Hydrogen-rich saline promotes microglia M2 polarization and complement-mediated synapse loss to restore behavioral deficits following hypoxia-ischemic in neonatal mice via AMPK activation

Authors
Journal
Journal of Neuroinflammation
Year
DOI
10.1186/s12974-019-1488-2
Study Type
Mouse
Outcome
Positive
Peer Reviewed
Yes
Country
China
Health Condition
Neonatal hypoxic-ischemic encephalopathy
Body System
Nervous system

TL;DR

Treating newborn mice with hydrogen-rich saline helps reduce brain damage and improve behavior after a lack of oxygen and blood flow to the brain by affecting immune cells and brain connections in a beneficial way.

Key Finding

Hydrogen-rich saline treatment restored behavioral deficits and reduced brain damage in newborn mice with hypoxia-ischemia (oxygen and blood flow deprivation) by activating a cellular pathway called AMPK that reduces inflammation and protects synapses (connections between brain cells).

Summary

This study examined how hydrogen-rich saline (a salt solution containing dissolved hydrogen gas) might protect the brains of newborn mice from injury caused by lack of oxygen and blood flow. Researchers found that the treatment reduced inflammation in the brain, helped immune cells adopt a protective mode, and prevented damage to connections between brain cells. The treated mice showed improved behavior and brain function compared to untreated mice.

Practical Takeaway

While these results are promising, this study was conducted only in newborn mice, not humans. The findings suggest hydrogen-rich saline may have potential as a neuroprotective treatment for perinatal brain injury, but much more research—including human clinical trials—would be needed before any therapeutic claims could be made. This early-stage evidence does not yet support use in human patients.

Abstract

Background Hypoxia-ischemia (HI) during the perinatal period is one of the most common causes of acute mortality and chronic neurologic morbidity. Hydrogen-rich saline (HS) treatment in neonatal mice has been reported to alleviate brain injury following HI, but the mechanisms involved are not known. Methods A modified version of the Rice-Vannucci method for the induction of neonatal HI brain injury was performed on postnatal day 7 mouse pups. Animals or BV2-cells received HS and an AMPK inhibitor at indicative time post-injury. Results In the current study, we show that HS treatment attenuated the accumulation of CD11b⁺/CD45high cells, suppressed HI-induced neuro-inflammation, induced microglial anti-inflammatory M2 polarization, was associated with promoting AMPK activation, and inhibited nuclear factor-κB activation as demonstrated both in vivo and in vitro. In addition, HS treatment reversed HI-induced neurological disabilities, was associated with improving damaged synapses, and restored the expression levels of synaptophysin and postsynaptic density protein 95 following HI insult. Furthermore, HI insult which increased levels of complement component C1q, C3, and C3aR1 was observed. Importantly, C1q deposited in the infarct core and lesion boundary zone following HI injury, was found to co-localize within regions of synapse loss, whereas HS treatment reversed these effects of HI on synapse loss and complement component levels. Notably, the AMPK inhibitor reversed the beneficial effects of HS as described above. Conclusions These results demonstrate that HS restored behavioral deficits after HI in neonatal mice. These beneficial effects, in part, involve promoting microglia M2 polarization and complement-mediated synapse loss via AMPK activation. Electronic supplementary material The online version of this article (10.1186/s12974-019-1488-2) contains supplementary material, which is available to authorized users.