Blockade of P2X7 Receptors or Pannexin-1 Channels Similarly Attenuates Postischemic Damage

Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Cavaliere, Fabio; Magnus, Tim; Koch-Nolte, Friedrich; Scemes, Eliana; Pérez-Samartı́n, Alberto; Matute, Carlos

doi:10.1038/jcbfm.2014.262

Cited by 59 publications

(63 citation statements)

References 36 publications

(52 reference statements)

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“…When open, Panx1 channels form transmembrane conduits allowing the passage of ions and hydrophilic molecules of less than 1 kilodalton, including adenosine triphosphate (ATP) (Bao et al 2004; Wang et al 2013). On several occasions, Panx1 channels have been linked to cell death (Chekeni et al 2010; Cisneros-Mejorado et al 2015; Gulbransen et al 2012; Orellana et al 2011a; Orellana et al 2011b; Sandilos et al 2012; Xiao et al 2012) and inflammatory processes (Bao et al 2013; Csak et al 2011; Ganz et al 2011; Qu et al 2011; Silverman et al 2009). Specifically, Panx1 channels play a role in inflammatory responses by facilitating cleavage of pro-caspase1 (Casp1) in the NACHT, LRR, and pyrin domain-containing protein 3 (Nalp3) inflammasome, an intracellular multiprotein complex that activates interleukin (IL) 1β and IL-18 (Brough et al 2009; Marina-García et al 2008; Silverman et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity

et al. 2016

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Background and aims Pannexins constitute a relatively new family of transmembrane proteins that form channels linking the cytoplasmic compartment with the extracellular environment. Presence of pannexin1 in the liver has been documented previously, where it underlies inflammatory responses, such as those occurring upon ischemia-reperfusion injury. In the present study, we investigated whether pannexin1 plays a role in acute drug-induced liver toxicity. Methods Hepatic expression of pannexin1 was characterized in a mouse model of acetaminophen-induced hepatotoxicity. Subsequently, mice were overdosed with acetaminophen followed by treatment with the pannexin1 channel inhibitor 10Panx1. Sampling was performed 1, 3, 6, 24 and 48 hours after acetaminophen administration. Evaluation of the effects of pannexin1 channel inhibition was based on a number of clinically relevant read-outs, including protein adduct formation, measurement of aminotransferase activity and histopathological examination of liver tissue as well as on a series of markers of inflammation, oxidative stress and regeneration. Results Although no significant differences were found in histopathological analysis, pannexin1 channel inhibition reduced serum levels of alanine and aspartate aminotransferase. This was parallelled by a reduced amount of neutrophils recruited to the liver. Furthermore, alterations in the oxidized status were noticed with upregulation of glutathione levels upon suppression of pannexin1 channel opening. Concomitant promotion of regenerative activity was detected as judged on increased proliferating cell nuclear antigen protein quantities in 10Panx1-treated mice. Conclusions Pannexin1 channels are important actors in liver injury triggered by acetaminophen. Inhibition of pannexin1 channel opening could represent a novel approach for the treatment of drug-induced hepatotoxicity.

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Section: Introductionmentioning

confidence: 99%

Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity

et al. 2016

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“…This suggests that Panx1 mRNA is regulated by IRI, similar to the effects of hypoxia on other cell types. 10 Littermate-and progeny-derived WT control mice had comparable increases in plasma creatinine after IRI (1.560.05 and 1.460.03 mg/dl for littermates and progeny-derived mice, respectively; P value was not significant) and comparable plasma creatinine values after sham surgery (0.1160.01 and 0.1760.1 mg/dl for littermates and progeny-derived mice, respectively; P value was not significant); progeny-derived controls were, therefore, used for all future experiments. After IRI, the increases in plasma creatinine ( Figure 1D) and kidney neutrophil gelatinase-associated lipocalin (Ngal) mRNA ( Figure 1E) observed in WT mice were markedly reduced in Panx1 2/2 mice.…”

