Improvement of Cerebral Ischemia-Reperfusion Injury via Regulation of Apoptosis by Exosomes Derived from BDNF-Overexpressing HEK293

Wang, Lizong; Jiang, Jinghan; Zhou, Taofeng; Xue, Xiang; Cao, Yongjun

doi:10.1155/2021/6613510

Cited by 14 publications

(21 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the field of exosomes, it has been reported that the BDNF/TrkB/CREB pathway was activated following treatment with miR-206 modified exosomes isolated from human umbilical cord mesenchymal stem cells (hucMSC) in a subarachnoid hemorrhage rat model [ 61 ], and enhancing BDNF level and balancing inflammatory response have been reported to be involved in the mechanism underlying the analgesic effects of hucMSC-derived exosomes [ 62 ]. Moreover, exosomes extracted from BDNF-pretreated MSCs could effectively promote functional recovery and neurogenesis of rats after traumatic brain injury, the mechanism may be related to the high expression of miR-216a-5p [ 63 ], and exosomes derived from BDNF-overexpressing 293 T cells were reported to have a stronger neuroprotective effect than that from cells without overexpression of BDNF [ 64 , 65 ]. In the present study, the expression of BDNF, Syt-1, and synapsin-1 was decreased in the hippocampus of STZ-intracerebroventricular injected mice, again suggesting the important role of BDNF and its associated synaptic proteins in the maintenance of learning and memory.…”

Section: Discussionmentioning

confidence: 99%

Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology

Liu

Fan

et al. 2022

J Neuroinflammation

114

View full text Add to dashboard Cite

Background Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognitive ability. Exosomes derived from bone-marrow mesenchymal stem cells (BMSC-exos) are extracellular vesicles that can execute the function of bone-marrow mesenchymal stem cells (BMSCs). Given the versatile therapeutic potential of BMSC and BMSC-exos, especially their neuroprotective effect, the aim of this study was to investigate the potential effect of BMSC-exos on AD-like behavioral dysfunction in mice and explore the possible molecular mechanism. Methods BMSC-exos were extracted from the supernatant of cultured mouse BMSCs, which were isolated from the femur and tibia of adult C57BL/6 mice, purified and sorted via flow cytometry, and cultured in vitro. BMSC-exos were identified via transmission electron microscopy, and typical marker proteins of exosomes were also detected via Western blot. A sporadic AD mouse model was established by intracerebroventricular injection of streptozotocin (STZ). Six weeks later, BMSC-exos were administered via lateral ventricle injection or caudal vein injection lasting five consecutive days, and the control mice were intracerebroventricularly administered an equal volume of solvent. Behavioral performance was observed via the open field test (OFT), elevated plus maze test (EPM), novel object recognition test (NOR), Y maze test (Y-maze), and tail suspension test (TST). The mRNA and protein expression levels of IL-1β, IL-6, and TNF-α in the hippocampus were measured via quantitative polymerase chain reaction (qPCR) and Western blot, respectively. Moreover, the protein expression of Aβ1-42, BACE, IL-1β, IL-6, TNF-α, GFAP, p-Tau (Ser396), Tau5, synaptotagmin-1 (Syt-1), synapsin-1, and brain-derived neurotrophic factor (BDNF) in the hippocampus was detected using Western blot, and the expression of GFAP, IBA1, Aβ1−42 and DCX in the hippocampus was measured via immunofluorescence staining. Results Lateral ventricle administration, but not caudal vein injection of BMSC-exos improved AD-like behaviors in the STZ-injected mouse model, as indicated by the increased number of rearing, increased frequency to the central area, and increased duration and distance traveled in the central area in the OFT, and improved preference index of the novel object in the NOR. Moreover, the hyperactivation of microglia and astrocytes in the hippocampus of the model mice was inhibited after treatment with BMSC-exos via lateral ventricle administration, accompanied by the reduced expression of IL-1β, IL-6, TNF-α, Aβ1-42, and p-Tau and upregulated protein expression of synapse-related proteins and BDNF. Furthermore, the results of the Pearson test showed that the preference index of the novel object in the NOR was positively correlated with the hippocampal expression of BDNF, but negatively correlated with the expression of GFAP, IBA1, and IL-1β. Apart from a positive correlation between the hippocampal expression of BDNF and Syt-1, BDNF abundance was found to be negatively correlated with markers of glial activation and the expression of the inflammatory cytokines, Aβ1-42, and p-Tau, which are characteristic neuropathological features of AD. Conclusions Lateral ventricle administration, but not caudal vein injection of BMSC-exos, can improve AD-like behavioral performance in STZ-injected mice, the mechanism of which might be involved in the regulation of glial activation and its associated neuroinflammation and BDNF-related neuropathological changes in the hippocampus.

