Skip to main content
SpringerLink
Log in

Cannabinoids Induce Cell Death and Promote P2X7 Receptor Signaling in Retinal Glial Progenitors in Culture

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Development of progenitors in the embryonic retina is modulated by signaling molecules, and cannabinoid receptors are highly expressed in the early developing retina. Here, we investigated whether the CB1/CB2 receptor agonist WIN 5212-2 (WIN) modulated the proliferation, viability, and calcium responses in chick embryo retinal progenitors in culture. A decline in [3H]-thymidine incorporation was observed when cultures were incubated with 0.5–1.0 μM WIN, an effect that was mimicked by URB602 and URB597, inhibitors of the monoacylglycerol lipase and fatty acid amide hydrolase, respectively. A reduction in the number of proliferating cell nuclear antigen-positive nuclei was also noticed in WIN-treated cultures, suggesting that activation of cannabinoid receptors decreases the proliferation of cultured retinal progenitors. WIN (0.5–5.0 μM), but not capsaicin, decreased retinal cell viability, an effect that was blocked by CB1 and CB2 receptor antagonists and by the P2X7 receptor antagonist A438079, implicating this nucleotide receptor in the cannabinoid-mediated cell death. Treatment with WIN also induced an increase in mitochondrial superoxide and P2X7 receptor-mediated uptake of sulforhodamine B in the cultured cells. While a high proportion of cultured cells responded to glutamate, GABA, and 50 mM KCl with intracellular calcium shifts, very few cells responded to the activation of P2X7 receptors by ATP. Noteworthy, while decreasing the number of cells responding to glutamate, GABA, and KCl, treatment of the cultures with WIN induced a significant increase in the number of cells responding to 1 mM ATP, suggesting that activation of cannabinoid receptors primes P2X7 receptor calcium signaling in retinal progenitors in culture.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Turner DL, Cepko CL (1987) A common progenitor for neurons and glia persists in rat retina late in development. Nature 328(6126):131–136. https://doi.org/10.1038/328131a0

    Article  CAS  PubMed  Google Scholar 

  2. Wetts R, Fraser SE (1988) Multipotent precursors can give rise to all major cell types of the frog retina. Science 239(4844):1142–1145

    Article  CAS  PubMed  Google Scholar 

  3. Wetts R, Serbedzija GN, Fraser SE (1989) Cell lineage analysis reveals multipotent precursors in the ciliary margin of the frog retina. Dev Biol 136(1):254–263

    Article  CAS  PubMed  Google Scholar 

  4. Cepko CL (1999) The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates. Curr Opin Neurobiol 9(1):37–46

    Article  CAS  PubMed  Google Scholar 

  5. Livesey FJ, Cepko CL (2001) Vertebrate neural cell-fate determination: lessons from the retina. Nat Rev Neurosci 2(2):109–118. https://doi.org/10.1038/35053522

    Article  CAS  PubMed  Google Scholar 

  6. Hatakeyama J, Kageyama R (2004) Retinal cell fate determination and bHLH factors. Semin Cell Dev Biol 15(1):83–89. https://doi.org/10.1016/j.semcdb.2003.09.005

    Article  CAS  PubMed  Google Scholar 

  7. de Mello MC, Ventura AL, Paes de Carvalho R, Klein WL, de Mello FG (1982) Regulation of dopamine- and adenosine-dependent adenylate cyclase systems of chicken embryo retina cells in culture. Proc Natl Acad Sci U S A 79(18):5708–5712

    Article  PubMed  PubMed Central  Google Scholar 

  8. Reis RA, Ventura AL, Kubrusly RC, de Mello MC, de Mello FG (2007) Dopaminergic signaling in the developing retina. Brain Res Rev 54(1):181–188. https://doi.org/10.1016/j.brainresrev.2007.01.001

    Article  CAS  PubMed  Google Scholar 

  9. Borba JC, Henze IP, Silveira MS, Kubrusly RC, Gardino PF, de Mello MC, Hokoc JN, de Mello FG (2005) Pituitary adenylate cyclase-activating polypeptide (PACAP) can act as determinant of the tyrosine hydroxylase phenotype of dopaminergic cells during retina development. Brain Res Dev Brain Res 156(2):193–201. https://doi.org/10.1016/j.devbrainres.2005.02.016

