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P2X7 Receptor Activation and Inflammatory/Nociceptive Signaling for Painful Diseases: Promising Target for Treatment

This article explores the activation of P2X7 receptors and its correlation with inflammatory and nociceptive signaling, highlighting its potential as a target for the treatment of painful diseases. The expression of P2X7 receptors in various cells and the effects associated with their activation are discussed. Diseases associated with P2X7 receptors and the use of P2X7 antagonists for pain attenuation in vivo models are also addressed.

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P2X7 Receptor Activation and Inflammatory/Nociceptive Signaling for Painful Diseases: Promising Target for Treatment

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  1. Ministry of Health Oswaldo Cruz Foundation Oswaldo Cruz Institute Cellular Comunication Laboratory Immunopharmacology Laboratory The P2X7R activation and its correlation with the inflammatory and nociceptive signaling: A promising target for the treatment of painful diseases. Rômulo José Soares Bezerra, PhD. E-mail: cyentysta@gmail.com

  2. Purinergic Receptors P1 Receptors (activated by adenosine) P2 Receptors (activated by nucleotides) P2X Ionotropic P2Y G-coupled A1, A2A, A2B, A3 P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, P2Y14 P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7 Purinergic Receptors Ravelic & Burnstock, 1998.

  3. Astrocytes Microglia Mast cells Dendritic cells Monocytes Macrophages Lymphocytes Oligodendrocytes Neurons Expression of P2X7R in mammals Cells from CNS: • Microglia; • Astrocytes; • Oligodendrocytes; • Some neurons populations. Cells of the hematopoietic lineage: • Monocytes; • Macrophages; • Lymphocytes; • Mast cells; • Dendritic cells. Ravelic & Burnstock, 1998; Lister et al., 2007; Coddou et al., 2011.

  4. BE BE BE IP IP LY LY LY YP YP YP ATP ATP ATP ATP ATP Activation of P2X7 Receptor Na+ Ca++ Na+ Ca++ Na+ Na+ Na+ ? Ca++ Na+ extracellular Ca++ ATP ATP intracellular K+ K+ 668,39 Da K+ K+ K+ 394,31 Da 457,24 Da 629 Da

  5. Effects associated to P2X7R P2X7R activated Cell death Inflammasome activation ROS generation Caspases activation Transcription factors activation such NF-κB and proinflammatory genes transcription such COX-2 and iNOS Cytokines secretion: IL-1β, IL-18 e TNF-α Phospholipases secretion: PLA2 and PLD MAPK activation Lister et al., 2007; Friedle et al., 2010; Bartlett et al., 2014; Rein & Torres, 2009; Riteau et al., 2012; Latz et al., 2013; Honore et al., 2006; Barberà-Cremades et al., 2012. 1. Proinflammatory profile; 2. Pro-nociceptive.

  6. Diseases associated with P2X7R Important therapeutic target - Neurophatic pain - Buchanan et al., 2006. - Neurodegenerative diseases - Friedle; Curet & Watters, 2010. - Rheumatoid arthritis - Burnstock et al., 2009. - Chronic inflammation - Lister et. al., 2007.

  7. Activity from new natural compounds discovered by our research group • Our aim: Identify new compounds from natural proucts that may be candidates for potential antagonist to P2X7 receptor.

  8. Screening Method

  9. Natural Products Library

  10. Inhibitory Concentration (IC50) obtained

  11. Inhibitory Concentration (IC50) obtained

  12. Inhibitory Concentration (IC50) obtained

  13. Activity on the IL-1β Release

  14. Activity on the Nitric Oxide Release

  15. Activity on the Reactive Oxygen Species (ROS) release

  16. Cytotoxicity

  17. Pharmacologic Characterization

  18. Nociception

  19. Nociception

  20. Next Steps

  21. Synthetic Compounds Alves, L.A. et al. 2013

  22. Natural Compounds

  23. Thank You!

  24. Inhibition of pain in vivo models using P2X7 antagonists Pain attenuation in vivo models of neurophatic pain Pain attenuation in vivo models of inflammatory pain Labasi et al., 2002; Honore et al., 2006; McGaraughty et al., 2007.

  25. Inhibition of pain in vivo models using P2X7 antagonists from natural products Rheedia longifolia Compound: Amentoflavone - P2X7 Santos, J.A.A et al., 2010. • Model of writhing induced by acetic acid using the leaves of Rheedia longifolia Triana & Planch

  26. Inhibition of pain in vivo models using P2X7 antagonists from natural products Number of indomethacin induced gastric lesions Model of neurogenic nociception induced by capsaicin Inflammatory nociception observed by von Frey model

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