Soluble Epoxide Hydrolase Inhibition Attenuates Excitotoxicity Involving 14,15-Epoxyeicosatrienoic Acid–Mediated Astrocytic Survival and Plasticity to Preserve Glutamate Homeostasis

Jul 2, 2019Molecular neurobiology

Blocking Soluble Epoxide Hydrolase May Reduce Nerve Cell Damage by Helping Support Cells Survive and Maintain Glutamate Balance

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Abstract

Inhibition of soluble epoxide hydrolase reduced NMDA-induced cell death in astrocyte-enriched cultures by preserving astroglial integrity.

Both the sEH inhibitor AUDA and 14,15-EET decreased neurite damage in astrocyte-enriched cultures but not in neuron-enriched cultures.
The protective effects of 14,15-EET and AUDA were blocked by the mGluR5 antagonist MPEP, indicating a dependency on mGluR5 signaling.
Knockdown of sEH expression reduced NMDA neurotoxicity through mechanisms involving mGluR5 and the glutamate transporter GLT-1.
In vivo, both sEH inhibition and genetic deletion of sEH improved outcomes in excitotoxic seizures and memory impairment.
The results indicate that 14,15-EET may protect astrocytes and maintain glutamate homeostasis, relevant for excitotoxic brain injuries.

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Astrocytes play pivotal roles in regulating glutamate homeostasis at tripartite synapses. Inhibition of soluble epoxide hydrolase (sEHi) provides neuroprotection by blocking the degradation of 14,15-epoxyeicosatrienoic acid (14,15-EET), a lipid mediator whose synthesis can be activated downstream from group 1 metabotropic glutamate receptor (mGluR) signaling in astrocytes. However, it is unclear how sEHi regulates glutamate excitotoxicity. Here, we used three primary rat cortical culture systems, neuron-enriched (NE), astrocyte-enriched glia-neuron mix (GN), and purified astrocytes, to delineate the underlying mechanism by which sEHi and 14,15-EET attenuate excitotoxicity. We found that sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) and 14,15-EET both attenuated N-methyl-D-aspartate (NMDA)-induced neurite damage and cell death in GN, not NE, cortical cultures. The anti-excitotoxic effects of 14,15-EET and AUDA were both blocked by the group 1 mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), as were their protective effects against NMDA-disrupted perineuronal astrocyte processes expressing glutamate transporter-1 (GLT-1) and subsequent glutamate uptake. Knockdown of sEH expression also attenuated NMDA neurotoxicity in mGluR5- and GLT-1-dependent manners. The 14,15-EET/AUDA-preserved astroglial integrity was confirmed in glutamate-stimulated primary astrocytes along with the reduction of the c-Jun N-terminal kinase 1 phosphorylation, in which the 14,15-EET effect is mGluR5-dependent. In vivo studies validated that sEHi and genetic deletion of sEH (Ephx2-KO) ameliorated excitotoxic kainic acid-induced seizure, memory impairment, and neuronal loss while preserving GLT-1-expressing perineuronal astrocytes in hippocampal CA3 subregions. These results suggest that 14,15-EET mediates mGluR5-dependent anti-excitotoxicity by protecting astrocytes to maintain glutamate homeostasis, which may account for the beneficial effect of sEH inhibition in excitotoxic brain injury and diseases.

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Soluble Epoxide Hydrolase Inhibition Attenuates Excitotoxicity Involving 14,15-Epoxyeicosatrienoic Acid–Mediated Astrocytic Survival and Plasticity to Preserve Glutamate Homeostasis

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