    Article  CAS  PubMed  Google Scholar 

  10. Guimaraes MZ, Hokoc JN, Duvoisin R, Reis RA, De Mello FG (2001) Dopaminergic retinal cell differentiation in culture: modulation by forskolin and dopamine. Eur J Neurosci 13(10):1931–1937

    Article  CAS  PubMed  Google Scholar 

  11. Cecyre B, Zabouri N, Huppe-Gourgues F, Bouchard JF, Casanova C (2013) Roles of cannabinoid receptors type 1 and 2 on the retinal function of adult mice. Invest Ophthalmol Vis Sci 54(13):8079–8090. https://doi.org/10.1167/iovs.13-12514

    Article  CAS  PubMed  Google Scholar 

  12. Leonelli M, Britto LR, Chaves GP, Torrao AS (2005) Developmental expression of cannabinoid receptors in the chick retinotectal system. Brain Res Dev Brain Res 156(2):176–182. https://doi.org/10.1016/j.devbrainres.2005.02.009

    Article  CAS  PubMed  Google Scholar 

  13. Schwitzer T, Schwan R, Angioi-Duprez K, Giersch A, Laprevote V (2016) The endocannabinoid system in the retina: from physiology to practical and therapeutic applications. Neural Plasticity 2016:2916732–2916710. https://doi.org/10.1155/2016/2916732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kubrusly RCC, Gunter A, Sampaio L, Martins RS, Schitine CS, Trindade P, Fernandes A, Borelli-Torres R et al (2018) Neuro-glial cannabinoid receptors modulate signaling in the embryonic avian retina. Neurochem Int 112:27–37. https://doi.org/10.1016/j.neuint.2017.10.016

    Article  CAS  PubMed  Google Scholar 

  15. De Melo Reis RA, Schitine CS, Kofalvi A, Grade S, Cortes L, Gardino PF, Malva JO, de Mello FG (2011) Functional identification of cell phenotypes differentiating from mice retinal neurospheres using single cell calcium imaging. Cell Mol Neurobiol 31(6):835–846. https://doi.org/10.1007/s10571-011-9673-6

    Article  CAS  PubMed  Google Scholar 

  16. Faria RX, Freitas HR, Reis RAM (2017) P2X7 receptor large pore signaling in avian Muller glial cells. J Bioenerg Biomembr 49:215–229. https://doi.org/10.1007/s10863-017-9717-9

    Article  CAS  PubMed  Google Scholar 

  17. Sholl-Franco A, Fragel-Madeira L, Macama Ada C, Linden R, Ventura AL (2010) ATP controls cell cycle and induces proliferation in the mouse developing retina. Int J Dev Neurosci 28(1):63–73. https://doi.org/10.1016/j.ijdevneu.2009.09.004

    Article  CAS  PubMed  Google Scholar 

  18. de Almeida-Pereira L, Magalhaes CF, Repossi MG, Thorstenberg MLP, Sholl-Franco A, Coutinho-Silva R, Ventura ALM, Fragel-Madeira L (2017) Adenine nucleotides control proliferation in vivo of rat retinal progenitors by P2Y1 receptor. Mol Neurobiol 54(7):5142–5155. https://doi.org/10.1007/s12035-016-0059-0

    Article  CAS  PubMed  Google Scholar 

  19. de Almeida-Pereira L, Repossi MG, Magalhaes CF, Azevedo RF, Correa-Velloso JDC, Ulrich H, Ventura ALM, Fragel-Madeira L (2018) P2Y12 but not P2Y13 purinergic receptor controls postnatal rat retinogenesis in vivo. Mol Neurobiol 55(11):8612–8624. https://doi.org/10.1007/s12035-018-1012-1

    Article  CAS  PubMed  Google Scholar 

  20. Pearson R, Catsicas M, Becker D, Mobbs P (2002) Purinergic and muscarinic modulation of the cell cycle and calcium signaling in the chick retinal ventricular zone. J Neurosci 22(17):7569–7579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nunes PH, Calaza Kda C, Albuquerque LM, Fragel-Madeira L, Sholl-Franco A, Ventura AL (2007) Signal transduction pathways associated with ATP-induced proliferation of cell progenitors in the intact embryonic retina. Int J Dev Neurosci 25(8):499–508. https://doi.org/10.1016/j.ijdevneu.2007.09.007

