Reactive Astrocytes Display Pro-inflammatory Adaptability with Modulation of Notch-PI3K-AKT Signaling Pathway Under Inflammatory Stimulation

Cheng, Yingying; Ding, Yin-Xiu; Bian, Ganlan; Chen, Liang-Wei; Yao, Xin-Yi; Lin, Ye-Bin; Wang, Zhe; Chen, Bei-Yu

doi:10.1016/j.neuroscience.2020.05.023

Cited by 23 publications

(25 citation statements)

References 72 publications

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“…We also noticed the inconsistency of the pro-inflammatory cytokine mRNA expressions between the sorted microglia and the spinal cord tissue, which indicated the possible involvement of other cells in spinal inflammation. Astrocytes, another type of glial cells in the CNS, have been reported to produce iNOS and CD86 as well as pro-inflammatory cytokines in response to stimulus in vitro ( Soos et al, 1999 ; Cheng et al, 2020 ). However, astrogliosis and increase in cyclooxygenase-2 (COX-2) have been mainly found in vivo in the spinal cord of neonatal rats after LPS injection ( Hsieh et al, 2018 , 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure

Wen

Gong

Cheung

et al. 2021

Front. Cell. Neurosci.

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Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.

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Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure

Wen

Gong

Cheung

et al. 2021

Front. Cell. Neurosci.

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“…In addition to the TRL pathway, the inflammatory response in brain cells can be triggered via the Notch receptors or inflammasomes. The pro-inflammatory phenotype of senescent astrocytes, i.e., increased production of inducible nitric oxide synthase (iNOS), IL1b, IL6, and TNFα, can be activated by the Notch—phosphatidylinositol 3-kinase—AKT signalling pathway, an alternative pathway to TRL, for activating an inflammation response in astrocytes [ 102 ]. Increased NLRP3 gene expression promoted inflammasome activation in microglia cells, with increased production of pro-inflammatory cytokines IL1β and IL18 [ 77 ].…”

Section: Chronic Neuroinflammation Has a Significant Impact On The In...mentioning

confidence: 99%

Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer’s Disease Patients

Ribarič

2022

IJMS

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This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer’s disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. Ageing is the most important risk factor for AD. A hallmark of the ageing process is a systemic low-grade chronic inflammation that also contributes to neuroinflammation. Neuroinflammation is associated with AD, Parkinson’s disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders. Pharmacological treatment of AD is currently limited to mitigating the symptoms and attenuating progression of the disease. AD animal model studies and human studies on patients with a clinical diagnosis of different stages of AD have concluded that PE attenuates cognitive decline not only by improving cardiovascular fitness but possibly also by attenuating neuroinflammation. Therefore, low-grade chronic inflammation and neuroinflammation should be considered potential modifiable risk factors for AD that can be attenuated by PE. This opens the possibility for personalised attenuation of neuroinflammation that could also have important health benefits for patients with other inflammation associated brain disorders (i.e., Parkinson’s disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders). In summary, life-long, regular, structured PE should be considered as a supplemental intervention for attenuating the progression of AD in human. Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual’s mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aβ peptides brain catabolism and brain clearance.

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“…Western blot was carried out in reference to protocol of our previous study (33). Fresh lysates from midbrains (n=5) were made in lysis buffer (Beyotime Biotechnology).…”

Section: Western Blotmentioning

confidence: 99%

“…Based on these literature evidences, we speculate that PD-1 signaling pathway may constitute a potential regulating factor in the activated glial cells and in ammation and neuronal damage during pathogenesis of PD. Thus, PD-1 knockout mice and MPTP mouse model were applied for this study (29)(30)(31)(32)(33), and immunohistochemistry, western blot and motor behavior detection were used to observe effects of PD-1 de ciency on glial cell reaction, neuroin ammation and motor dysfunction of animals, for purpose to determine possible mechanistic involvement of PD-1 signaling abnormality in PD pathogenesis or progression, which may thereafter provide a new basis for exploring immunotherapy potentially for PD (2,4).…”

Section: Introductionmentioning

confidence: 99%

Programmed Death-1 Deficiency Aggravates Motor Dysfunction in MPTP Model of Parkinson's Disease by Inducing Microglial Activation and Neuroinflammation in Mice

et al. 2022

Self Cite

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Abundant reactive gliosis and neuroin ammation are typical pathogenetic hallmarks of brains inParkinson's disease (PD) patients, but regulation mechanisms are poorly understood. We are interested in role of programmed death-1 (PD-1) in glial reaction, neuroin ammation and neuronal injury in PD pathogenesis. Using PD mouse model and PD-1 knockout (KO) mice, we designed wild-type-control (WT-CON), WT-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (WT-MPTP), PD-1-KO-control (KO-CON) and PD-1-KO-MPTP (KO-MPTP), and observed motor dysfunction of animal, morphological distribution of PD-1positive cells, dopaminergic neuronal injury, glial activation and generation of in ammatory cytokines in midbrains by motor behavior detection, immunohistochemistry and western blot. WT-MPTP mouse model exhibited decrease of PD-1/Iba1-positive microglial cells in the substantia nigra compared with WT-CON mice. By comparison of four groups, PD-1 de ciency showed exacerbation in motor dysfunction of animals, decreased expression of TH protein and TH-positive neuronal protrusions. PD-1 de ciency enhanced microglial activation, production of pro-in ammatory cytokines like inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β and interleukin-6, and expression and phosphorylation of AKT and ERK1/2 in the substantia nigra of MPTP model. We concluded that PD-1 de ciency could aggravate motor dysfunction of MPTP mouse model by inducing microglial activation and neuroin ammation in midbrains, suggesting that PD-1 signaling abnormality might be possibly involved in PD pathogenesis.

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Reactive Astrocytes Display Pro-inflammatory Adaptability with Modulation of Notch-PI3K-AKT Signaling Pathway Under Inflammatory Stimulation

Cited by 23 publications

References 72 publications

Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure

Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure

Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer’s Disease Patients

Programmed Death-1 Deficiency Aggravates Motor Dysfunction in MPTP Model of Parkinson's Disease by Inducing Microglial Activation and Neuroinflammation in Mice

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