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Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra

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Abstract

Whether cannabinoids act as neuroprotectants or, on the contrary, even worsen neuronal damage after cerebral ischemia is currently under discussion. We have previously shown that treatment with the cannabinoid (CB1) receptor antagonist SR141716A reduces infarct volume by ∼40% after experimental stroke. Since it is suggested that SR141716A may exert neuroprotection besides its cannabinoid receptor-blocking effect, we addressed the question whether SR141716A may act via modulation of postischemic ligand binding to excitatory NMDA and/or α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. For this purpose, rats (n = 12) were treated with either intravenous saline (control) or CB1 receptor antagonist SR141716A (1 mg/kg) 30 min after permanent middle cerebral artery occlusion. Five hours after ischemia, quantitative receptor autoradiography was performed using [3H]CP 55,940, [3H]MK-801, and [3H]AMPA for labeling of CB1, NMDA, and AMPA receptors, respectively. Ligand binding was analyzed within the infarct core, cortical penumbra, and corresponding areas of the contralateral hemisphere and compared to that of sham-operated rats (n = 5). Both in ischemic controls and SR141716A-treated rats [3H]CP 55,940 ligand binding was not specifically regulated in the cortical penumbra or contralateral cortex. Importantly, reduced infarct volumes in SR141716A-treated rats were associated with maintained [3H]MK-801 binding to excitotoxic NMDA receptors in the penumbra, compared to a decrease in the control group. In summary, our data suggest that SR141716A may possess additional intrinsic neuroprotective properties independent of receptor-coupled pathways or due to action as a partial agonist.

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References

  1. Araki T, Kanai Y, Murakami F, Kato H, Kogure K (1993) Postischemic changes in the binding of excitatory and inhibitory neurotransmitters in the gerbil brain. Pharmacol Biochem Behav 45:945–949

    Article  PubMed  CAS  Google Scholar 

  2. Auclair N, Otani S, Soubrie P, Crepel F (2000) Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pryramidal neurons. J Neurophysiol 83:3287–3293

    PubMed  CAS  Google Scholar 

  3. Berdyshev EV, Schmid PC, Krebsbach RJ, Hillard CJ, Huang C, Chen N, Dong Z, Schmid HHO (2001) Cannabinoid-receptor-independent cell signalling by N-acylethanolamines. Biochem J 360:67–75

    Article  PubMed  CAS  Google Scholar 

  4. Berger C, Schmid PC, Schäbitz WR, Wolf M, Schwab S, Schmid HHO (2004) Massive accumulation of N-acylethanolamines after stroke. Cell signalling in acute cerebral ischemia? J Neurochem 88:1159–1167

    Article  PubMed  CAS  Google Scholar 

  5. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, Shohami E (2004) Dynamic changes in N-methyl-d-aspartate receptors after closed head injury in mice: implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci USA 101:5117–5122

    Article  PubMed  CAS  Google Scholar 

  6. Bouaboula M, Perrachon S, Milligan L, Canat X, Rinaldi-Carmona M, Portier M, Barth F, Calandra B, Pecceu F, Lupker J, Maffrand JP, Le Fur G, Casellas P (1997) A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. J Biol Chem 272:22330–22339

    Article  PubMed  CAS  Google Scholar 

  7. Chan GC, Hinds TR, Impey S, Storm DR (1998) Hippocampal neurotoxicity of Δ9-tetrahydrocannabinol. J Neurosci 18:5322–5332

    PubMed  CAS  Google Scholar 

  8. Di Marzo V, Melck D, Bisogno T, De Petrocellis L (1998) Endocannabinoids: endogenous receptor ligands with neuromodulatory action. Trends Neurosci 21:521–528

    Article  PubMed  CAS  Google Scholar 

  9. Di Marzo V, Breivogel CS, Tao Q, Bridgen DT, Razdan RK, Zimmer AM, Zimmer A, Martin BR (2000) Levels, metabolism and pharmacological activity of anandamide in CB1 cannabionoid receptor knockout mice: evidence for non-CB1, non-CB2 receptor-mediated actions of anandamide in mouse brain. J Neurochem 75:2434–2444

    Article  PubMed  CAS  Google Scholar 

  10. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated review. Trends Neurosci 22:391–397

    Article  PubMed  CAS  Google Scholar 

  11. Downer E, Boland B, Fogarty M, Campbell V (2001) Δ9-tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurones via activation of the CB1 receptor. Neuroreport 12:3973–3978

    Article  PubMed  CAS  Google Scholar 

  12. Gérard CM, Mollereau C, Vassart G, Parmentier M (1991) Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochemistry 279:129–134

