Tripchlorolide ameliorates experimental autoimmune encephalomyelitis by down‐regulating ERK1/2‐NF‐κB and <scp>JAK</scp>/<scp>STAT</scp> signaling pathways

Zhang, Jian; Zeng, Yuqi; Zhang, Jing; Pan, Xiaodong; Kang, De-yong; Huang, Tianwen; Chen, Xiaochun

doi:10.1111/jnc.13058

Cited by 24 publications

(10 citation statements)

References 43 publications

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“…Moreover, CCH induces memory impairment and accelerates A β generation [9, 53]. Interestingly, TRC produces anti-inflammatory effects by downregulating extracellular signal-regulated protein kinases 1/2 (ERK1/2) nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κ B) and JAK/STAT signaling pathways [24, 54]. TRC also attenuates A β generation by inhibiting BACE1 activity and protects neurons against microglia-mediated A β neurotoxicity by suppressing NF- κ B and JNK signaling [23, 25].…”

Section: Discussionmentioning

confidence: 99%

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Yao

Zhang

et al. 2019

Neural Plasticity

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Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

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Section: Discussionmentioning

confidence: 99%

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Yao

Zhang

et al. 2019

Neural Plasticity

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“…Berberine (BBR), an isoquinoline alkaloid derived from plants, also ameliorated EAE symptoms through a mechanism involving inhibition of JAK/STAT signaling in Th1 and Th17 cells, as well as reduced production of IL-6 by innate immune cells [141]. Similar studies have demonstrated the efficacy of other natural compounds, such as Tripchlorolide [142], Quercetin [143], and vitamin D3 [144], in ameliorating EAE through inhibition of JAK/STAT signaling and Th1 and Th17 differentiation.…”

Section: Therapeutic Value Of Inhibitors Of Jak/stat Signaling In mentioning

confidence: 99%

Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases

Yan

Gibson

Buckley

et al. 2018

Clinical Immunology

218

125

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The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway is utilized by numerous cytokines and interferons, and is essential for the development and function of both innate and adaptive immunity. Aberrant activation of the JAK/STAT pathway is evident in neuroinflammatory diseases such as Multiple Sclerosis and Parkinson’s Disease. Innate immunity is the front line defender of the immune system and is composed of various cell types, including microglia, macrophages and neutrophils. Innate immune responses have both pathogenic and protective roles in neuroinflammation, depending on disease context and the microenvironment in the central nervous system. In this review, we discuss the role of innate immunity in the pathogenesis of neuroinflammatory diseases, how the JAK/STAT signaling pathway regulates the innate immune response, and finally, the potential for ameliorating neuroinflammation by utilization of JAK/STAT inhibitors.

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“…A recent study by Zhang et al reported that tripchlorolide (T4), an extract of the natural herb Tripterygium wilfordii Hook F (TWHF), reduces the severity of EAE and inhibits ongoing disease by suppressing the JAK2/STAT1/ STAT3 axis. 147 Additionally, another study using an EAE model in rats demonstrated that cornel iridoid glycoside (CIG), the main component extracted from Cornus officinalis , reduced disease severity, incidence, disease onset and ongoing paralysis through blocking the JAK/STAT1/3 axis in the brain 148 (Table 1). …”

Section: The Jak/stat Pathway As a Promising Therapeutic Target mentioning

confidence: 99%

Opportunities for Translation from the Bench: Therapeutic Intervention of the JAK/STAT Pathway in Neuroinflammatory Diseases

et al. 2015

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Pathogenic CD4+ T cells and myeloid cells play critical roles in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These immune cells secrete aberrantly high levels of pro-inflammatory cytokines that pathogenically bridge the innate and adaptive immune systems and damage neurons and oligodendrocytes. These cytokines include interleukin-2 (IL-2), IL-6, IL-12, IL-21, IL-23, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon-γ (IFN-γ). It is, therefore, not surprising that both the dysregulated expression of these cytokines and the subsequent activation of their downstream signaling cascades is a common feature in MS/EAE. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is utilized by numerous cytokines for signal transduction and is essential for the development and regulation of immune responses. Unbridled activation of the JAK/STAT pathway by pro-inflammatory cytokines has been demonstrated to be critically involved in the pathogenesis of MS/EAE. In this review, we discuss recent advancements in our understanding of the involvement of the JAK/STAT signaling pathway in the pathogenesis of MS/EAE, with a particular focus on therapeutic approaches to target the JAK/STAT pathway.

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Tripchlorolide ameliorates experimental autoimmune encephalomyelitis by down‐regulating ERK1/2‐NF‐κB and JAK/STAT signaling pathways

Cited by 24 publications

References 43 publications

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases

Opportunities for Translation from the Bench: Therapeutic Intervention of the JAK/STAT Pathway in Neuroinflammatory Diseases

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