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https://www.readbyqxmd.com/read/28318085/inflammatory-double-hit-model-of-temporomandibular-joint-disorder-with-elevated-ccl2-cxcl9-cxcl10-rantes-and-behavioural-hypersensitivity-in-tnfr1-r2-mice
#1
S L McIlwrath, R Nesemeier, F Ma, H S Oz, L Zhang, K N Westlund
BACKGROUND: Patients with temporomandibular joint disorders (TMD), reactive arthritis and rheumatoid arthritis often have combined etiology of hereditary and microenvironmental factors contributing to joint pain. Multiple clinical and animal studies indicate 'double-hit' inflammatory insults can cause chronic inflammation. The first inflammatory insult primes the immune system and subsequent insults elicit amplified responses. The present 'double hit' study produced a chronic orofacial pain model in mice with genetic deletion of both TNFα receptors (TNFR1/R2-/-), investigating the main nociceptive signalling pathways in comparisons to wild type mice...
March 20, 2017: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/28300164/role-of-purinergic-signaling-in-experimental-pneumococcal-meningitis
#2
Marco Zierhut, Susanne Dyckhoff, Ilias Masouris, Matthias Klein, Sven Hammerschmidt, Hans-Walter Pfister, Korcan Ayata, Marco Idzko, Uwe Koedel
Excessive neutrophilic inflammation contributes to brain pathology and adverse outcome in pneumococcal meningitis (PM). Recently, we identified the NLRP3 inflammasome/interleukin (IL)-1β pathway as a key driver of inflammation in PM. A critical membrane receptor for NLRP3 inflammasome activation is the ATP-activated P2 purinoceptor (P2R) P2X7. Thus, we hypothesized involvement of ATP and P2Rs in PM. The functional role of ATP was investigated in a mouse meningitis model using P2R antagonists. Brain expression of P2Rs was assessed by RT-PCR...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28297661/t-follicular-helper-cells-promote-a-beneficial-gut-ecosystem-for-host-metabolic-homeostasis-by-sensing-microbiota-derived-extracellular-atp
#3
Lisa Perruzza, Giorgio Gargari, Michele Proietti, Bruno Fosso, Anna Maria D'Erchia, Caterina Elisa Faliti, Tanja Rezzonico-Jost, Daniela Scribano, Laura Mauri, Diego Colombo, Giovanni Pellegrini, Annalisa Moregola, Catherine Mooser, Graziano Pesole, Mauro Nicoletti, Giuseppe Danilo Norata, Markus B Geuking, Kathy D McCoy, Simone Guglielmetti, Fabio Grassi
The ATP-gated ionotropic P2X7 receptor regulates T follicular helper (Tfh) cell abundance in the Peyer's patches (PPs) of the small intestine; deletion of P2rx7, encoding for P2X7, in Tfh cells results in enhanced IgA secretion and binding to commensal bacteria. Here, we show that Tfh cell activity is important for generating a diverse bacterial community in the gut and that sensing of microbiota-derived extracellular ATP via P2X7 promotes the generation of a proficient gut ecosystem for metabolic homeostasis...
March 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28286160/p2x7-receptor-promotes-intestinal-inflammation-in-chemically-induced-colitis-and-triggers-death-of-mucosal-regulatory-t-cells
#4
Vanessa R Figliuolo, Luiz Eduardo Baggio Savio, Hanaa Safya, Hayandra Nanini, Cláudio Bernardazzi, Alessandra Abalo, Heitor S P de Souza, Jean Kanellopoulos, Pierre Bobé, Cláudia M L M Coutinho, Robson Coutinho-Silva
P2X7 receptor activation contributes to inflammation development in different pathologies. We previously reported that the P2X7 receptor is over-expressed in the gut mucosa of patients with inflammatory bowel disease, and that P2X7 inhibition protects against chemically induced colitis. Here, we investigated in detail the role of the P2X7 receptor in inflammatory bowel disease development, by treating P2X7 knockout (KO) and WT mice with two different (and established) colitis inductors. P2X7 KO mice were protected against gut inflammation induced by 2,4,6-trinitrobenzenesulfonic acid or oxazolone, with no weight loss or gut histological alterations after treatment...
