Investigating the Effects of Epoxy Fatty Acids against LPS and Pesticide Induced Toxicity

Abstract

Neuroinflammation is a hallmark of many neurodegenerative diseases including Parkinson’s Disease (PD) and Alzheimer’s Disease (AD), and mitigating neuroinflammation could avert the progression of these disorders. While it is commonly known that inflammation is propagated by COX metabolites of arachidonic acid (ARA) called prostaglandins, it is less known that metabolites of ARA produced by CYP450 called epoxyeicosatrienoic acids (EETs) have been shown to have an anti‐inflammatory and anti‐apoptotic effect in many disease models. Previous studies have demonstrated that increasing the biological availability of EETs by inhibiting soluble epoxide hydrolases (sEH) reduces MPTP or paraquat induced neuroinflammation and prevents the loss of dopaminergic neurons caused by these toxicants. However, the mechanisms underlying such effect is still unknown. In this study, we have treated primary rat astrocyte mixtures with LPS to determine how EETs can affect regulation of growth factors such as its BDNF, GDNF, and VEGF‐A/B. In addition, primary microglia culture was treated with LPS to determine whether microglial activation can be mitigated through the addition of EETs. Finally, N27 dopaminergic neurons were treated with a pesticide rotenone, and the effect of EETs on the survival of dopaminergic neurons were assessed. We have found that EETs and/or sEH inhibition can affect all cells in ways that are be neuroprotective against neuroinflammatory disorders such as Parkinson’s Disease, with reduced inlammatory marker, increased growth factor signaling, and increased neural viability. Future studies may investigate how inhibition of sEH can be used to combat PD in human patients.Support or Funding InformationThis work was supported by the National Institute of Environmental Health Sciences (NIEHS) Grant R01 ES002710, NIEHS Superfund Research Program P42 ES004699, and NIEHS T32 ES007059 (J.A).EETs and sEH inhibitors cause reduction in rotenone induced loss of N27 cell viability.Figure 1EETs and sEH inhibitor along with LPS stimulate growth factor signaling and reduce LPS induced IL‐1b induction.Figure 2