    Google Scholar 

  13. Greiner C, Schmidinger A, Hülsmann S, Moskopp D, Wolfer J, Köhling R, Speckmann E-J, Wassmann H (2000) Acute protective effect of nimodipine and dimethyl sulfoxide against hypoxic and ischemic brain damage in brain slices. Brain Res 887:316–322

    Article  PubMed  CAS  Google Scholar 

  14. Hansen HH, Schmid PC, Bittigau P, Lastres-Becker I, Berrendero F, Manzanares J, Ikonomidou C, Schmid HH, Fernandez-Ruiz JJ, Hansen HS (2001) Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J Neurochem 78:1415–1427

    Article  PubMed  CAS  Google Scholar 

  15. Hansen HH, Azcoitia I, Pons S, Romero J, Garcia-Segura LM, Ramos JA, Hansen HS, Fernández-Ruiz J (2002) Blockade of cannabinoid CB(1) receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity. J Neurochem 82:154–158

    Article  PubMed  CAS  Google Scholar 

  16. Herkenham M, Lynn AB, Little MD, Johnson R, Melvin LS, De Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87:1932–1936

    Article  PubMed  CAS  Google Scholar 

  17. Herkenham M, Lynn AB, Johnson MR, Melvin LS, De Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583

    PubMed  CAS  Google Scholar 

  18. Jin KL, Moa XO, Goldsmith PC, Greenberg DA (2000) CB1 cannabinoid receptor induction in experimental stroke. Ann Neurol 48:257–261

    Article  PubMed  CAS  Google Scholar 

  19. Jolkkonen J, Gallagher NP, Zilles K, Sivenius J (2003) Behavioral deficits and recovery following transient focal cerebral ischemia in rats: glutamatergic and GABAergic receptor densities. Behav Brain Res 138:187–200

    Article  PubMed  CAS  Google Scholar 

  20. Landfield PW, Cadwallader LB, Vinsant S (1988) Quantitative changes in hippocampal structures following long-term exposure to delta 9-tetrahydrocannabinol: possible mediation by glucocorticoid system. Brain Res 443:47–62

    Article  PubMed  CAS  Google Scholar 

  21. Lei S, Pelkey A, Topolnik L, Congar P, Lacaille JC, McBain CJ (2003) Depolarization-induced long-term depression at hippocampal mossy fiber-CA3 pyramidal neuron synapses. J Neurosci 23:9786–9795

    PubMed  CAS  Google Scholar 

  22. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91

    PubMed  CAS  Google Scholar 

  23. Louw DF, Yang FW, Sutherland GR (2000) The effect of δ-9-tetrahydrocannabinol on forebrain ischemia in rat. Brain Res 857:183–187

    Article  PubMed  CAS  Google Scholar 

  24. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodrigues ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88

    Article  PubMed  CAS  Google Scholar 

  25. Martinez-Orgado J, Fernandez-Frutos B, Gonzalez R, Romero E, Uriguen L, Romero J, Viveros MP (2003) Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia. Brain Res Mol Brain Res 1141:32–139

    Google Scholar 

  26. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    Article  PubMed  CAS  Google Scholar 

  27. Muthian S, Rademacher DJ, Roelke CT, Gross GJ, Hillard CJ (2004) Anandamide content is increased and CB1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia. Neuroscience 129:743–750

    Article  PubMed  CAS  Google Scholar 

  28. Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, Greenberg DA (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 19:2987–2995

    PubMed  CAS  Google Scholar 

  29. Obrenovitch TP, Urenjak J (1997) Altered glutamatergic transmission in neurological disorders: from high extracellular glutamate to excessive synaptic efficacy. Prog Neurobiol 51:39–87

    Article  PubMed  CAS  Google Scholar 

  30. Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413:527–531

    Article  PubMed  CAS  Google Scholar 

  31. Panikashvili D, Mechoulam R, Beni SM, Alexandrovich A, Shohami E (2005) CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition. J Cereb Blood Flow Metab 25:477–484

    Article  PubMed  CAS  Google Scholar 

  32. Parmentier-Batteur S, Jin K, Mao XO, Xie L, Greenberg DA (2002) Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci 22:9771–9775

    PubMed  CAS  Google Scholar 

  33. Qü M, Mittmann T, Luhmann HJ, Schleicher A, Zilles K (1998) Long-term changes of ionotropic glutamate and GABA receptors after unilateral permanent focal cerebral ischemia in the mouse brain. Neuroscience 85:29–43

    Article  PubMed  Google Scholar 

  34. Que M, Schiene K, Witte OW, Zilles K (1999) Widespread up-regulation of NMDA receptors after focal photothrombotic lesion in rat brain. Neurosci Lett 273:77–80