March 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28280004/connexin-purinergic-signaling-in-enteric-glia-mediates-the-prolonged-effect-of-morphine-on-constipation
#5
Sukhada Bhave, Aravind Gade, Minho Kang, Kurt F Hauser, William L Dewey, Hamid I Akbarali
Morphine is one of the most widely used drugs for the treatment of pain. However, side effects, including persistent constipation and antinociceptive tolerance limit its clinical efficacy. Prolonged morphine treatment results in a "leaky" gut predisposing to colonic inflammation that is facilitated by microbial dysbiosis and associated bacterial translocation. In this study, we examined the role of enteric glia in mediating this secondary inflammatory response to prolonged treatment with morphine. We found that purinergic P2X receptor activity was significantly enhanced in enteric glia that were isolated from mice with long-term morphine treatment (in vivo) but not upon direct exposure of glia to morphine (in vitro)...
March 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28279849/discovery-and-pharmacological-evaluation-of-a-novel-series-of-adamantyl-cyanoguanidines-as-p2x7-receptor-antagonists
#6
James O'Brien-Brown, Alexander Jackson, Tristan A Reekie, Melissa L Barron, Eryn L Werry, Paolo Schiavini, Michelle McDonnell, Lenka Munoz, Shane Wilkinson, Benjamin Noll, Shudong Wang, Michael Kassiou
Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X7R antagonists...
March 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28277328/isobolographic-analysis-of-drug-combinations-with-intrathecal-brl52537-%C3%AE%C2%BA-opioid-agonist-pregabalin-calcium-channel-modulator-af-353-p2x3-receptor-antagonist-and-a804598-p2x7-receptor-antagonist-in-neuropathic-rats
#7
Young-Hwan Jung, Yeo Ok Kim, Jung Hyun Han, Yong-Chul Kim, Myung Ha Yoon
BACKGROUND: Neuropathic pain should be treated with drug combinations exhibiting multiple analgesic mechanisms of action because the mechanism of neuropathic pain involves multiple physiological causes and is mediated by multiple pathways. In this study, we defined the pharmacological interaction of BRL52537 (κ-opioid agonist), pregabalin (calcium channel modulator), AF 353 (P2X3 receptor antagonist), and A804598 (P2X7 receptor antagonist). METHODS: Animal models of neuropathic pain were established by spinal nerve ligation (SNL) in male Sprague-Dawley rats, and responses to the mechanical stimulation using von Frey filaments were measured...
March 8, 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/28266268/p2x7-receptor-orchestrates-multiple-signalling-pathways-triggering-inflammation-autophagy-and-metabolic-trophic-responses
#8
Elisa Orioli, Elena De Marchi, Anna Lisa Giuliani, Elena Adinolfi
P2X7 receptor is an ion channel activated by extracellular adenosine trisphosphate (eATP) that attracted increasing attention for its role in immune reactions, neurobiology and oncology. As receptor for an extracellular ligand, P2X7 activates a series of intracellular signalling pathways mainly via alterations of the ion permeability, but also through formation of a large unselective pore and direct interaction with other proteins. Here we wish to give an overview on the main biochemical paths initiated by P2X7 activation by revising recent and established literature on P2X7-triggered signalling cascades leading to cell death, inflammatory and immune response activation, proliferation and metabolism modulation...
March 3, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28265522/p2x7-antagonism-using-brilliant-blue-g-reduces-body-weight-loss-and-prolongs-survival-in-female-sod1-g93a-amyotrophic-lateral-sclerosis-mice
#9
Rachael Bartlett, Vanessa Sluyter, Debbie Watson, Ronald Sluyter, Justin J Yerbury
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterised by the accumulation of aggregated proteins, microglia activation and motor neuron loss. The mechanisms underlying neurodegeneration and disease progression in ALS are unknown, but the ATP-gated P2X7 receptor channel is implicated in this disease. Therefore, the current study aimed to examine P2X7 in the context of neurodegeneration, and investigate whether the P2X7 antagonist, Brilliant Blue G (BBG), could alter disease progression in a murine model of ALS...
2017: PeerJ
https://www.readbyqxmd.com/read/28263802/abacavir-induces-platelet-endothelium-interactions-by-interfering-with-purinergic-signalling-a-step-from-inflammation-to-thrombosis
#10
Angeles Alvarez, Cesar Rios-Navarro, Maria Amparo Blanch-Ruiz, Victor Collado-Diaz, Isabel Andujar, Maria Angeles Martinez-Cuesta, Samuel Orden, Juan V Esplugues
The controversy connecting Abacavir (ABC) with cardiovascular disease has been fuelled by the lack of a credible mechanism of action. ABC shares structural similarities with endogenous purines, signalling molecules capable of triggering prothrombotic/proinflammatory programmes. Platelets are leading actors in the process of thrombosis. Our study addresses the effects of ABC on interactions between platelets and other vascular cells, while exploring the adhesion molecules implicated and the potential interference with the purinergic signalling pathway...