show abstract

Section: Discussionmentioning

confidence: 99%

Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology

Liu

Fan

et al. 2022

J Neuroinflammation

114

View full text Add to dashboard Cite

show abstract

“…BDNF belongs to the neurotrophin (NT) family, which is composed of four structurally related members: BDNF, neuronal growth factor (NGF), neurotrophin‐3 (NT‐3), and NT‐4/5 28 . It has been well recognized that BDNF is the most abundant endogenous neurotrophic factor in the body, and reduced levels of BDNF were reported to play a key role in rodent models during the development of neurological disorders, such as cerebral ischemia‐reperfusion injury 2 and neuroinflammation‐related brain injury 3 . Besides, it is clear that the NT actions are mediated by interacting with two transmembrane receptors with different affinity.…”

Section: Discussionmentioning

confidence: 99%

The effect of propofol on hypoxia‐ and TNF‐α‐mediated BDNF/TrkB pathway dysregulation in primary rat hippocampal neurons

Tao

Ding

et al. 2022

CNS Neurosci Ther

View full text Add to dashboard Cite

Aims: Hypoxia and inflammation may lead to BDNF/TrkB dysregulation and neurological disorders. Propofol is an anesthetic with neuroprotective properties. We wondered whether and how propofol affected BDNF/TrkB pathway in hippocampal neurons and astrocytes.Methods: Primary rat hippocampal neurons and astrocytes were cultured and exposed to propofol followed by hypoxia or TNF-α treatment. The expression of BDNF and the expression/truncation/phosphorylation of TrkB were measured. The underlying mechanisms were investigated. Results: Hypoxia and TNF-α reduced the expression of BDNF, which was reversed by pretreatment of 25 μM propofol in hippocampal neurons. Furthermore, hypoxia and TNF-α increased the phosphorylation of ERK and phosphorylation of CREB at Ser142, while reduced the phosphorylation of CREB at Ser133, which were all reversed by 25 μM propofol and 10 μM ERK inhibitor. In addition, hypoxia or TNF-α did not affect TrkB expression, truncation, or phosphorylation in hippocampal neurons and astrocytes. However, in hippocampal neurons, 50 μM propofol induced TrkB phosphorylation, which may be mediated by p35 expression and Cdk5 activation, as suggested by the data showing that blockade of p35 or Cdk5 expression mitigated propofolinduced TrkB phosphorylation. Conclusions: Propofol modulated BDNF/TrkB pathway in hippocampal neurons via ERK/CREB and p35/Cdk5 under the condition of hypoxia or TNF-α exposure.

show abstract

“…Hypoxia-and TNF-α-mediated dysregulation of BDNF/TrkB pathway BDNF belongs to the neurotrophin (NT) family, which is composed of four structurally related members: BDNF, neuronal growth factor (NGF), neurotrophin-3 (NT-3) and NT-4/5 (Chao et al 2006). It has been well recognized that BDNF is the most abundant endogenous neurotrophic factor in the body, and reduced levels of BDNF were reported to play a key role in rodent models during the development of neurological disorders, such as cerebral ischemia-reperfusion injury (Wang et al 2021) and neuroin ammation-related brain injury (Lima et al 2019). Besides, it is clear that the NT actions are mediated by interacting with two transmembrane receptors with different a nity.…”

Section: Discussionmentioning

confidence: 99%

“…A large amount of in vitro studies revealed that propofol may improve BBB function (Chen et al 2019), protect neuron apoptosis (Xu et al 2017) and autophagy (Li et al 2020), and maintain microglia function ). In addition, animal studies demonstrated that propofol may improve brain function in rats with ischemia-reperfusion injury (Chen et al 2021) and may ameliorate neuroin ammatory injury in rats (Ma et al 2020, Jiang et al 2021.…”

