Soluble Epoxide Hydrolase Inhibitor and 14,15-Epoxyeicosatrienoic Acid-Facilitated Long-Term Potentiation through cAMP and CaMKII in the Hippocampus.

Han-Fang Wu,Yi-Chao Lee,Chi-Wei Lee,Yi-Ju Chen,Su-Zhen Wu,Chih-Wei Tang,I-Tuan Chen,Chi-Chen Huang,Chung-Hsi Hsing,Hui-Ching Lin

doi:10.1155/2017/3467805

Abstract

Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid and metabolized by soluble epoxide hydrolase (sEH). The role of EETs in synaptic function in the central nervous system is still largely unknown. We found that pharmacological inhibition of sEH to stabilize endogenous EETs and exogenous 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing high-frequency stimulation- (HFS-) induced long-term potentiation (LTP) and forskolin- (FSK-) induced LTP. sEH inhibitor (sEHI) N-[1-(oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy) phenyl)-urea (TPPU) and exogenous 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- or 14,15-EET-facilitated FSK-mediated LTP can be potentiated by an A1 adenosine receptor antagonist and a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. sEHI and 14,15-EET upregulated the activation of extracellular signal-regulated kinases (ERKs) and Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII). Phosphorylation of synaptic receptors NR2B and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 was increased by TPPU and 14,15-EET administration. These results indicated that EETs increased NMDAR- and FSK-mediated synaptic potentiation via the AC-cAMP-PKA signaling cascade and upregulated the ERKs and CaMKII, resulting in increased phosphorylation of NR2B and GluR1 in the hippocampus.

Highlights

Epoxyeicosatrienoic acids (EETs) are epoxide derivatives formed from arachidonic acid (ARA)
These results demonstrated that soluble epoxide hydrolase (sEH) inhibitor TPPU increased the endogenous EET level in the hippocampus, and TPPU and exogenous 14,15-EET, but not 20-HETE, enhanced excitatory synaptic transmission
The findings of this study suggested that inhibition of sEH by TPPU and 14,15-EET administration could modulate the synaptic response in the hippocampus area

Summary

Introduction

Epoxyeicosatrienoic acids (EETs) are epoxide derivatives formed from arachidonic acid (ARA). Increasing levels of 14,15-EET enhance the viability of astrocytes and prevent brain damage during ischemic injury [8]. No study has examined the effects of exogenous and endogenous 14,15-EETs in terms of regulating synaptic activity and synapse function. Exogenous EETs 14,15-EET or 11,12-EET have been shown to prevent amyloid β-induced mitochondria dysfunction in cultured hippocampal astrocytes [14]. These previous studies raise the possibility that exogenous EETs might play a role in the modulation of LTP in the CA1 region of the hippocampus. We examined whether exogenous 14,15-EET administration and pharmacologic inhibition of sEH to stabilize endogenous EETs influenced HFS-induced LTP and forskolin-induced LTP. We determined the possible mechanisms underlying LTP enhancement by EETs in the induction phase and maintenance phase

Materials and Methods

Results

Discussion