March 2, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28257396/maxi-anion-channels-play-a-key-role-in-glutamate-induced-atp-release-from-mouse-astrocytes-in-primary-culture
#11
Bin Zhao, Li Gu, Kaixi Liu, Mingming Zhang, Hongtao Liu
Astrocytes are an abundant source of ATP, which might be released from the cytosol into extracellular spaces under various conditions and even affect cell fate under some circumstances. In the present study, we aimed to evaluate the pathway(s) contributing toward glutamate-induced ATP release from mouse astrocytes. Firstly, our study of cultured astrocytes showed marked ATP release in response to stimuli of glutamate at different concentrations (0.1-1 mM), with an interesting bimodal distribution in time course...
March 2, 2017: Neuroreport
https://www.readbyqxmd.com/read/28250280/species-difference-in-sensitivity-of-human-and-mouse-p2x7-receptors-to-inhibitory-effects-of-divalent-metal-cations
#12
Makiko Fujiwara, Kenshi Ohbori, Akihiro Ohishi, Kentaro Nishida, Yoshinobu Uozumi, Kazuki Nagasawa
P2X7 receptor (P2X7R), a purinergic receptor, is involved in pathophysiological events such as inflammation and cell death, and thus is an attractive target for therapeutic approaches. It is reported that divalent metal cations (DMCs) inhibit P2X7R activation and that there are species differences in their inhibitory effects. To extrapolate the findings in experimental animals to humans, these species differences have to be clarified, but species differences in the sensitivity of P2X7R to DMCs between man and mouse have not been demonstrated...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28248151/p2x7-antagonists-for-cns-indications-recent-patent-disclosures
#13
REVIEW
Paolo Pevarello, Silvia Bovolenta, Paola Tarroni, Lorena Za, Elda Severi, Domenica Torino, Rocco Vitalone
P2X7, a ligand-gated purinergic ion channel, has been at the center of intense efforts in the pharmaceutical industry in the last 15 years due to the growing appreciation of its role in inflammation. Since 2008-2009, increased focus on CNS available compounds has led to the publication of various patents on behalf of several pharmaceutical companies. This patent review aims at analyzing the recent patent literature (2008-2016) with a particular emphasis on those patents that are thought to deal with CNS penetrant compounds on the basis of their physicochemical features, the assays described in the patents and the uses these compounds are claimed for...
March 2017: Pharmaceutical Patent Analyst
https://www.readbyqxmd.com/read/28246166/differential-role-of-pannexin-1-atp-p2x7-axis-in-il-1%C3%AE-release-by-human-monocytes
#14
Katarzyna Parzych, Anna V Zetterqvist, William R Wright, Nicholas S Kirkby, Jane A Mitchell, Mark J Paul-Clark
IL-1β release is integral to the innate immune system. The release of mature IL-1β depends on 2 regulated events: the de novo induction of pro-IL-1β, generally via NF-κB-dependent transduction pathways; and the assembly and activation of the NLRP3 inflammasome. This latter step is reliant on active caspase-1, pannexin-1, and P2X7 receptor activation. Pathogen-associated molecular patterns in gram-positive and gram-negative bacteria activate IL-1β release from immune cells via TLR2 and TLR4 receptors, respectively...
February 28, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28244110/the-p2x7-receptor-links-mechanical-strain-to-cytokine-il-6-upregulation-and-release-in-neurons-and-astrocytes
#15
Wennan Lu, Farraj Albalawi, Jonathan M Beckel, Jason C Lim, Alan M Laties, Claire H Mitchell
BACKGROUND: Mechanical strain in neural tissues can lead to the upregulation and release of multiple cytokines including IL-6. In the retina, the mechanosensitive release of ATP can autostimulate P2X7 receptors on both retinal ganglion cell neurons and optic nerve head astrocytes. Here we asked whether the purinergic signaling contributed to the IL-6 response to increased intraocular pressure (IOP) in vivo, and stretch or swelling in vitro. METHODS: Rat and mouse eyes were exposed to non-ischemic elevations in IOP to 50-60 mmHg for 4 hrs...
