FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of vascular dementia

Behav Brain Res. 2019 Jan 1;356:98-106. doi: 10.1016/j.bbr.2018.05.023. Epub 2018 Jun 7.


Vascular dementia (VD) is a heterogeneous group of brain disorders in which cognitive impairment is attributed to cerebrovascular pathologies. Autophagy, a self-cannibalization mechanism, has been demonstrated to be involved in VD progression. Molecular hydrogen is known for its powerful anti-oxidative, anti-apoptotic, and anti-inflammatory activities, and it is also involved in autophagy. However, the effects of hydrogen on VD remain unclear. The current study found that hydrogen-rich water (HRW) significantly alleviated spatial learning and memory impairments. Similar to donepezil treatment, HRW also inhibited neuron loss and shrinkage in the hippocampal CA1 region. In addition, we found that HRW significantly increased the Bcl-2/Bax expression ratio and decreased cleaved caspase-3 expression levels in the hippocampus of VD rats. Moreover, electron microscopy revealed that HRW decreased the number of autophagosomes. We also observed that HRW reduced the increased ratio of LC3-II/I and Beclin 1 expression and saliently upregulated p62 expression. Furthermore, FoxO1 (a major mediator of autophagy regulation) and Atg7 levels were apparently decreased in the hippocampus of HRW-treated bilateral common carotid artery occlusion (2VO) rats. Taken together, these data show that molecular hydrogen exerts beneficial effects on cognitive impairment induced by chronic cerebral hypoperfusion. FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of VD. Furthermore, the present findings highlight that HRW should be further investigated as a new therapeutic strategy for VD treatment in the future.

Keywords: Apoptosis; Autophagy; FoxO1; Hydrogen; Vascular dementia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Autophagy / physiology
  • Beclin-1 / metabolism
  • Brain Ischemia / pathology
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism
  • Caspase 3 / metabolism
  • Cognitive Dysfunction / drug therapy
  • Dementia, Vascular / metabolism*
  • Dementia, Vascular / physiopathology
  • Disease Models, Animal
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hydrogen / metabolism
  • Hydrogen / pharmacology*
  • Male
  • Maze Learning / drug effects
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / physiology
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Spatial Learning / drug effects


  • Beclin-1
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Foxo1 protein, rat
  • Hydrogen
  • Caspase 3