Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease

Thawkar, Baban S; Kaur, Ginpreet

doi:10.1016/j.jneuroim.2018.11.010

Cited by 205 publications

(133 citation statements)

References 146 publications

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“…At present, the role of nod-like receptor protein 3 (NLRP3) inflammasome in neuroinflammation has received considerable attention [11] because the activation of its pathway is involved in microglia-mediated IL-1β production [12]. Therefore, the inhibition of NLRP3 activation in microglia reduces IL-1β release and brain damage [13].…”

Section: Introductionmentioning

confidence: 99%

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

Xie

et al. 2020

J Neuroinflammation

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Background: Microglia activation is associated with the development of hypoxic-ischemic brain injury (HIBI). Neuroinflammation suppression might be a suitable therapeutic target in hypoxic oligodendrocyte injury. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated microglia and promoting the maturation of oligodendrocyte progenitor cells (OPCs) in HIBI. Methods: A bilateral common carotid artery occlusion (BCCAO) rat model that received continuous intraperitoneal injection (1 mg/kg) for 14 days was employed to elaborate the neuroprotection effects of clemastine. Interleukin-1β (IL-1β), nod-like receptor protein 3 (NLRP3), histamine H1 receptor, and OPC differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of microglia and OPCs were used to explore the link between microglia activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher's protected least significant difference test. Results: Clemastine treatment could reverse hypomyelination and restrain the upregulation of IL-1β and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1β showed failed maturation. However, clemastine could also reverse the OPC maturation arrest by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Co-culture of microglia and OPCs with oxygen glucose deprivation treatment exhibited IL-1β and NLRP3 upregulation. Clemastine could downregulate NLRP3 and IL-1β and reverse hypomyelination by inhibiting the p38 signaling pathway. Conclusions: Clemastine could restrain microglia activation, improve axonal hypomyelination in BCCAO rats, and thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI.

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Section: Introductionmentioning

confidence: 99%

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

Xie

et al. 2020

J Neuroinflammation

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“…161,162 In this section, we will discuss the double-edged nature of inflammation in AD. [163][164][165][166][167][168][169][170] Resting levels of pro-inflammatory cytokines are found to be higher in the blood and cerebrospinal fluid (CSF) of AD patients, suggesting a role for them in disease pathogenesis. 171 The deposition of Aβ and resultant neuronal damage provide ligands to activate microglial phagocytosis of Aβ while also promoting microglia-mediated production of pro-inflammatory cytokines.…”

Section: Inflammatory Mediation Of Admentioning

confidence: 99%

The role of innate immunity in Alzheimer's disease

Ennerfelt

Lukens

2020

Immunological Reviews

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The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment in AD. Recent research in the AD field has identified the brain‐resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD. In this review, we will highlight recent advancements in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, there has been mounting evidence suggesting pivotal contributions of environmental factors and lifestyle choices in AD pathogenesis. Therefore, we will also discuss recent findings, suggesting that many of these AD risk factors influence AD progression via modulation of microglia and immune responses.

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“…Acute myocardial infarction augmented the expression levels of microglia P2X7 receptor to stimulate a sympathoexcitatory response in model rats with acute myocardial infarction. Inhibiting pro‐inflammatory cytokines, IL‐1β and IL‐6, and silencing the P2X7 receptor alleviated inflammatory responses and moderated the process of cardiac remodeling via influencing nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase (MAPK) signaling (Thawkar and Kaur, ; Ding et al, ). Mice with the overexpression of cardiac‐specific P2X4 receptor can be protected against heart failure (Yang et al, ).…”

Section: P2x Receptors and Myocardial Ischemia Or Other Visceral Pathmentioning

confidence: 99%

P2X receptors mediated abnormal interaction between satellite glial cells and neurons in visceral pathological changes

Wang

Yang

et al. 2019

Cell Biology International

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The adenosine triphosphate (ATP)-gated P2X receptor cation channel family consists of permeable ligand-gated ion channels that expand on the binding of extracellular adenosine 5'-ATP. ATP-gated P2X receptors are trimer ion channels that assemble homo or isomer from seven cloned subunits. P2X receptors are discovered mostly in mammalian and are being found in an increasing number of non-vertebrates, such as zebrafish, bullfrog, and ameba. P2X receptors are involved in many physiological processes, including regulation of heart rhythm and contractility, and regulation of pain, especially chronic pain and glia integration. This review summarizes the current studies on the regulation of P2X receptors in abnormal neuronal-glial interaction and the pathological changes in viscera, especially in myocardial ischemia.

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Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease

Cited by 205 publications

References 146 publications

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

Clemastine improves hypomyelination in rats with hypoxic–ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

The role of innate immunity in Alzheimer's disease

P2X receptors mediated abnormal interaction between satellite glial cells and neurons in visceral pathological changes

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