Depression, plus the accompanying memory impairment, is one of the leading causes of disability worldwide. Thus, there is a critical need to develop new drugs based on distinct strategies. FG-4592, an inhibitor of prolyl hydroxylase, activates the hypoxia-inducible factor-1 (HIF-1) pathway, to produce multiple effects on cell properties. Here, we examined whether FG-4592 has antidepressant effects, using a chronic unpredictable mild stress (CUMS) procedure to establish rodent depression models. We found that FG-4592 not only reversed depressive behaviors but also improved CUMS-induced memory impairment. Mechanistically, FG-4592 could play an important role in promoting hippocampal neurogenesis and synaptic plasticity. At the molecular level, FG-4592 was found to activate HIF-1 and cAMP-responsive element-binding protein/brain-derived neurotrophic factor signaling pathways in vivo, as well as promote the expression of postsynaptic density (PSD) proteins, PSD95 and Homer1. An examination of primary hippocampal neurons showed that FG-4592 promoted dendritic growth. Taken together, our results not only provide an experimental basis for the future application of FG-4592 in clinical treatment of depression but also support the argument that the HIF-1 signaling pathway is a promising target for the treatment of depression.

Hypoxia is involved in the regulation of various cell functions in the body, including the regulation of stem cells. The hypoxic microenvironment is indispensable from embryonic development to the regeneration and repair of adult cells. In addition to embryonic stem cells, which need to maintain their self‐renewal properties and pluripotency in a hypoxic environment, adult stem cells, including neural stem cells (NSCs), also exist in a hypoxic microenvironment. The subventricular zone (SVZ) and hippocampal dentate gyrus (DG) are the main sites of adult neurogenesis in the brain. Hypoxia can promote the proliferation, migration, and maturation of NSCs in these regions. Also, because most neurons in the brain are non‐regenerative, stem cell transplantation is considered as a promising strategy for treating central nervous system (CNS) diseases. Hypoxic treatment also increases the effectiveness of stem cell therapy. In this review, we firstly describe the role of hypoxia in different stem cells, such as embryonic stem cells, NSCs, and induced pluripotent stem cells, and discuss the role of hypoxia‐treated stem cells in CNS diseases treatment. Furthermore, we highlight the role and mechanisms of hypoxia in regulating adult neurogenesis in the SVZ and DG and adult proliferation of other cells in the CNS.

Oxygen (O 2 ) is essential for bodily tissues, and hypoxia usually causes transient or irreversible tissue damage and dysfunction. 1 Environmental hypoxia is common in aerospace activities, deep sea diving, mountain climbing, and plateau travel, and it usually increases the probability of body or organ damage. 2 As the most sensitive organ to hypoxia, the brain undergoes a series of response processes when exposed to hypoxia. 3 Short-term or mild hypoxia triggers hypoxic responses or conditioning mechanisms in the brain,

IntroductionThis study aimed to investigate the preventive and therapeutic effects of crocetin on ischaemic stroke in cell and animal models.Material and methodsA cell model of oxygen and glucose deprivation (OGD) and a rat model of middle cerebral artery occlusion were established to simulate ischaemic stroke. The infarct volume was measured by TTC assay, and the apoptotic cell number was counted by TUNEL. Relative protein and gene expression levels in the rats were measured by immunohistochemical and RT-qPCR assays. The apoptosis rate and relative protein and gene expression levels were determined by flow cytometry, WB and RT-qPCR assay, respectively.ResultsCompared with those in the normal control (NC) group, the brain tissue injury and apoptotic cell number significantly increased (P < 0.001) and the miR-145-5p gene expression significantly decreased in the cell and animal experiments. In the animal experiment, the infarct volume, apoptotic cell number and pathological improved in the Cro-treated groups. In the cell experiment, the apoptosis rates significantly depressed in the Cro-treated groups (P < 0.05). However, the cell apoptosis rate significantly increased after miR-145-5p inhibitor transfection (P < 0.001). The protein and gene expression levels of Toll-like receptor 4, myeloid differentiation factor 88 and nuclear factor (NF)-κB(p65) significantly depressed (P < 0.05). In addition, p-NF-κB(p65) nuclear volume significantly decreased (P < 0.05).ConclusionsCrocetin improved ischaemic stroke by regulating the miR-145-5p/TLR4 axis in cell and animal experiments.

