BackgroundMemory impairment is a frequent complication of brain ischemia. Neurogenesis is implicated in learning and memory and is regulated by the transcription factor c-Fos. Preconditioning intermittent hypoxia (IH) attenuates ischemia-related memory impairments, but it is not known whether post-ischemia IH intervention has a similar effect. We investigated the effects of post-ischemia IH on hippocampal neurogenesis and c-Fos expression as well as spatial learning and memory in rats.Methodology/Principal FindingsFocal cerebral ischemia was induced in some rats by middle cerebral artery occlusion (MCAO), while other rats received sham MCAO surgery. Beginning a week later, half of the rats of each group received IH interventions (12% oxygen concentration, 4 hrs/d, for 7 d) and half received sham IH sessions. An additional group of rats received MCAO, IH, and injections of the neurogenesis-impairing agent 3′-AZT. Spatial learning and memory was measured in the Morris water maze, and hippocampal neurogenesis and c-Fos expression were examined. Hypoxia-inducible factor 1α (HIF-1α) and phosphorylated mitogen-activated protein kinase (pMAPK) were considered as possible mediators of IH-induced changes in neurogenesis and c-Fos expression. IH intervention following MCAO resulted in recovered spatial memory, increased hippocampal neurogenesis, and increased expression of c-Fos in newborn hippocampal cells. These effects were blocked by 3′-AZT. IH intervention following MCAO also was associated with increased hippocampal pMAPK and HIF-1α expression.Conclusions/SignificanceIH intervention following MCAO rescued ischemia-induced spatial learning and memory impairments, likely by inducing hippocampal neurogenesis and c-Fos expression through mediators including pMAPK and HIF-1α

Adult hippocampal neurogenesis is important for learning and memory, especially after a brain injury such as ischemia. Newborn hippocampal neurons contribute to memory performance by establishing functional synapses with target cells. This study demonstrated that the maturation of hippocampal neurons is enhanced by postischemia intermittent hypoxia (IH) intervention. The effects of IH intervention in cultured neurons were mediated by increased synaptogenesis, which was primarily regulated by brain-derived neurotrophic factor (BDNF)/PI3K/AKT. Hippocampal neo-neurons expressed BDNF and exhibited enhanced presynaptic function as indicated by increases in the pSynapsin expression, synaptophysin intensity, and postsynapse density following IH intervention after ischemia. Postischemia IH-induced hippocampal neo-neurons were affected by presynaptic activity, which reflected the dynamic plasticity of the glutamatergic receptors. These alterations were also associated with the alleviation of ischemia-induced long-term memory impairment. Our results suggest that postischemia IH intervention rescued ischemia-induced spatial learning and memory impairment by inducing hippocampal neurogenesis and functional synaptogenesis via BDNF expression.

The aim of this study was to investigate the effects of hyperbaric oxygenation (HBO) after brain ischemia. Middle cerebral artery occlusion (MCAO) procedure was used to induce the brain ischemia. Rats were assigned to control or HBO group after brain ischemia. In order to examine the role of glutathione after HBO treatment, another group of brain ischemic rats were included to receive the glutathione synthesis inhibitor and HBO treatment. HBO was administered at a pressure of 3 atmospheres absolute for 1 h with 100% oxygen, starting at 3 h post brain ischemia in HBO groups. Animals in control group were placed in their home cage and exposed to normobaric room air. The infarct volume (IV), activation of astrocyte, and level of total glutathione and lipid peroxidation (LP) were assessed 24 h post-reperfusion. Significant reduction in IV was noted in HBO group when compared with control group. The activation of astrocyte was significantly increased in the right cerebral cortex and right striatum in the HBO group when compared with those of the control group. The glutathione level was higher with lower LP level in right cortex and right striatum after HBO as compared with those of the control. However, such effects of HBO treatment were markedly reduced by glutathione synthesis inhibitor administration. These results show that inhibiting glutathione synthesis dramatically reduces the effectiveness of HBO in acute transient focal cerebral ischemia.