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Endocannabinoids and Reactive Nitrogen and Oxygen Species in Neuropathologies

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Abstract

Neuropathologies that affect our population include ischemic stroke and neurodegenerative diseases of immune origin, including multiple sclerosis. The endocannabinoid system in the brain, including agonists anandamide (arachidonyl ethanolamide) and 2-arachidonoylglycerol, and the CB1 and CB2 cannabinoid receptors, has been implicated in the pathophysiology of these disease states, and can be a target for therapeutic interventions. This review concentrates on cellular signal transduction pathways believed to be involved in the cellular damage.

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References

  • Abood ME, Rizvi G, Sallapudi N, McAllister SD (2001) Activation of the CB1 cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci Lett 309:197–201

    PubMed  CAS  Google Scholar 

  • Ahern GP, Klyachko VA, Jackson MB (2002) cGMP and S-nitrosylation: two routes for modulation of neuronal excitability by NO. Trends Neurosci 25:510–517

    PubMed  CAS  Google Scholar 

  • Andoh T, Chiueh CC, Chock PB (2003) Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. J Biol Chem 278:885–890

    PubMed  CAS  Google Scholar 

  • Arevalo-Martin A, Vela JM, Molina-Holgado E, Borrell J, Guaza C (2003) Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J Neurosci 23:2511–2516

    PubMed  CAS  Google Scholar 

  • Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J Neurosci 21:7724–7732

    PubMed  CAS  Google Scholar 

  • Baker D, Pryce G (2003) The therapeutic potential of cannabis in multiple sclerosis. Expert Opin Investig Drugs 12:561–567

    PubMed  CAS  Google Scholar 

  • Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404:84–87

    PubMed  CAS  Google Scholar 

  • Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, Khanolkar A, Layward L, Fezza F, Bisogno T, Di MV (2001) Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 15:300–302

    PubMed  CAS  Google Scholar 

  • Baker D, Pryce G, Giovannoni G, Thompson AJ (2003) The therapeutic potential of cannabis. Lancet Neurol 2:291–298

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Bolan EA, Gracy KN, Chan J, Trifiletti RR, Pickel VM (2000) Ultrastructural localization of nitrotyrosine within the caudate-putamen nucleus and the globus pallidus of normal rat brain. J Neurosci 20:4798–4808

    PubMed  CAS  Google Scholar 

  • Brenman JE, Bredt DS (1997) Synaptic signaling by nitric oxide. Curr Opin Neurobiol 7:374–378

    PubMed  CAS  Google Scholar 

  • Brooks JW, Pryce G, Bisogno T, Jaggar SI, Hankey DJ, Brown P, Bridges D, Ledent C, Bifulco M, Rice AS, Di MV, Baker D (2002) Arvanil-induced inhibition of spasticity and persistent pain: evidence for therapeutic sites of action different from the vanilloid VR1 receptor and cannabinoid CB(1)/CB(2) receptors. Eur J Pharmacol 439:83–92

    PubMed  CAS  Google Scholar 

  • Bryan NS, Rassaf T, Maloney RE, Rodriguez CM, Saijo F, Rodriguez JR, Feelisch M (2004) Cellular targets and mechanisms of nitrosylation: an insight into their nature and kinetics in vivo. Proc Natl Acad Sci U S A 101:4308–4313

    PubMed  CAS  Google Scholar 

  • Campbell VA (2001) Tetrahydrocannabinol-induced apoptosis of cultured cortical neurones is associated with cytochrome c release and caspase-3 activation. Neuropharmacology 40:702–709

    PubMed  CAS  Google Scholar 

  • Cappelletti G, Maggioni MG, Tedeschi G, Maci R (2003) Protein tyrosine nitration is triggered by nerve growth factor during neuronal differentiation of PC12 cells. Exp Cell Res 288:9–20

    PubMed  CAS  Google Scholar 

  • Cappelletti G, Tedeschi G, Maggioni MG, Negri A, Nonnis S, Maci R (2004) The nitration of tau protein in neurone-like PC12 cells. FEBS Lett 562:35–39

    PubMed  CAS  Google Scholar 

  • Carney S, Lloyd ML, Howlett AC, Norford DC (2005) Cannabinoid-induced NO production in N18TG2 neuronal cells. Symposium on the Cannabinoids 2005 15:97