    Article  CAS  PubMed  Google Scholar 

  22. Franca GR, Freitas RC, Ventura AL (2007) ATP-induced proliferation of developing retinal cells: regulation by factors released from postmitotic cells in culture. Int J Dev Neurosci 25(5):283–291. https://doi.org/10.1016/j.ijdevneu.2007.05.006

    Article  CAS  PubMed  Google Scholar 

  23. Sanches G, de Alencar LS, Ventura AL (2002) ATP induces proliferation of retinal cells in culture via activation of PKC and extracellular signal-regulated kinase cascade. Int J Dev Neurosci 20(1):21–27

    Article  CAS  PubMed  Google Scholar 

  24. Ornelas IM, Ventura AL (2010) Involvement of the PI3K/AKT pathway in ATP-induced proliferation of developing retinal cells in culture. Int J Dev Neurosci 28(6):503–511. https://doi.org/10.1016/j.ijdevneu.2010.06.001

    Article  CAS  PubMed  Google Scholar 

  25. Jacques FJ, Silva TM, da Silva FE, Ornelas IM, Ventura ALM (2017) Nucleotide P2Y13-stimulated phosphorylation of CREB is required for ADP-induced proliferation of late developing retinal glial progenitors in culture. Cell Signal 35:95–106. https://doi.org/10.1016/j.cellsig.2017.03.019

    Article  CAS  PubMed  Google Scholar 

  26. Anccasi RM, Ornelas IM, Cossenza M, Persechini PM, Ventura AL (2013) ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors. Purinergic Signal 9(1):15–29. https://doi.org/10.1007/s11302-012-9324-5

    Article  CAS  PubMed  Google Scholar 

  27. da Silva Sampaio L, Kubrusly RCC, Colli YP, Trindade PP, Ribeiro-Resende VT, Einicker-Lamas M, Paes-de-Carvalho R, Gardino PF et al (2018) Cannabinoid receptor type 1 expression in the developing avian retina: morphological and functional correlation with the dopaminergic system. Front Cell Neurosci 12:58. https://doi.org/10.3389/fncel.2018.00058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hamburger V, Hamilton HL (1951) A series of normal stages in the development of the chick embryo. J Morphol 88(1):49–92

    Article  CAS  PubMed  Google Scholar 

  29. Paes de Carvalho R, de Mello FG (1982) Adenosine-elicited accumulation of adenosine 3′, 5′-cyclic monophosphate in the chick embryo retina. J Neurochem 38(2):493–500

    Article  CAS  PubMed  Google Scholar 

  30. Freitas HR, Ferraz G, Ferreira GC, Ribeiro-Resende VT, Chiarini LB, do Nascimento JL, Matos Oliveira KR, Pereira TL et al (2016) Glutathione-induced calcium shifts in chick retinal glial cells. PLoS One 11(4):e0153677. https://doi.org/10.1371/journal.pone.0153677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schitine CS, Mendez-Flores OG, Santos LE, Ornelas I, Calaza KC, Perez-Toledo K, Lopez-Bayghen E, Ortega A et al (2015) Functional plasticity of GAT-3 in avian Muller cells is regulated by neurons via a glutamatergic input. Neurochem Int 82:42–51. https://doi.org/10.1016/j.neuint.2015.02.004

    Article  CAS  PubMed  Google Scholar 

  32. Pohl-Guimaraes F, Calaza Kda C, Yamasaki EN, Kubrusly RC, Reis RA (2010) Ethanol increases GABA release in the embryonic avian retina. Int J Dev Neurosci 28(2):189–194. https://doi.org/10.1016/j.ijdevneu.2009.11.003

    Article  CAS  PubMed  Google Scholar 

  33. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  34. Petit JM, Denis-Gay M, Ratinaud MH (1993) Assessment of fluorochromes for cellular structure and function studies by flow cytometry. Biol Cell 78(1–2):1–13

