Memantine ameliorates cognitive impairment induced by exposure to chronic hypoxia environment at high altitude by inhibiting excitotoxicity

Ji, Weizhong; Zhang, Yaqing; Luo, Jun; Wan, Yaqi; Liu, Jie; Ge, Ri‐Li

doi:10.1016/j.lfs.2020.119012

Cited by 15 publications

(13 citation statements)

References 53 publications

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“…Cognitive functions, such as memory and learning, are a crucial nature of the hippocampus. It has been verified that hypoxia-induced neuronal death is one of the significant factors bringing about cognitive impairment ( Chen et al, 2017 ; Ding et al, 2018 ; Ji et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression

et al. 2021

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Background: Neuron apoptosis, regulated by endoplasmic reticulum (ER) stress in the hippocampus, is an essential factor influencing the cognitive impairment induced by hypobaric hypoxia. Hypoxia mainly changes the activating transcription factor (ATF6) pathway of ER stress. However, the role of ATF6 in neuron survival, apoptosis, and upstream regulation is still controversial.Methods: We established a hypobaric hypoxia-induced C57BL/6 murine model and cell lines exposed to 1% hypoxia, including PC12 and HT22. First, we tested the expressions of interleukin 6 (IL-6), IL-1β, and IL-10 in C57BL/6 mice’s hippocampus under hypoxia using enzyme-linked immunosorbent assay (ELISA). We determined the signal transducer and activator of transcription 3 (STAT3) phosphorylation at tyrosine (Tyr)705 by western blot and the expression of ATF6, 78-kDa glucose-regulated protein (GRP78), and C/-EBP homologous protein (CHOP) related to ER stress by immunofluorescence (IF), western blot, and qRT-PCR; they were then verified on the cell model. Additionally, IL-6 (40 ng/mL) and STAT3 siRNA were used to treat the PC12 cells for 48 and 4 h to activate or silence STAT3, respectively. Subsequently, the cells of siRNA group were exposed to 1% hypoxia for 48 h. Furthermore, the ATF6 and CHOP expressions were detected with western blot and qRT-PCR. Finally, we examined the binding of STAT3 to the ATF6 promoter by chromatin immunoprecipitation (ChIP)-seq.Results: The results showed that IL-6 increased, IL-10 decreased in the hypoxia group, and IL-1β showed no difference between the hypoxia and the normoxia groups. Neuron apoptosis was significantly elevated by exposure to hypoxia for 48h in PC12 cells. The hypobaric hypoxia-induced ER stress proteins, ATF6, GRP78, and CHOP, and the p-STAT3 (Tyr705) expressions increased both in in vivo and in vitro. Besides, STAT3 silencing significantly promoted the ATF6 expression and inhibited CHOP, while STAT3 activation downregulated the expression of ATF6 and upregulated CHOP in PC12 cells. The ChIP-seq assay demonstrated that p-STAT3 (Tyr705) protein could bind to the ATF6 promoter region in HT22 cells.Conclusion: Phosphorylation of STAT3 at the Tyr705 site contributes to hypoxia-induced neuron apoptosis by downregulating ATF6, which might explain the inflammatory reaction and apoptosis of the hippocampal neurons induced by ER stress.

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Section: Introductionmentioning

confidence: 99%

IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression

et al. 2021

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“…This resulted in excitotoxicity, which eventually led to neurological damage and cognitive impairment ( Ji et al, 2021b ). After an 8-week exposure to 4300 m altitude, increased neuronal apoptosis and abnormal expression of cysteine-3 protein were observed, which led to the cognitive impairment of rats ( Ji et al, 2021a ). Zhao et al (2019) gave rats 6000 m-altitude exposure for 24 h and observed neuronal damage and apoptosis in their hippocampal CA1 neuron.…”

Section: Discussionmentioning

confidence: 99%

CX3CL1/CX3CR1 signal mediates M1-type microglia and accelerates high-altitude-induced forgetting

Wang

Xie

Niu

et al. 2023

Front. Cell. Neurosci.

