Epoxy Fatty Acids and Inhibition of the Soluble Epoxide Hydrolase Selectively Modulate GABA Mediated Neurotransmission to Delay Onset of Seizures

Abstract

In the brain, seizures lead to release of large amounts of polyunsaturated fatty acids including arachidonic acid (ARA). ARA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert ARA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosatrienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory and reduce the excitability of neurons. Recent evidence suggests a GABA-related mode of action potentially mediated by neurosteroids. Here we tested this hypothesis using models of chemically induced seizures. The level of EETs in the brain was modulated by inhibiting the soluble epoxide hydrolase (sEH), the major enzyme that metabolizes EETs to inactive molecules, by genetic deletion of sEH and by direct administration of EETs into the brain. All three approaches delayed onset of seizures instigated by GABA antagonists but not seizures through other mechanisms. Inhibition of neurosteroid synthesis by finasteride partially blocked the anticonvulsant effects of sEH inhibitors while the efficacy of an inactive dose of neurosteroid allopregnanolone was enhanced by sEH inhibition. Consistent with earlier findings, levels of prostanoids in the brain were elevated. In contrast, levels of bioactive EpFAs were decreased following seizures. Overall these results demonstrate that EETs are natural molecules which suppress the tonic component of seizure related excitability through modulating the GABA activity and that exploration of the EET mediated signaling in the brain could yield alternative approaches to treat convulsive disorders.

Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality

“…44 AA is also converted to a range of active metabolites, including potent resolvers of inflammation such as lipoxins and epoxy fatty acids (EETs). 45, 46 However, our findings do not support substantial influence of circulating AA, GLA, or DGLA on total mortality in older adults. The inverse association of AA and death from dementia deserves further investigation as prior observational studies provide mixed evidence for associations of AA with dementia and cognitive function.…”

Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain

“…The rapid effects of EpFAs and sEHI suggest it is more likely that phosphorylation of key targets may be altered by EpFAs. Although these pending questions about details of mechanism of action of EpFAs remain to be understood, stronger evidence points toward positive modulation of the GABAergic signaling because sEHI and EpFAs are anticonvulsant in models of seizures, only when GABA antagonists are used (16). Furthermore, their efficacy is reversible by blockage of the steroid and neurosteroid synthetic pathways at distinct steps.…”

The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling

“…The EETs have demonstrated activity on centrally mediated pain and seizure via intrathecal and i.c.v. injection [36, 100]. Picrotoxin, an antagonist of GABA signaling, blocks antinociception mediated by elevated EpFAs and EpFAs demonstrate efficacy altering GABA signaling in chemically but not electrically induced seizure models [100, 101].…”