    Article  CAS  PubMed  Google Scholar 

  35. Carayon P, Marchand J, Dussossoy D, Derocq JM, Jbilo O, Bord A, Bouaboula M, Galiegue S et al (1998) Modulation and functional involvement of CB2 peripheral cannabinoid receptors during B-cell differentiation. Blood 92(10):3605–3615

    CAS  PubMed  Google Scholar 

  36. Jin K, Xie L, Kim SH, Parmentier-Batteur S, Sun Y, Mao XO, Childs J, Greenberg DA (2004) Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol 66(2):204–208. https://doi.org/10.1124/mol.66.2.204

    Article  CAS  PubMed  Google Scholar 

  37. Xapelli S, Agasse F, Sarda-Arroyo L, Bernardino L, Santos T, Ribeiro FF, Valero J, Braganca J et al (2013) Activation of type 1 cannabinoid receptor (CB1R) promotes neurogenesis in murine subventricular zone cell cultures. PLoS One 8(5):e63529. https://doi.org/10.1371/journal.pone.0063529

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rodrigues RS, Ribeiro FF, Ferreira F, Vaz SH, Sebastiao AM, Xapelli S (2017) Interaction between cannabinoid type 1 and type 2 receptors in the modulation of subventricular zone and dentate gyrus neurogenesis. Front Pharmacol 8:516. https://doi.org/10.3389/fphar.2017.00516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Burnstock G, Verkhratsky A (2010) Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death. Cell Death Dis 1:e9. https://doi.org/10.1038/cddis.2009.11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA (2017) Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr Neurosci 21:1–20. https://doi.org/10.1080/1028415x.2017.1347373

    Article  CAS  Google Scholar 

  41. Freitas HR, Ferreira GDC, Trevenzoli IH, Oliveira KJ, de Melo Reis RA (2017) Fatty acids, antioxidants and physical activity in brain aging. Nutrients 9(11). https://doi.org/10.3390/nu9111263

  42. Galve-Roperh I, Sanchez C, Cortes ML, Gomez del Pulgar T, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6(3):313–319. https://doi.org/10.1038/73171

    Article  CAS  PubMed  Google Scholar 

  43. Ellert-Miklaszewska A, Kaminska B, Konarska L (2005) Cannabinoids down-regulate PI3K/Akt and Erk signalling pathways and activate proapoptotic function of Bad protein. Cell Signal 17(1):25–37. https://doi.org/10.1016/j.cellsig.2004.05.011

    Article  CAS  PubMed  Google Scholar 

  44. Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47. https://doi.org/10.1146/annurev-psych-113011-143739

    Article  PubMed  Google Scholar 

  45. Begbie J, Doherty P, Graham A (2004) Cannabinoid receptor, CB1, expression follows neuronal differentiation in the early chick embryo. J Anat 205(3):213–218. https://doi.org/10.1111/j.0021-8782.2004.00325.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z et al (2005) The endocannabinoid system drives neural progenitor proliferation. FASEB J: Off Publ Fed Am Soc Exp Biol 19(12):1704–1706. https://doi.org/10.1096/fj.05-3995fje

    Article  CAS  Google Scholar 

  47. Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzman M, Galve-Roperh I (2006) Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J: Off Publ Fed Am Soc Exp Biol 20(13):2405–2407. https://doi.org/10.1096/fj.06-6164fje

    Article  CAS  Google Scholar 

  48. Xu D, Wang J, Zhou Z, He Z, Zhao Q (2015) Cannabinoid WIN55, 212-2 induces cell cycle arrest and inhibits the proliferation and migration of human BEL7402 hepatocellular carcinoma cells. Mol Med Rep 12(6):7963–7970. https://doi.org/10.3892/mmr.2015.4477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Robinson RH, Meissler JJ, Breslow-Deckman JM, Gaughan J, Adler MW, Eisenstein TK (2013) Cannabinoids inhibit T-cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed lymphocyte reaction. J Neuroimmune Pharmacol 8(5):1239–1250. https://doi.org/10.1007/s11481-013-9485-1