February 28, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28240322/influence-of-extracellular-zinc-on-m1-microglial-activation
#16
Youichirou Higashi, Takaaki Aratake, Shogo Shimizu, Takahiro Shimizu, Kumiko Nakamura, Masayuki Tsuda, Toshio Yawata, Tetuya Ueba, Motoaki Saito
Extracellular zinc, which is released from hippocampal neurons in response to brain ischaemia, triggers morphological changes in microglia. Under ischaemic conditions, microglia exhibit two opposite activation states (M1 and M2 activation), which may be further regulated by the microenvironment. We examined the role of extracellular zinc on M1 activation of microglia. Pre-treatment of microglia with 30-60 μM ZnCl2 resulted in dose-dependent increases in interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNFα) secretion when M1 activation was induced by lipopolysaccharide administration...
February 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28239332/characterization-of-the-circumlimbal-suture-model-of-chronic-iop-elevation-in-mice-and-assessment-of-changes-in-gene-expression-of-stretch-sensitive-channels
#17
Da Zhao, Christine T O Nguyen, Vickie H Y Wong, Jeremiah K H Lim, Zheng He, Andrew I Jobling, Erica L Fletcher, Holly R Chinnery, Algis J Vingrys, Bang V Bui
To consider whether a circumlimbal suture can be used to chronically elevate intraocular pressure (IOP) in mice and to assess its effect on retinal structure, function and gene expression of stretch sensitive channels. Anesthetized adult C57BL6/J mice had a circumlimbal suture (10/0) applied around the equator of one eye. In treated eyes (n = 23) the suture was left in place for 12 weeks whilst in sham control eyes the suture was removed at day two (n = 17). Contralateral eyes served as untreated controls. IOP was measured after surgery and once a week thereafter...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28237817/p2x7-receptor-sensitivity-of-astrocytes-and-neurons-in-the-substantia-gelatinosa-of-organotypic-spinal-cord-slices-of-the-mouse-depends-on-the-length-of-the-culture-period
#18
Po Gao, Xiaowei Ding, Tahir Muhammad Khan, Weifang Rong, Heike Franke, Peter Illes
The whole-cell patch-clamp technique was used to record current responses to AMPA, N-methyl-d-aspartate (NMDA), muscimol and dibenzoyl-ATP (Bz-ATP) in superficial (reactive/gliotic) substantia gelatinosa (SG) astrocytes and neurons of spinal cord slices kept for different periods of time in organotypic culture. Currents induced by AMPA, NMDA and muscimol confirmed the existence of their specific receptors in 2-week-old neurons; astrocytes cultured for the same period of time responded to AMPA and muscimol, but not to NMDA...
February 22, 2017: Neuroscience
https://www.readbyqxmd.com/read/28235784/localization-of-the-gate-and-selectivity-filter-of-the-full-length-p2x7-receptor
#19
Anja Pippel, Michaela Stolz, Ronja Woltersdorf, Achim Kless, Günther Schmalzing, Fritz Markwardt
The P2X7 receptor (P2X7R) belongs to the P2X family of ATP-gated cation channels. P2X7Rs are expressed in epithelial cells, leukocytes, and microglia, and they play important roles in immunological and inflammatory processes. P2X7Rs are obligate homotrimers, with each subunit having two transmembrane helices, TM1 and TM2. Structural and functional data regarding the P2X2 and P2X4 receptors indicate that the central trihelical TM2 bundle forms the intrinsic transmembrane channel of P2X receptors. Here, we studied the accessibility of single cysteines substituted along the pre-TM2 and TM2 helix (residues 327-357) of the P2X7R using as readouts (i) the covalent maleimide fluorescence accessibility of the surface-bound P2X7R and (ii) covalent modulation of macroscopic and single-channel currents using extracellularly and intracellularly applied methanethiosulfonate (MTS) reagents...
February 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28210205/the-atp-gated-p2x7-receptor-as-a-target-for-the-treatment-of-drug-resistant-epilepsy
#20
REVIEW
Edward Beamer, Wolfgang Fischer, Tobias Engel
Despite the progress made in the development of new antiepileptic drugs (AEDs), the biggest challenges that epilepsy presents to drug development have remained unchanged for the last 80 years: finding a treatment with potential for modifying disease progression and reducing the percentage of patients resistant to all pharmacological interventions. The mechanism of action of the majority of AEDs is based on blocking Na(+) and/or Ca(2+) channels, promotion of GABA or inhibition of glutamate signaling. In order for further progress to be made, however, a fuller picture of epilepsy will need to be considered, including changes to blood-brain barrier permeability, synaptic plasticity, network reorganization, and gliosis...
2017: Frontiers in Neuroscience
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