The microglial ATP‐gated ion channel P2X7 as a CNS drug target

Bhattacharya, Anindya; Biber, Knut

doi:10.1002/glia.23001

Cited by 174 publications

(157 citation statements)

References 145 publications

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“…Microglial ion channels have recently been identified as potential therapeutic targets in neurological diseases [24, 30, 31], while K + , H + , transient receptor potential (TRP) and Cl - channels have been found to regulate microglial production of ROS [10, 32–37]. In this study, we elucidated a novel role of microglial Kir2.1 inward rectifier K + channels, namely regulation of microglial priming processes, which lead to enhanced microglial ROS production.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

et al. 2016

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Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP. Priming of microglial ROS production was substantially reduced by inhibition of p38 MAPK activity with SB203580, by increases in intracellular glutathione levels with N-Acetyl-L-cysteine, by blockade of NADPH oxidase subunit NOX2 activity with gp91ds-tat or by inhibition of nitric oxide production with L-NAME. Together, our data indicate that priming of microglial ROS production involves reduction of intracellular glutathione levels, upregulation of NADPH oxidase subunit NOX2 and increases in nitric oxide production, and suggest that these simultaneously occurring processes result in enhanced production of neurotoxic peroxynitrite. Furthermore, IFNγ-induced priming of microglial ROS production was reduced upon blockade of Kir2.1 inward rectifier K+ channels with ML133. Inhibitory effects of ML133 on microglial priming were mediated via regulation of intracellular glutathione levels and nitric oxide production. These data suggest that microglial Kir2.1 channels may represent novel therapeutic targets to inhibit excessive ROS production by primed microglia in brain pathology.

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Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

et al. 2016

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“…Over the last decade, enormous effort has been made to develop a number of structurally distinct P2X7 specific antagonists, some of which have been demonstrated to alleviate chronic pain in animal models (Honore et al, 2006a; McGaraughty et al, 2007; Bartlett et al, 2014). However, mechanisms of action for these drugs remain poorly understood, hampering the development of effective therapeutic compounds for human patients (Keystone et al, 2012; Stock et al, 2012; Bhattacharya and Biber, 2016). …”

Section: Introductionmentioning

confidence: 99%

Structural basis for subtype-specific inhibition of the P2X7 receptor

Karasawa

Kawate

2016

eLife

233

301

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The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits. This novel drug-binding pocket accommodates a diversity of small molecules mainly through hydrophobic interactions. Functional assays propose that these compounds allosterically prevent narrowing of the drug-binding pocket and the turret-like architecture during channel opening, which is consistent with a site of action distal to the ATP-binding pocket. These novel mechanistic insights will facilitate the development of P2X7-specific drugs for treating human diseases.DOI: http://dx.doi.org/10.7554/eLife.22153.001

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“…It has been a consistent finding that activation of P2X7 receptors releases IL-1β and IL-18 from microglia in the brain, although other inflammatory mediators, such as IL-6, may also be released. Thus, P2X7 receptors are intimately involved in neuroinflammation and inhibiting the activation of these receptors has been proposed as a therapeutic method for various diseases in the brain, such as stroke and neurodegenerative diseases, in which neuroinflammation plays a detrimental role (Bhattacharya and Biber, 2016). We and others have shown that IL-1β plays a critical role in anesthesia and surgery-induced cognitive dysfunction (Cao et al, 2012; Cibelli et al, 2010; Lin and Zuo, 2011).…”

Section: Introductionmentioning

confidence: 99%

Critical role of P2X7 receptors in the neuroinflammation and cognitive dysfunction after surgery

Zheng

Lai

et al. 2017

Brain, Behavior, and Immunity

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Postoperative cognitive dysfunction worsens patient outcome after surgery. Neuroinflammation is a critical neuropathological process for it. We determined the role of P2X7 receptors, proteins that participate in inflammatory response, in the neuroinflammation induction after surgery, and whether the choice of volatile anesthetics affects its occurrence. Eight-week old C57BL/6J or P2X7 receptor knockout male mice were subjected to right carotid arterial exposure under anesthesia with 1.8% isoflurane, 2.5% sevoflurane or 10% desflurane. They were tested by Barnes maze and fear conditioning from 2 weeks after the surgery. Hippocampus was harvested 6 h, 24 h and 7 days after the surgery for immunohistochemical staining and Western blotting. Mice with surgery under anesthesia with isoflurane, sevoflurane or desflurane took longer than control mice to identify the target box 1 or 8 days after the training sessions in Barnes maze. Mice anesthetized by isoflurane or sevoflurane, but not by desflurane, had less freezing behavior than control mice in fear conditioning test. Mice with surgery and anesthesia had increased ionized calcium binding adapter molecule 1 and interleukin 1β in the hippocampus but this increase was smaller in mice anesthetized with desflurane than mice anesthetized with isoflurane. Mice with surgery had increased P2X7 receptors and its downstream molecule caspase 1. Inhibition or knockout of P2X7 receptors attenuated surgery and anesthesia-induced neuroinflammation and cognitive impairment. We conclude that surgery under desflurane anesthesia may have reduced neuroinflammation and cognitive impairment compared with surgery under isoflurane anesthesia. P2X7 receptors may mediate the neuroinflammation and cognitive impairment after surgery.

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The microglial ATP‐gated ion channel P2X7 as a CNS drug target

Cited by 174 publications

References 145 publications

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

Structural basis for subtype-specific inhibition of the P2X7 receptor

Critical role of P2X7 receptors in the neuroinflammation and cognitive dysfunction after surgery

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