Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model

Kenji Imai,Akira Iwase,Taku Nagai,Hiroyuki Tsuda,Tomomi Kotani,Fumitaka Kikkawa,Shinya Toyokuni,Takafumi Ushida,Tomoko Nakano,Akio Suzumura

doi:10.1038/s41598-018-27626-4

Abstract

The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H2) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H2 attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H2 administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H2 on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H2-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H2 administration. Overall, these findings indicate that maternal H2 administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.

Highlights

The association between maternal immune activation (MIA) and subsequent neurodevelopmental disorders in offspring has become increasingly recognized, with both epidemiological evidence and research findings in various animal models[1,2,3,4]
We have previously suggested that the maternal administration of molecular hydrogen (H2) plays a neuroprotective role in the fetal brain against injury caused by oxidative stress and inflammation[12,13,14]
Since MIA has been considered to be a cause of behavioral abnormalities in offspring, including autism spectrum disorder (ASD)/ Schizophrenia-like behavior, we subsequently evaluated the effect of LPS and maternal administration of Hydrogen water (HW) on short-term memory, sociability, social novelty, and sensorimotor gating

Summary

Introduction

The association between maternal immune activation (MIA) and subsequent neurodevelopmental disorders in offspring has become increasingly recognized, with both epidemiological evidence and research findings in various animal models[1,2,3,4]. It has been suggested that MIA has a strong impact on microglial development, and microglial disturbance disrupts neurogenesis, neuronal migration, and myelination, leading to consequent impairments in the brain function of the offspring[2] Based on these findings, MIA is believed to be a disease primer[1]. We demonstrated that the administration of H2 to pregnant mouse dams significantly increased H2 concentration in the fetal brain, through the maternal-fetal interface, in a mouse model of lipopolysaccharide (LPS)-induced MIA12 Fetal damage in this MIA model and the effect of maternal H2 administration on this damage can be summarized as follows[12]: (1) high mortality rate of MIA fetuses, (2) brain injury associated with elevated levels of pro-inflammatory cytokines, aberrant microglial activation, and oxidative damage in the MIA fetal brains, and (3) attenuation of these adverse outcomes by maternal H2 administration. In the present study, the MIA-related astrocytic activation and its modification by H2 administration were investigated, both in vivo and in vitro

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Conclusion