    Article  PubMed  Google Scholar 

  50. Marcu JP, Christian RT, Lau D, Zielinski AJ, Horowitz MP, Lee J, Pakdel A, Allison J et al (2010) Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol Cancer Ther 9(1):180–189. https://doi.org/10.1158/1535-7163.mct-09-0407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Walter L, Dinh T, Stella N (2004) ATP induces a rapid and pronounced increase in 2-arachidonoylglycerol production by astrocytes, a response limited by monoacylglycerol lipase. J Neurosci 24(37):8068–8074. https://doi.org/10.1523/jneurosci.2419-04.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Witting A, Walter L, Wacker J, Moller T, Stella N (2004) P2X7 receptors control 2-arachidonoylglycerol production by microglial cells. Proc Natl Acad Sci U S A 101(9):3214–3219. https://doi.org/10.1073/pnas.0306707101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Solymosi K, Kofalvi A (2017) Cannabis: a treasure trove or Pandora’s box? Mini-Rev Med Chem 17(13):1223–1291. https://doi.org/10.2174/1389557516666161004162133

    Article  CAS  PubMed  Google Scholar 

  54. Fernandez-Ruiz J, Romero J, Velasco G, Tolon RM, Ramos JA, Guzman M (2007) Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci 28(1):39–45. https://doi.org/10.1016/j.tips.2006.11.001

    Article  CAS  PubMed  Google Scholar 

  55. Jackson SJ, Pryce G, Diemel LT, Cuzner ML, Baker D (2005) Cannabinoid-receptor 1 null mice are susceptible to neurofilament damage and caspase 3 activation. Neuroscience 134(1):261–268. https://doi.org/10.1016/j.neuroscience.2005.02.045

    Article  CAS  PubMed  Google Scholar 

  56. Vrechi TA, Crunfli F, Costa AP, Torrao AS (2018) Cannabinoid receptor type 1 agonist ACEA protects neurons from death and attenuates endoplasmic reticulum stress-related apoptotic pathway signaling. Neurotox Res 33(4):846–855. https://doi.org/10.1007/s12640-017-9839-1

    Article  CAS  PubMed  Google Scholar 

  57. Tomiyama K, Funada M (2011) Cytotoxicity of synthetic cannabinoids found in “Spice” products: the role of cannabinoid receptors and the caspase cascade in the NG 108-15 cell line. Toxicol Lett 207(1):12–17. https://doi.org/10.1016/j.toxlet.2011.08.021

    Article  CAS  PubMed  Google Scholar 

  58. Tomiyama K, Funada M (2014) Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death. Toxicol Appl Pharmacol 274(1):17–23. https://doi.org/10.1016/j.taap.2013.10.028

    Article  CAS  PubMed  Google Scholar 

  59. Benard G, Massa F, Puente N, Lourenco J, Bellocchio L, Soria-Gomez E, Matias I, Delamarre A et al (2012) Mitochondrial CB(1) receptors regulate neuronal energy metabolism. Nat Neurosci 15(4):558–564. https://doi.org/10.1038/nn.3053

    Article  CAS  PubMed  Google Scholar 

  60. Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza PV, Benard G et al (2014) Cannabinoid control of brain bioenergetics: exploring the subcellular localization of the CB1 receptor. Mol Metab 3(4):495–504. https://doi.org/10.1016/j.molmet.2014.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fisar Z, Singh N, Hroudova J (2014) Cannabinoid-induced changes in respiration of brain mitochondria. Toxicol Lett 231(1):62–71. https://doi.org/10.1016/j.toxlet.2014.09.002

    Article  CAS  PubMed  Google Scholar 

  62. Galindo L, Moreno E, Lopez-Armenta F, Guinart D, Cuenca-Royo A, Izquierdo-Serra M, Xicota L, Fernandez C et al (2018) Cannabis users show enhanced expression of CB1-5HT2A receptor heteromers in olfactory neuroepithelium cells. Mol Neurobiol 55(8):6347–6361. https://doi.org/10.1007/s12035-017-0833-7