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IntroductionHypoxia-induced neuronal damage is the primary cause of cognitive impairment induced by high-altitude exposure. Microglia play a crucial regulatory role in the central nervous system (CNS) homeostasis and synaptic plasticity. M1-type polarized microglia are suspected to be responsible for CNS injury under hypoxic conditions, but the exact molecular mechanism is still unelucidated.MethodsCX3CR1 knock out and wide type mice were exposed to a simulated plateau at 7000 m for 48 h to construct the model of hypobaric hypoxia-induced memory impairment. The memory impairment of mice was assessed by Morris water maze. The dendritic spine density in the hippocampus was examined by Golgi staining. The synapses in the CA1 region and the number of neurons in the DG region were examined by immunofluorescence staining. The synapses in microglia activation and phagocytosis were examined by immunofluorescence. The levels of CX3CL1/CX3CR1 and their downstream proteins were detected. CX3CR1 knockout primary microglia were treated with CX3CL1 combined with 1% O2. The levels of proteins related to microglial polarization, the uptake of synaptosome and phagocytotic ability of microglia were detected.ResultsIn this study, mice exposed to a simulated 7000 m altitude for 48 h developed significant amnesia for recent memories, but no significant change in their anxiety levels was observed. Hypobaric hypoxia exposure (7000 m altitude above sea level for 48 h) resulted in synapse loss in the CA1 region of the hippocampus, but no significant changes occurred in the total number of neurons. Meanwhile, microglia activation, increased phagocytosis of synapses by microglia, and CX3CL1/CX3CR1 signal activation were observed under hypobaric hypoxic exposure. Further, we found that after hypobaric hypoxia exposure, CX3CR1-deficient mice showed less amnesia, less synaptic loss in the CA1 region, and less increase in M1 microglia, compared to their wildtype siblings. CX3CR1-deficient microglia did not exhibit M1-type polarization in response to either hypoxia or CX3CL1 induction. Both hypoxia and CX3CL1 induced the phagocytosis of synapses by microglia through the upregulation of microglial phagocytosis.DiscussionThe current study demonstrates that CX3CL1/CX3CR1 signal mediates the M1-type polarization of microglia under high-altitude exposure and upregulates microglial phagocytosis, which increases the phagocytosis of synapses in the CA1 region of the hippocampus, causing synaptic loss and inducing forgetting.

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“…It can improve the patient's nerve function and ability of daily living. [112][113][114][115][116] Salvia It can effectively reduce edema and improve neurological function. [117][118][119][120][121] Puerarin lobata It can significantly improve neurological function and has high safety.…”

Section: Leechmentioning

confidence: 99%

Application value and challenge of traditional Chinese medicine carried by ZIF‐8 in the therapy of ischemic stroke

Zhu

Guo

Chen

et al. 2021

Ibrain

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Stroke is a group of major diseases that cause death or disability in adults, with high incidence and lack of available therapeutic strategies. Although traditional Chinese medicine (TCM) has continuously achieved good effects in the therapy of stroke while there is still not convincing due to the limitation of blood-brain permeability, as well as the individual differences in usage and dosage. With the improvement of nanotechnology, TCM nanopreparation has gradually become a research hotspot in various fields due to its advantages in permeating the blood-brain barrier, targeting delivery, enhancing sustainedrelease drug delivery, changing the distribution in the body, and improving bioavailability. Zeolitic imidazolate framework-8 (ZIF-8) is an ideal nano-drug delivery system for adsorption, catalysis, and drug loading, which is a biocompatible metal-organic framework framed by 2-methylimidazole and zinc ions. At present, ZIF-8 was wildly used in the treatment of ischemic stroke. However, challenges remain persists for its clinical application, such as preparation technology, detection technology in vivo, targeting specificity, safety and stability, and so forth. Therefore, more efforts need to overcome the above problems to develop the application of TCM nanopreparations in the therapy of ischemia/reperfusion in the future.

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Memantine ameliorates cognitive impairment induced by exposure to chronic hypoxia environment at high altitude by inhibiting excitotoxicity

Cited by 15 publications

References 53 publications

IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression

IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression

CX3CL1/CX3CR1 signal mediates M1-type microglia and accelerates high-altitude-induced forgetting

Application value and challenge of traditional Chinese medicine carried by ZIF‐8 in the therapy of ischemic stroke

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