Section: Cbx Protects Kidneys From Irimentioning

confidence: 99%

“…9 Panx1 is the most ubiquitously expressed of the three pannexins and has been found in neurons, muscle, and immune cells. [10][11][12] It is also present in polarized epithelial cells in lung and kidney, which are a rich source of extracellular ATP. 13,14 In the kidney, Panx1 expression was found in apical membranes of proximal tubules (PTs), thick descending limbs, and collecting ducts as well as in renal vasculature.…”

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confidence: 99%

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Jankowski¹,

Perry²,

Medina

et al. 2018

JASN

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Pannexin1 (Panx1), an ATP release channel, is present in most mammalian tissues, but the role of Panx1 in health and disease is not fully understood. Panx1 may serve to modulate AKI; ATP is a precursor to adenosine and may function to block inflammation, or ATP may act as a danger-associated molecular pattern and initiate inflammation. We used pharmacologic and genetic approaches to evaluate the effect of Panx1 on kidney ischemia-reperfusion injury (IRI), a mouse model of AKI. Pharmacologic inhibition of gap junctions, including Panx1, by administration of carbenoxolone protected mice from IRI. Furthermore, global deletion of preserved kidney function and morphology and diminished the expression of proinflammatory molecules after IRI. Analysis of bone marrow chimeric mice revealed that Panx1 expressed on parenchymal cells is necessary for ischemic injury, and both proximal tubule and vascular endothelial tissue-specific knockout mice were protected from IRI. ,-deficient proximal tubule cells released less and retained more ATP under hypoxic stress. Panx1 is involved in regulating ATP release from hypoxic cells, and reducing this ATP release may protect kidneys from AKI.

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“…P2X7 receptors are upregulated in microglial cells at the infarct and peri-infarct region 1 and 4 days after permanent MCAo (Franke et al, 2004; Melani et al, 2006). P2X7 receptor antagonism at the onset or within 30 minutes after ischemia onset is neuroprotective in permanent and transient MCAo model, respectively, by reducing infarction volume and neurological deficits (Arbeloa et al, 2012; Cisneros-Mejorado et al, 2015; Melani et al, 2006). There is no evidence to support any positive effect of administration outside of the acute phase of microglial activation.…”

Section: Other Pharmacological Modulations Of Inflammatory Signalimentioning

confidence: 99%

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors

Anttila

Whitaker

Wires

et al. 2017

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Stroke is the leading cause of disability in adults. Drug treatments that target stroke-induced pathological mechanisms and promote recovery are desperately needed. In the brain, an ischemic event triggers major inflammatory responses that are mediated by the resident microglial cells. In this review, we focus on the microglia activation after ischemic brain injury as a target of immunomodulatory therapeutics. We divide the microglia-mediated events following ischemic stroke into three categories: acute, subacute, and long-term events. This division encompasses the spatial and temporal dynamics of microglia as they participate in the pathophysiological changes that contribute to the symptoms and sequela of a stroke. The importance of Toll-like receptor (TLR) signaling in the outcomes of these pathophysiological changes is highlighted. Increasing evidence shows that microglia have a complex role in stroke pathophysiology and they mediate both detrimental and beneficial effects on stroke outcome. So far, most of the pharmacological studies in experimental models of stroke have focused on neuroprotective strategies which are impractical for clinical applications. Post-ischemic inflammation is long lasting and thus, could provide a therapeutic target for novel delayed drug treatment. However, more studies are needed to elucidate the role of microglia in the recovery process from an ischemic stroke and to evaluate the therapeutic potential of modulating post-ischemic inflammation to promote functional recovery.

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Blockade of P2X7 Receptors or Pannexin-1 Channels Similarly Attenuates Postischemic Damage

Cited by 59 publications

References 36 publications

Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity

Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity

Epithelial and Endothelial Pannexin1 Channels Mediate AKI

Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors

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