    Article  CAS  PubMed  Google Scholar 

  63. Coke CJ, Scarlett KA, Chetram MA, Jones KJ, Sandifer BJ, Davis AS, Marcus AI, Hinton CV (2016) Simultaneous activation of induced heterodimerization between CXCR4 chemokine receptor and cannabinoid receptor 2 (CB2) reveals a mechanism for regulation of tumor progression. J Biol Chem 291(19):9991–10005. https://doi.org/10.1074/jbc.M115.712661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Perrey DA, Gilmour BP, Thomas BF, Zhang Y (2014) Toward the development of bivalent ligand probes of cannabinoid CB1 and orexin OX1 receptor heterodimers. ACS Med Chem Lett 5(6):634–638. https://doi.org/10.1021/ml4004759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hojo M, Sudo Y, Ando Y, Minami K, Takada M, Matsubara T, Kanaide M, Taniyama K et al (2008) Mu-opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis. J Pharmacol Sci 108(3):308–319

    Article  CAS  PubMed  Google Scholar 

  66. Khan SS, Lee FJ (2014) Delineation of domains within the cannabinoid CB1 and dopamine D2 receptors that mediate the formation of the heterodimer complex. J Mol Neurosci 53(1):10–21. https://doi.org/10.1007/s12031-013-0181-7

    Article  CAS  PubMed  Google Scholar 

  67. Przybyla JA, Watts VJ (2010) Ligand-induced regulation and localization of cannabinoid CB1 and dopamine D2L receptor heterodimers. J Pharmacol Exp Ther 332(3):710–719. https://doi.org/10.1124/jpet.109.162701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bouskila J, Javadi P, Casanova C, Ptito M, Bouchard JF (2013) Muller cells express the cannabinoid CB2 receptor in the vervet monkey retina. J Comp Neurol 521(11):2399–2415. https://doi.org/10.1002/cne.23333

    Article  CAS  PubMed  Google Scholar 

  69. Freitas HR, Reis RA (2017) Glutathione induces GABA release through P2X7R activation on Muller glia. Neurogenesis (Austin, Tex) 4(1):e1283188. https://doi.org/10.1080/23262133.2017.1283188

    Article  CAS  Google Scholar 

  70. Di Virgilio F, Ceruti S, Bramanti P, Abbracchio MP (2009) Purinergic signalling in inflammation of the central nervous system. Trends Neurosci 32(2):79–87. https://doi.org/10.1016/j.tins.2008.11.003

    Article  CAS  PubMed  Google Scholar 

  71. Burnstock G (2014) Purinergic signalling: from discovery to current developments. Exp Physiol 99(1):16–34. https://doi.org/10.1113/expphysiol.2013.071951

    Article  CAS  PubMed  Google Scholar 

  72. Resta V, Novelli E, Di Virgilio F, Galli-Resta L (2005) Neuronal death induced by endogenous extracellular ATP in retinal cholinergic neuron density control. Development 132(12):2873–2882. https://doi.org/10.1242/dev.01855

    Article  CAS  PubMed  Google Scholar 

  73. Puthussery T, Fletcher E (2009) Extracellular ATP induces retinal photoreceptor apoptosis through activation of purinoceptors in rodents. J Comp Neurol 513(4):430–440. https://doi.org/10.1002/cne.21964

    Article  CAS  PubMed  Google Scholar 

  74. Xue B, Xie Y, Xue Y, Hu N, Zhang G, Guan H, Ji M (2016) Involvement of P2X7 receptors in retinal ganglion cell apoptosis induced by activated Muller cells. Exp Eye Res 153:42–50. https://doi.org/10.1016/j.exer.2016.10.005

    Article  CAS  PubMed  Google Scholar 

  75. Sugiyama T, Kawamura H, Yamanishi S, Kobayashi M, Katsumura K, Puro DG (2005) Regulation of P2X7-induced pore formation and cell death in pericyte-containing retinal microvessels. Am J Phys Cell Phys 288(3):C568–C576. https://doi.org/10.1152/ajpcell.00380.2004

    Article  CAS  Google Scholar 

  76. Gehring MP, Pereira TC, Zanin RF, Borges MC, Braga Filho A, Battastini AM, Bogo MR, Lenz G et al (2012) P2X7 receptor activation leads to increased cell death in a radiosensitive human glioma cell line. Purinergic Signal 8(4):729–739. https://doi.org/10.1007/s11302-012-9319-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Di Virgilio F, Schmalzing G, Markwardt F (2018) The elusive P2X7 macropore. Trends Cell Biol 28(5):392–404. https://doi.org/10.1016/j.tcb.2018.01.005

