Journal
NEUROCHEMICAL RESEARCH
Volume 45, Issue 11, Pages 2664-2678Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-020-03118-8
Keywords
Epilepsy; Ergothioneine; Metabolomics; Pentylenetetrazole; Seizure; Slc22a4
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [19K07126, 15H04664]
- Hoansha Foundation (Osaka, Japan)
- Grants-in-Aid for Scientific Research [19K07126, 15H04664] Funding Source: KAKEN
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Understanding of the underlying mechanism of epilepsy is desired since some patients fail to control their seizures. The carnitine/organic cation transporter OCTN1/SLC22A4 is expressed in brain neurons and transports food-derived antioxidant ergothioneine (ERGO),l-carnitine, and spermine, all of which may be associated with epilepsy. This study aimed to clarify the possible association of this transporter with epileptic seizures. In both pentylenetetrazole (PTZ)-induced acute seizure and kindling models,ocnt1gene knockout mice (octn1(-/-)) showed lower seizure scores compared with wild-type mice. Up-regulation of the epilepsy-related genes,c-fosandArc,and the neurotrophic factor BDNF following PTZ administration was observed in the hippocampus of wild-type, but notoctn1(-/-)mice. To find the OCTN1 substrate associated with the seizure, untargeted metabolomics analysis using liquid chromatography-quadrupole time-of-flight mass spectrometry was conducted on extracts from the hippocampus, frontal cortex, and plasma of both strains, leading to the identification of a plant alkaloid homostachydrine as a compound present in a lower concentration inoctn1(-/-)mice. OCTN1-mediated uptake of deuterium-labeled homostachydrine was confirmed in OCTN1-transfected HEK293 cells, suggesting that this compound is a substrate of OCTN1. Homostachydrine administration increased PTZ-induced acute seizure scores and the expression ofArcin the hippocampus and that ofArc,Egr1, and BDNF in the frontal cortex. Conversely, administration of the OCTN1 substrate/inhibitor ERGO inhibited PTZ-induced kindling and reduced the plasma homostachydrine concentration. Thus, these results suggest that OCTN1 is at least partially associated with PTZ-induced seizures, which is potentially deteriorated by treatment with homostachydrine, a newly identified food-derived OCTN1 substrate.
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