OLFM3 may be involved in the formation of AMPAR complexes ( Schwenk et al, 2012 ; Shanks et al, 2012 ).…”

Food-Derived Peptides: Beneficial CNS Effects and Cross-BBB Transmission Strategies

“…In addition, after EGAR treatment, epileptic seizures in mice models are shorter and lighter; EGAR shows potential as an antiepileptic drug targeting AMPAR inhibition. 41 Walnut peptide has shown a significant neuroprotective effect on three different mouse epileptic seizure models. Further research shows that walnut peptides play an anticonvulsant role by regulating benzodiazepine receptors (GABA, an ion channel).…”

“…The salmon skin peptide (EGAR) selectively inhibits synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propylene receptor (AMPAR) overactivation in vitro, without affecting the electrophysiological characteristics of hippocampal vertebral neurons, while reducing neuronal peaks in epileptic seizure models. In addition, after EGAR treatment, epileptic seizures in mice models are shorter and lighter; EGAR shows potential as an antiepileptic drug targeting AMPAR inhibition . Walnut peptide has shown a significant neuroprotective effect on three different mouse epileptic seizure models.…”