Background: The association between the premorbid use of statin and the early outcomes of acute ischemic stroke (AIS) after intravenous thrombolysis (IVT) remains uncertain. We performed a meta-analysis of observational studies to evaluate the influence of the premorbid use of statin on functional outcome and symptomatic intracranial hemorrhage (SIH) in AIS after IVT. Methods: Relevant studies were identified by search of PubMed, Embase, and Cochrane's Library databases. Only studies with multivariate analyses were included. A random-effect model, incorporating inter-study heterogeneity, was used to pool the results. Results: Twenty observational studies with 20,752 AIS patients who were treated with IVT were included. The pooled results showed that the premorbid use of statin was not associated with improved 3-month favorable functional outcome [odds ratio (OR): 1.05, 95% confidence interval (CI): 0.87–1.26, p = 0.60, I 2 = 52%), 3-month functional independence (OR: 1.13, 95% CI: 0.96–1.33, p = 0.15, I 2 = 52%), or 3-month mortality (OR: 1.12, 95% CI: 0.94–1.34, p = 0.20, I 2 = 20%). Moreover, the premorbid use of statin was associated with an increased risk of SIH in AIS after IVT (OR: 1.48, 95% CI: 1.12–1.95, p = 0.006, I 2 = 60%). Subgroup analyses according to study design, adjustment of baseline low-density lipoprotein cholesterol, and definitions of SIH showed consistent results ( p -values for subgroup difference all >0.05). Conclusions: The premorbid use of statin is not associated with improved functional outcomes or mortality but is associated with a higher risk of SIH in AIS patients after IVT.

Chronic hypoxia leads to irreversible cognitive impairment, primarily due to hippocampal neurodegeneration, for which the underlying mechanism remains poorly understood. We administered hypoxia (13%) to C57BL mice for 1–14 days in this study. Chronic hypoxia for 7 or 14 d, but not 1 or 3 d, resulted in alpha-synuclein hyperphosphorylation at serine129 (α-Syn p-S129) and protein aggregation, hippocampal neurodegeneration, and cognitive deficits, whereas the latter could be prevented by alpha-synuclein knockdown or an administered short peptide competing at α-Syn S129. These results suggest that α-Syn p-S129 mediates hippocampal degeneration and cognitive impairment following chronic hypoxia. Furthermore, we found that chronic hypoxia enhanced ceramide catabolism by inducing hypoxia-inducible factor (HIF)-2α and HIF-2α-dependent transcriptional activation of alkaline ceramidase 2 (Acer2). Thus, the enzymatic activity of protein phosphatase 2A (PP2A), a specific phosphatase for α-syn, is inhibited, leading to the sustained induction of α-Syn p-S129. Finally, we found that intermittent hypoxic preconditioning protected against subsequent chronic hypoxia-induced hippocampal neurodegeneration and cognitive impairment by preventing α-Syn p-S129. These results proved the critical role of α-syn pathology in chronic hypoxia-afforded cognitive impairment and revealed a novel mechanism underlying α-syn hyperphosphorylation during chronic hypoxia. The findings bear implications in developing novel therapeutic interventions for chronic hypoxia-related brain disorders.

Chronic hypoxia leads to irreversible cognitive impairment, primarily due to hippocampal neurodegeneration, for which the underlying mechanism remains poorly understood. We administered hypoxia (13%) to C57BL mice for 1–14 days in this study. Chronic hypoxia for 7 or 14d, but not 1 or 3d, resulted in alpha-synuclein hyperphosphorylation at serine129 (α-Syn p-S129) and protein aggregation, hippocampal neurodegeneration, and cognitive deficits, whereas the latter could be prevented by alpha-synuclein knockdown or an administered short peptide competing at α-Syn S129. These results suggest that α-Syn p-S129 mediates hippocampal degeneration and cognitive impairment following chronic hypoxia. Furthermore, we found that chronic hypoxia enhanced ceramide catabolism by inducing hypoxia-inducible factor (HIF)-2α and HIF-2α-dependent transcriptional activation of alkaline ceramidase 2 (Acer2). Thus, the enzymatic activity of protein phosphatase 2A (PP2A), a specific phosphatase for α-syn, is inhibited, leading to the sustained induction of α-Syn p-S129. Finally, we found that intermittent hypoxic preconditioning protected against subsequent chronic hypoxia-induced hippocampal neurodegeneration and cognitive impairment by preventing α-Syn p-S129. These results proved the critical role of α-syn pathology in chronic hypoxia-afforded cognitive impairment and revealed a novel mechanism underlying α-syn hyperphosphorylation during chronic hypoxia. The findings bear implications in developing novel therapeutic interventions for chronic hypoxia-related brain disorders.

Hypoxic stress occurs in various physiological and pathological states, such as aging, disease, or high-altitude exposure, all of which pose a challenge to many organs in the body, necessitating adaptation. However, the exact mechanisms by which hypoxia affects advanced brain function (learning and memory skills in particular) remain unclear. In this study, we investigated the effects of hypoxic stress on hippocampal function. Specifically, we studied the effects of the dysfunction of mitochondrial oxidative phosphorylation using global proteomics. First, we found that hypoxic stress impaired cognitive and motor abilities, whereas it caused no substantial changes in the brain morphology or structure of mice. Second, bioinformatics analysis indicated that hypoxia affected the expression of 516 proteins, of which 71.1% were upregulated and 28.5% were downregulated. We demonstrated that mitochondrial function was altered and manifested as a decrease in NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 expression, accompanied by increased reactive oxygen species generation, resulting in further neuronal injury. These results may provide some new insights into how hypoxic stress alters hippocampal function via the dysfunction of mitochondrial oxidative phosphorylation.