Section: Discussionmentioning

confidence: 99%

“…Brain-derived neurotrophic factor (BDNF) is one of the most studied and well characterized neurotrophic factors in the central nervous system (CNS), and is mainly produced in the brain by hippocampal neurons and astrocytes. BDNF plays an extensively role in neuronal growth, differentiation, survival, synaptic plasticity and neurotransmitter regulation (Chen et al 2017), and therefore has been considered to have potential therapeutic values during the development of neurological disorders, such as cerebral ischemiareperfusion injury (Wang et al 2021), neuroin ammation-related brain injury (Lima et al 2019), agerelated memory impairment (Mizoguchi et al 2020), Parkinson's disease (Chen et al 2020), Alzheimer's disease (Choung et al 2021) and postoperative cognitive dysfunction (Jiang et al 2019). It was originally thought that BDNF exerts its biological functions through binding to two transmembrane receptors, the tropomyosin receptor tyrosine kinase B (TrkB) and p75 neurotrophin receptor (p75 NTR).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Effect of Propofol on Hypoxia- and TNF-α-Mediated Brain-Derived Neurotrophic Factor/Tyrosine Kinase Receptor B Pathway Dysregulation in Primary Rat Hippocampal Neurons

Tao

Ding

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Brain-derived neurotrophic factor/tyrosine kinase receptor B (BDNF/TrkB) pathway dysregulation may be induced by hypoxia and inflammation, and play pivotal roles during the development of neurological disorders. Propofol is an anesthetic agent with neuro-protective properties. We aimed to verify whether propofol affected BDNF/TrkB pathway in neurons and astrocytes exposed to hypoxia and inflammation.Methods: Primary rat hippocampal neurons and astrocytes were cultured and exposed to propofol followed by hypoxia or TNF-α treatment. The production of BDNF and the expression/truncation/phosphorylation of TrkB were measured. The underlying mechanisms such as ERK, CREB, p35 and Cdk5 were investigated.Results: In hippocampal neurons and astrocytes, hypoxia and TNF-α reduced the production of BDNF. Pretreatment of hippocampal neurons with 25μM propofol reversed the inhibitory effect of hypoxia or TNF-α on BDNF production. However, even 100μM propofol had no such effect in astrocytes. Further, we found that in hippocampal neurons hypoxia and TNF-α increased the phosphorylation of ERK (p-ERK) and CREB at Ser142 (p-CREB Ser142), while reduced the phosphorylation of CREB at Ser133 (p-CREB Ser133), which were all reversed by 25μM propofol and 10μM ERK inhibitor. In addition, we reported that hypoxia- and TNF-α-mediated reduction of BDNF was mitigated by 10μM ERK inhibitor, and the beneficial effect of propofol was abolished by 10μM ERK activator. We also found neither hypoxia nor TNF-α affected TrkB expression, truncation or phosphorylation in hippocampal neurons and astrocytes. However 50μM propofol induced TrkB phosphorylation without affecting its expression and truncation only in hippocampal neurons. Furthermore, we detected that in hippocampal neurons, 50μM propofol induced p35 expression and Cdk5 activation, and blockade of p35 or Cdk5 mitigated propofol-induced TrkB phosphorylation.Conclusions: Propofol, via ERK/CREB and p35/Cdk5, may modulate BDNF/TrkB pathway in hippocampal neurons that were exposed to hypoxia or TNF-α.

show abstract

Improvement of Cerebral Ischemia-Reperfusion Injury via Regulation of Apoptosis by Exosomes Derived from BDNF-Overexpressing HEK293

Cited by 14 publications

References 29 publications

Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology

Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology

The effect of propofol on hypoxia‐ and TNF‐α‐mediated BDNF/TrkB pathway dysregulation in primary rat hippocampal neurons

The Effect of Propofol on Hypoxia- and TNF-α-Mediated Brain-Derived Neurotrophic Factor/Tyrosine Kinase Receptor B Pathway Dysregulation in Primary Rat Hippocampal Neurons

Contact Info

Product

Resources

About