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

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

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 (H(2)) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H(2) 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 H(2) administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H(2) 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 H(2)-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H(2) administration. Overall, these findings indicate that maternal H(2) administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.