Spreading Depression Triggers Headache by Activating Neuronal Panx1 Channels

Karataş, Hülya; Erdener, Şefik Evren; Gürsoy‐Özdemir, Yasemin; Lüle, Sevda; Eren-Koçak, Emine; Şen, Zümrüt Duygu; Dalkara, Turgay

doi:10.1126/science.1231897

Cited by 444 publications

(475 citation statements)

References 42 publications

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“…Second, as an effective panx-1 channel inhibitor (IC 50 < 5 μmol/L), CBX simultaneously inhibited LPS-induced P2X 7 R/ panx-1 channel activation and HMGB1 release, suggesting that the CBX-mediated inhibition of HMGB1 release is likely associated with the blockade of P2X 7 R-gated panx-1 channel activities. Consistent with this notion, CBX and other panx-1 channel blockers have recently been shown to block HMGB1 release by neurons during cortical spreading depression (54).…”

Section: Discussionsupporting

confidence: 52%

Carbenoxolone Blocks Endotoxin-Induced Protein Kinase R (PKR) Activation and High Mobility Group Box 1 (HMGB1) Release

Sama

et al. 2013

Mol Med

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The pathogen-and damage-associated molecular patterns (for example, bacterial endotoxin and adenosine 5′-triphosphate [ATP]) activate the double-stranded RNA-activated protein kinase R (PKR) to trigger the inflammasome-dependent high mobility group box 1 (HMGB1) release. Extracellular ATP contributes to the inflammasome activation through binding to the plasma membrane purinergic P2X 7 receptor (P2X 7 R), triggering the opening of P2X 7 R channels and the pannexin-1 (panx-1) hemichannels permeable for larger molecules up to 900 daltons. It was previously unknown whether panx-1 channel blockers can abrogate lipopolysaccharide (LPS)-induced PKR activation and HMGB1 release in innate immune cells. Here we demonstrated that a major gancao (licorice) component (glycyrrhizin, or glycyrrhizic acid) derivative, carbenoxolone (CBX), dose dependently abrogated LPS-induced HMGB1 release in macrophage cultures with an estimated IC 50 ≈ 5 μmol/L. In an animal model of polymicrobial sepsis (induced by cecal ligation and puncture [CLP]), repetitive CBX administration beginning 24 h after CLP led to a significant reduction of circulating and peritoneal HMGB1 levels, and promoted a significant increase in animal survival rates. As did P2X 7 R antagonists (for example, oxidized ATP, oATP), CBX also effectively attenuated LPS-induced P2X 7 R/panx-1 channel activation (as judged by Lucifer Yellow dye uptake) and PKR phosphorylation in primary peritoneal macrophages. Collectively, these results suggested that CBX blocks LPS-induced HMGB1 release possibly through impairing PKR activation, supporting the involvement of PKR in the regulation of HMGB1 release.

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Section: Discussionsupporting

confidence: 52%

Carbenoxolone Blocks Endotoxin-Induced Protein Kinase R (PKR) Activation and High Mobility Group Box 1 (HMGB1) Release

Sama

et al. 2013

Mol Med

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“…Although initially developed for retinal imaging, LSCI has become predominantly used for neurovascular applications from small animals to humans [1][2][3][4][5]. Given technical and inversemodeling improvements the technique has increased its quantitative accuracy in observing functional hemodynamics beyond just qualitative angiography.…”

Section: Introductionmentioning

confidence: 99%

Optimization of camera exposure durations for multi-exposure speckle imaging of the microcirculation

Kazmi

Balial

Dunn

2014

Biomed. Opt. Express

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Improved Laser Speckle Contrast Imaging (LSCI) blood flow analyses that incorporate inverse models of the underlying laser-tissue interaction have been used to develop more quantitative implementations of speckle flowmetry such as Multi-Exposure Speckle Imaging (MESI). In this paper, we determine the optimal camera exposure durations required for obtaining flow information with comparable accuracy with the prevailing MESI implementation utilized in recent in vivo rodent studies. A looping leave-one-out (LOO) algorithm was used to identify exposure subsets which were analyzed for accuracy against flows obtained from analysis with the original full exposure set over 9 animals comprising n = 314 regional flow measurements. From the 15 original exposures, 6 exposures were found using the LOO process to provide comparable accuracy, defined as being no more than 10% deviant, with the original flow measurements. The optimal subset of exposures provides a basis set of camera durations for speckle flowmetry studies of the microcirculation and confers a twofold faster acquisition rate and a 28% reduction in processing time without sacrificing accuracy. Additionally, the optimization process can be used to identify further reductions in the exposure subsets for tailoring imaging over less expansive flow distributions to enable even faster imaging.

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“…ATP is released from many cell types, including astrocytes, neurons, platelets, and endothelial cells, primarily via exocytosis and pannexin/connexin hemichannels [6][7][8][9]. Notably, pannexin channels are opened during migraine aura-related cortical spreading depression (CSD) wave suggesting a massive release of ATP during a migraine attack [10]. Extracellular ATP binds to and activates ligand-gated P2X and metabotropic P2Y receptors [9].…”

Section: Introductionmentioning

confidence: 99%

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions

Yegutkin

Guerrero-Toro

Kılınç

et al. 2016

Purinergic Signalling

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Extracellular ATP is suspected to contribute to migraine pain but regulatory mechanisms controlling pronociceptive purinergic mechanisms in the meninges remain unknown. We studied the peculiarities of metabolic and signaling pathways of ATP and its downstream metabolites in rat meninges and in cultured trigeminal cells exposed to the migraine mediator calcitonin gene-related peptide (CGRP). Under resting conditions, meningeal ATP and ADP remained at low nanomolar levels, whereas extracellular AMP and adenosine concentrations were one-two orders higher. CGRP increased ATP and ADP levels in meninges and trigeminal cultures and reduced adenosine concentration in trigeminal cells. Degradation rates for exogenous nucleotides remained similar in control and CGRP-treated meninges, indicating that CGRP triggers nucleotide release without affecting nucleotide-inactivating pathways. Lead nitrate-based enzyme histochemistry of whole mount meninges revealed the presence of high ATPase, ADPase, and AMPase activities, primarily localized in the medial meningeal artery. ATP and ADP induced large intracellular Ca 2+ transients both in neurons and in glial cells whereas AMP and adenosine were ineffective. In trigeminal glia, ATP partially operated via P2X7 receptors. ATP, but not other nucleotides, activated nociceptive spikes in meningeal trigeminal nerve fibers providing a rationale for high degradation rate of pro-nociceptive ATP. Pronociceptive effect of ATP in meningeal nerves was reproduced by α,β-meATP operating via P2X3 receptors. Collectively, extracellular ATP, which level is controlled by CGRP, can persistently activate trigeminal nerves in meninges which considered as the origin site of migraine headache. These data are consistent with the purinergic hypothesis of migraine pain and suggest new targets against trigeminal pain.

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Spreading Depression Triggers Headache by Activating Neuronal Panx1 Channels

Cited by 444 publications

References 42 publications

Carbenoxolone Blocks Endotoxin-Induced Protein Kinase R (PKR) Activation and High Mobility Group Box 1 (HMGB1) Release

Carbenoxolone Blocks Endotoxin-Induced Protein Kinase R (PKR) Activation and High Mobility Group Box 1 (HMGB1) Release

Optimization of camera exposure durations for multi-exposure speckle imaging of the microcirculation

Nucleotide homeostasis and purinergic nociceptive signaling in rat meninges in migraine-like conditions

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