    Article  CAS  PubMed  Google Scholar 

  78. Faria RX, Reis RA, Ferreira LG, Cezar-de-Mello PF, Moraes MO (2016) P2X7R large pore is partially blocked by pore forming proteins antagonists in astrocytes. J Bioenerg Biomembr 48(3):309–324. https://doi.org/10.1007/s10863-016-9649-9

    Article  CAS  PubMed  Google Scholar 

  79. Rodriguez-Munoz M, Sanchez-Blazquez P, Merlos M, Garzon-Nino J (2016) Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction. Oncotarget 7(34):55840–55862. https://doi.org/10.18632/oncotarget.10095

    Article  PubMed  PubMed Central  Google Scholar 

  80. Brown TM, Brotchie JM, Fitzjohn SM (2003) Cannabinoids decrease corticostriatal synaptic transmission via an effect on glutamate uptake. J Neurosci 23(35):11073–11077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li Q, Yan H, Wilson WA, Swartzwelder HS (2010) Modulation of NMDA and AMPA-mediated synaptic transmission by CB1 receptors in frontal cortical pyramidal cells. Brain Res 1342:127–137. https://doi.org/10.1016/j.brainres.2010.04.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sanchez-Blazquez P, Rodriguez-Munoz M, Garzon J (2014) The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Front Pharmacol 4:169. https://doi.org/10.3389/fphar.2013.00169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are indebted to the technical support of Luciano C. Ferreira, Maria Leite Eduardo, Sarah Rodrigues, and Aurizete Bizerra.

Funding

Grants from Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Instituto Nacional de Ciência e Tecnologia de Neurociência Translacional (INCT-INNT), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) supported this work.

Author information

Authors and Affiliations

  1. Laboratory of Neurochemistry, Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Hércules Rezende Freitas, Alinny Rosendo Isaac, Fernando Garcia de Mello & Ricardo Augusto de Melo Reis

  2. School of Health Sciences, Centro Universitário IBMR, Rio de Janeiro, RJ, Brazil

    Hércules Rezende Freitas

  3. Laboratory of Neurochemistry, Institute of Biology, Universidade Federal Fluminense, Niterói, RJ, Brazil

    Thayane Martins Silva & Ana Lucia Marques Ventura

  4. Biomedical Institute, Universidade Federal do Estado do Rio de Janeiro, Rua Frei Caneca, 94, Rio de Janeiro, RJ, 20211-040, Brazil

    Geyzzara Oliveira Ferreira Diniz, Yara dos Santos Dabdab & Guilherme Rapozeiro França

  5. Laboratory of Retina Neurobiology, Institute of Biology, Universidade Federal Fluminense, Niterói, RJ, Brazil

    Eduardo Cosendey Bockmann & Karin da Costa Calaza

  6. Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Marília Zaluar Passos Guimarães

Authors
  1. Hércules Rezende Freitas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alinny Rosendo Isaac
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thayane Martins Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Geyzzara Oliveira Ferreira Diniz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yara dos Santos Dabdab
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eduardo Cosendey Bockmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marília Zaluar Passos Guimarães
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Karin da Costa Calaza
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fernando Garcia de Mello
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ana Lucia Marques Ventura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ricardo Augusto de Melo Reis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Guilherme Rapozeiro França
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HRF and ALMV: conception and design, provision of the study material, collection and assembly of the data, data analysis and interpretation, manuscript writing, and final approval of the manuscript.

AIR, TMS, ECB, GOD, YSD, and MPG: collection and assembly of the data, and data analysis and interpretation.

FGM, RMR, GRF, and KCC: conception and design, provision of the study material, assembly of the data, data analysis and interpretation, manuscript writing, final approval of manuscript, financial support, and administrative support.

Corresponding author

Correspondence to Guilherme Rapozeiro França.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Freitas, H.R., Isaac, A.R., Silva, T.M. et al. Cannabinoids Induce Cell Death and Promote P2X7 Receptor Signaling in Retinal Glial Progenitors in Culture. Mol Neurobiol 56, 6472–6486 (2019). https://doi.org/10.1007/s12035-019-1537-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-1537-y

Keywords

Search

Navigation