    Article  PubMed  CAS  Google Scholar 

  35. Rinaldi-Carmora M, Barth F, Heaulme M, Alonso R, Shire D, Congy C, Soubrie P, Breliere JC, Le Fur G (1995) Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist. Life Sci 56:1941–1947

    Article  Google Scholar 

  36. Sakurai SY, Cha J-HJ, Penney JB, Young AB (1991) Regional distribution and properties of [3H]MK-801 binding sites determined by quantitative autoradiography in rat brain. Neuroscience 40:533–543

    Article  PubMed  CAS  Google Scholar 

  37. Scallet AC (1991) Neurotoxicology of cannabis and THS: a review of chronic exposure studies in animals. Pharmacol Biochem Behav 40:671–676

    Article  PubMed  CAS  Google Scholar 

  38. Schomacher M, Müller HD, Sommer C (2006) Short-term ischemia usually used for ischemic preconditioning down-regulates central cannabinoid receptors in the gerbil hippocampus. Acta Neuropathol (Berl) 111:8–14

    Article  Google Scholar 

  39. Shimizu S, Simon RP, Graham SH (1997) Dimethylsulfloxide (DMSO) treatment reduces infarction volume after permanent focal cerebral ischemia in rats. Neurosci Lett 239:125–127

    Article  PubMed  CAS  Google Scholar 

  40. Sommer C, Fahrner A, Kiessling M (2002) [3H]Muscimol binding to GABAA receptors is upregulated in CA1 neurons of the gerbil hippocampus in the ischemia tolerant state. Stroke 33:1093–1100

    Article  PubMed  CAS  Google Scholar 

  41. Sommer C, Kollmar R, Schwab S, Kiessling M, Schäbitz WR (2003) Exogenous brain-derived neurotrophic factor prevents postischemic downregulation of [3H]muscimol binding to GABAA receptors in the cortical penumbra. Mol Brain Res 111:24–30

    Article  PubMed  CAS  Google Scholar 

  42. Standley S, Tocco G, Tourigny M-F, Massicotte F, Thompson RF, Baudry M (1995) Developmental changes in a-amino-3-hydroxy-5-methyl-4-isoxazole proprionate receptor properties and expression in the rat hippocampal formation. Neuroscience 67:881–892

    Article  PubMed  CAS  Google Scholar 

  43. Suarez I, Bodega G, Fernandez-Ruiz J, Ramos JA, Rubio M, Fernandez B (2004) Down-regulation of the AMPA glutamate receptor subunits GluR1 and GluR2/3 in the rat cerebellum following pre- and perinatal delta9-tetrahydrocannabinol exposure. Cerebellum 3:66–74

    Article  PubMed  CAS  Google Scholar 

  44. Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR (1990) A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:290–293

    PubMed  CAS  Google Scholar 

  45. van der Stelt M, Veldhuis WB, Van Haaften GW, Fezza F, Bisogno T, Bar PR, Veldink GA, Vliegenthart JF, Di Marzo V, Nicolay K (2001) Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neurosci 21:8765–8771

    PubMed  Google Scholar 

  46. Vogel J, Mobius C, Kuschinsky W (1999) Early delineation of ischemic tissue in rat brain cryosections by high-contrast staining. Stroke 30:1134–1141

    PubMed  CAS  Google Scholar 

  47. Zilles K, Wu J, Crusio WEH, Schwegler H (2000) Water maze and radial maze learning and the density of binding sites of glutamate, GABA, and serotonin receptors in the hippocampus of inbred mouse strains. Hippocampus 10:213–225

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was in part supported by the Bundesministerium für Bildung und Forschung. SR141716A was a generous gift from Sanofi Synthelabo, Berlin, Germany. The authors greatly acknowledge the excellent technical assistance of Stephan Hennes and Jessica Saba. Astrid Wöber kindly gave editorial assistance.

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Authors and Affiliations

  1. Department of Neuropathology, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany

    Clemens Sommer & Harald D. Müller

  2. Department of Neurology, University of Heidelberg, Heidelberg, Germany

    Markus Schomacher, Christian Berger, Stefan Schwab & Wolf-Rüdiger Schäbitz

  3. Department of Neurology, University of Münster, Münster, Germany

    Katharina Kuhnert & Wolf-Rüdiger Schäbitz

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  1. Clemens Sommer
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  2. Markus Schomacher
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  7. Wolf-Rüdiger Schäbitz
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Correspondence to Clemens Sommer.

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Sommer, C., Schomacher, M., Berger, C. et al. Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra. Acta Neuropathol 112, 277–286 (2006). https://doi.org/10.1007/s00401-006-0110-8

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  • DOI: https://doi.org/10.1007/s00401-006-0110-8

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