Inflammation inhibitor blocks neurodevelopmental disorders in mouse model

Summary: Increased levels of epoxide hydrolase in the prefrontal cortex were found in the brains of young mice whose mothers had suffered infection during pregnancy. Inhibiting epoxide hydrolase reverses cognitive and social deficits associated with neurodevelopmental disorders, such as ASD.

Source: UC Davis

Work published this week in the journal Proceedings of the National Academy of Sciences shows that an enzyme inhibitor developed by Professor Bruce Hammock and colleagues at UC Davis reduced inflammation in the brains of mice born to mothers with maternal immune activation. Inflammation triggered by the enzyme, soluble epoxide hydrolase, is linked to neurodevelopmental disorders in these mice.

“Inhibiting that enzyme stops the inflammation and the development of autism-like and schizophrenia-like symptoms in animal models,” said co-author Kenji Hashimoto, a professor with the Chiba University Center for Forensic Mental Health, Japan.

The work flows from the idea that the development of disorders such as autism or schizophrenia can be influenced by infections during pregnancy that expose the developing fetus to inflammatory chemicals. These disorders also have a strong genetic component.

By inhibiting soluble epoxide hydrolase, the researchers reversed cognitive and social interaction deficiencies in the mice pups. This might be due to an increase in natural brain chemicals that prevent brain inflammation.

Maternal immune response and autism

“There is mounting evidence that inappropriate maternal immune responses during pregnancy to infection contributes elevated risk to autism spectrum disorder, at least in a fraction of cases,” said Isaac Pessah, distinguished professor of molecular biosciences and associate dean of research and graduate education at the UC Davis School of Veterinary Medicine. Pessah was not involved in the study.

The researchers are shown

UC Davis researchers (L to R) Jun Yang, Sung Hee Hwang and Bruce Hammock are looking into the many roles of soluble epoxide hydrolase (sEH), originally discovered by Hammock in caterpillars. An inhibitor of the enzyme protects mice from neurodevelopment disorders. The image is credited to Kathy Keatley Garvey.

The findings show that a mouse model of some of the symptoms in autistic children can be suppressed by inhibiting soluble epoxide hydrolase, a target not previously explored, Pessah said.

Additional authors on the paper are: Min Ma, Qian Ren, Kai Zhang, Zhongwei Xiong, Tamaki Ishima and Yaoyu Pu at the Chiba University Center for Forensic Mental Health, Japan; Sung Hee Hwang and Jun Yang, UC Davis; Manabu Toyoshima, Yoshimi Iwayama, Yasuko Hisano, Takeo Yoshikawa, RIKEN Center for Brain Science, Wako, Japan.

Hammock js a distinguished professor in the UC Davis Department of Entomology and Nematology and Comprehensive Cancer Center. His interest in soluble epoxide hydrolase began decades ago when he was investigating how caterpillars turn into butterflies. Hammock is also a founder of EicOsis, a Davis-based company developing inhibitors to sEH to treat unmet medical needs in humans and companion animals.

Funding: The work was funded by grants from the National Institutes of Health.

About this neuroscience research article

Source:
UC Davis
Media Contacts:
Andy Fell – UC Davis
Image Source:
The image is credited to Kathy Keatley Garvey.

Original Research: Closed access
Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation”
Min Ma, Qian Ren, Jun Yang, Kai Zhang, Zhongwei Xiong, Tamaki Ishima, Yaoyu Pu, Sung Hee Hwang, Manabu Toyoshima, Yoshimi Iwayama, Yasuko Hisano, Takeo Yoshikawa, Bruce D. Hammock, Kenji Hashimoto
Proceedings of the National Academy of Sciences Mar 2019, 201819234; doi:10.1073/pnas.1819234116

Abstract

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

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 cell-derived 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.

Feel free to share this Neuroscience News.
Join our Newsletter
I agree to have my personal information transferred to AWeber for Neuroscience Newsletter ( more information )
Sign up to receive the latest neuroscience headlines and summaries sent to your email daily from NeuroscienceNews.com
We hate spam and only use your email to contact you about newsletters. We do not sell email addresses. You can cancel your subscription any time.