The hypoxia mimetic protocatechuic acid ethyl ester inhibits synaptic signaling and plasticity in the rat hippocampus

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Title: The hypoxia mimetic protocatechuic acid ethyl ester inhibits synaptic signaling and plasticity in the rat hippocampus
Authors: Lanigan, Sinead
O'Connor, J. J.
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Date: 15-Jan-2018
Online since: 2019-03-20T10:55:40Z
Abstract: During hypoxia a number of physiological changes occur within neurons including the stabilization of hypoxia-inducible factors (HIFs). The activity of these proteins is regulated by O2, Fe2+, 2-OG and ascorbate-dependant hydroxylases which contain prolyl-4-hydroxylase domains (PHDs). PHD inhibitors have been widely used and have been shown to have a preconditioning and protective effect against a later and more severe hypoxic insult. In this study we have investigated the neuroprotective effects of the PHD inhibitor, protocatechuic acid ethyl ester (ethyl 3,4, dihydroxybenzoate: EDHB) as well as its effects on synaptic transmission and plasticity in the rat hippocampus using electrophysiological techniques. We report for the first time, an acute concentration-dependent and reversible inhibitory effect of EDHB (10–100 μM) on synaptic transmission in the dentate gyrus but not Cornu Ammonis 1 (CA1) region which does not affect cell viability. This effect was attenuated through the application of the NMDA or GABAA receptor antagonists, AP-5 and picrotoxin in the dentate gyrus. There were no changes in the ratio of paired responses after EDHB application suggesting a post-synaptic mechanism of action. EDHB (100 μM), was found to inhibit synaptic plasticity in both the dentate gyrus and CA1 regions. Application of exogenous Fe2+ (100 μM) or digoxin (100 nM) did not reverse EDHB’s inhibitory effect on synaptic transmission or plasticity in both regions, suggesting that its effects may be HIF-independent. These results highlight a novel modulatory role for the PHD inhibitor EDHB in hippocampal synaptic transmission and plasticity. A novel post-synaptic mechanism of action may be involved possibly involving NMDA and GABAA receptor activation.
Type of material: Journal Article
Publisher: Elsevier
Journal: Neuroscience
Volume: 369
Start page: 168
End page: 182
Copyright (published version): 2017 Elsevier
Keywords: Protocatechuic acid ethyl ester/ethyl 3,4, dihydroxybenzoateProlyl hydroxylaseEPSPHypoxiaLTPHippocampus
DOI: 10.1016/j.neuroscience.2017.11.011
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Biomolecular and Biomedical Science Research Collection

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