Soluble epoxide hydrolase: a new therapeutic target for depression

Hashimoto, Kenji

doi:10.1080/14728222.2016.1226284

Cited by 23 publications

(34 citation statements)

References 16 publications

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“…Thus, it seems that increases in the sEH in the PFC might play a role in the behavioral and biochemical abnormalities seen in juvenile offspring after MIA. Previously, we reported increased levels of sEH in the parietal cortex from schizophrenia patients compared with controls (22). In this study, we found higher levels of EPHX2 mRNA in the neurospheres from iPSC from schizophrenia patients and in the postmortem brain samples from ASD patients.…”

Section: Discussionsupporting

confidence: 63%

“…iPSC technologies have provided an unprecedented opportunity to establish pluripotent stem cells from patients with schizophrenia and differentiate them into a neuronal lineage, enabling an in vitro recapitulation of the pathogenesis of the disease (32). Previously, we reported that expression of sEH in the parietal cortex [Brodmann area (BA) 7] from schizophrenia patients was significantly higher than that of controls (22). Therefore, we measured whether sEH gene expression alters in the neurospheres from iPSCs from schizophrenia patients with the 22q11.2 deletion (SI Appendix, Table S4) and healthy controls (33).…”

Section: Levels Of Seh and Eicosanoid Metabolites In The Brain From Jmentioning

confidence: 99%

“…However, these mediators are broken down into their corresponding diols by soluble epoxide hydrolase (sEH), and inhibition of sEH enhances the beneficial effects of EpFAs such as EETs (16)(17)(18). Potent antiinflammatory effects of EETs and key role of sEH have been reported in multiple animal models, including pain, obesity, depression, and Parkinson's disease (19)(20)(21)(22)(23)(24)(25)(26)(27). However, there are no reports showing the role of sEH in the pathogenesis of neurodevelopmental disorders in offspring after MIA.…”

mentioning

confidence: 99%

“…Furthermore, we measured the expression of EPHX2 mRNA in postmortem brain samples from ASD patients, as well as age-matched control subjects. Third, we examined whether 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor (22,30,31), during juvenile and adolescent stages could prevent behavioral abnormalities and reduction of parvalbumin (PV) and glutamic acid decarboxylase (GAD 67 ) immunoreactivity (IR) in the medial prefrontal cortex (mPFC) in adult offspring after MIA. Furthermore, the effects of TPPU on endoplasmic reticulum (ER) stress in the brain from adult offspring after MIA were also examined.…”

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confidence: 99%

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Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

Ren

Yang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia-and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cellderived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA. epoxy fatty acid | ER stress | iPSCs | maternal infection | prevention E pidemiological studies implicate prenatal environmental factors, including maternal immune activation (MIA), in playing a key role in the etiology of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) (1-7). A number of studies suggest associations between maternal infections or inflammatory biomarkers and schizophrenia and ASD (2-4, 7). For example, there are key epidemiological results supporting associations between maternal infectious pathogens (i.e., influenza virus, herpes simplex virus, Toxoplasma gondii, rubella, and bacterial pathogens) and inflammatory biomarkers (i.e., cytokines and Creactive protein) and schizophrenia (2,7,8). The Finnish Prenatal Studies birth cohort showed that elevated maternal levels of Creactive protein in early to midgestation was related to an increased risk of ASD in offspring (9), although maternal midpregnancy levels of C-reactive protein were related to a decreased risk of ASD (10). A meta-analysis suggests that maternal infection during pregnancy increases the risk of ASD in offspring (4). Collectively, MIA during pregnancy can increase the risk of neurodevelopmental disorders in offspring. The onset of schizop...

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Section: Discussionsupporting

confidence: 63%

Section: Levels Of Seh and Eicosanoid Metabolites In The Brain From Jmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

Ren

Yang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…This rapid anti-depressive action is without any observable side effects unlike ketamine which is now known to have rapid effects against depression but has major psychotomimetic side effects and abuse potential (Kirby, 2015). Thus, it is now suggested that sEHI may be a promising new strategy to combat depression (Hashimoto, 2016). …”

Section: Seh As a Target For Neurodegenerative Diseasesmentioning

confidence: 99%

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

Wagner

McReynolds

Schmidt

et al. 2017

Pharmacology & Therapeutics

217

204

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Eicosanoids are biologically active lipid signaling molecules derived from polyunsaturated fatty acids. Many of the actions of eicosanoid metabolites formed by cyclooxygenase and lipoxygenase enzymes have been characterized, however, the epoxy-fatty acids (EpFAs) formed by cytochrome P450 enzymes are newly described by comparison. The EpFA metabolites modulate a diverse set of physiologic functions that include inflammation and nociception among others. Regulation of EpFAs occurs primarily via release, biosynthesis and enzymatic transformation by the soluble epoxide hydrolase (sEH). Targeting sEH with small molecule inhibitors has enabled observation of the biological activity of the EpFAs in vivo in animal models, greatly contributing to the overall understanding of their role in the inflammatory response. Their role in modulating inflammation has been demonstrated in disease models including cardiovascular pathology and inflammatory pain, but extends to neuroinflammation and neuroinflammatory disease. Moreover, while the EpFA demonstrate activity against inflammatory pain, interestingly, this action extends to blocking chronic neuropathic pain as well. This review outlines the role of modulating sEH and the biological action of EpFA in models of pain and inflammatory diseases.

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Recent Advances in the Early Intervention in Schizophrenia: Future Direction from Preclinical Findings

Hashimoto

2019

Curr Psychiatry Rep

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Soluble epoxide hydrolase: a new therapeutic target for depression

Cited by 23 publications

References 16 publications

Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

Recent Advances in the Early Intervention in Schizophrenia: Future Direction from Preclinical Findings

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