    Google Scholar 

  • Carracedo A, Geelen MJ, Diez M, Hanada K, Guzman M, Velasco G (2004) Ceramide sensitizes astrocytes to oxidative stress: protective role of cannabinoids. Biochem J 380:435–440

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Chen HH, Wang DL (2004) Nitric oxide inhibits matrix metalloproteinase-2 expression via the induction of activating transcription factor 3 in endothelial cells. Mol Pharmacol 65:1130–1140

    PubMed  CAS  Google Scholar 

  • Chen J, Errico SL, Freed WJ (2005) Reactive oxygen species and p38 phosphorylation regulate the protective effect of Δ9-tetrahydrocannabinol in the apoptotic response to NMDA. Neurosci Lett 389:99–103

    PubMed  CAS  Google Scholar 

  • Crack PJ, Taylor JM (2005) Reactive oxygen species and the modulation of stroke. Free Radic Biol Med 38:1433–1444

    PubMed  CAS  Google Scholar 

  • Croxford JL (2003) Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 17:179–202

    PubMed  CAS  Google Scholar 

  • Croxford JL, Miller SD (2003) Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212. J Clin Invest 111:1231–1240

    PubMed  CAS  Google Scholar 

  • Croxford JL, Miller SD (2004) Towards cannabis and cannabinoid treatment of multiple sclerosis. Drugs Today (Barc ) 40:663–676

    CAS  Google Scholar 

  • Cunningham LA, Wetzel M, Rosenberg GA (2005) Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50:329–339

    PubMed  Google Scholar 

  • Dawson VL, Dawson TM (1996) Nitric oxide actions in neurochemistry. Neurochem Int 29:97–110

    PubMed  CAS  Google Scholar 

  • de Lago E, Fernandez-Ruiz J, Ortega-Gutierrez S, Cabranes A, Pryce G, Baker D, Lopez-Rodriguez M, Ramos JA (2006) UCM707, an inhibitor of the anandamide uptake, behaves as a symptom control agent in models of Huntington's disease and multiple sclerosis, but fails to delay/arrest the progression of different motor-related disorders. Eur Neuropsychopharmacol 16:7–18

    PubMed  Google Scholar 

  • De Petrocellis L, Cascio MG, Di Marzo, V (2004) The endocannabinoid system: a general view and latest additions. Br J Pharmacol 141:765-774

    PubMed  Google Scholar 

  • Di Marzo V (1999) Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators. Life Sci 65:645–655

    PubMed  Google Scholar 

  • Di Stasi AM, Mallozzi C, Macchia G, Petrucci TC, Minetti M (1999) Peroxynitrite induces tryosine nitration and modulates tyrosine phosphorylation of synaptic proteins. J Neurochem 73:727–735

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Downer EJ, Fogarty MP, Campbell VA (2003) Tetrahydrocannabinol-induced neurotoxicity depends on CB1 receptor-mediated c-Jun N-terminal kinase activation in cultured cortical neurons. Br J Pharmacol 140:547–557

    PubMed  CAS  Google Scholar 

  • Duncan AJ, Heales SJ (2005) Nitric oxide and neurological disorders. Mol Aspects Med 26:67–96

    PubMed  CAS  Google Scholar 

  • Eagleton MJ, Peterson DA, Sullivan VV, Roelofs KJ, Ford JA, Stanley JC, Upchurch, Jr. GR (2002) Nitric oxide inhibition increases aortic wall matrix metalloproteinase-9 expression. J Surg Res 104:15–21

    PubMed  CAS  Google Scholar 

  • El Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI (2003) Neuroprotective effect of (−)Δ9-tetrahydrocannabinol and cannabidiol in N-methyl-d-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol 163:1997–2008

    PubMed  Google Scholar 

  • Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O (2006) The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49:67–79

    PubMed  CAS  Google Scholar 

  • Esposito G, Izzo AA, Di Rosa M, Iuvone T (2001) Selective cannabinoid CB1 receptor-mediated inhibition of inducible nitric oxide synthase protein expression in C6 rat glioma cells. J Neurochem 78:835–841

    PubMed  CAS  Google Scholar 

  • Fimiani C, Liberty T, Aquirre AJ, Amin I, Ali N, Stefano GB (1999a) Opiate, cannabinoid, and eicosanoid signaling converges on common intracellular pathways nitric oxide coupling. Prostaglandins Other Lipid Mediat 57:23–34

    PubMed  CAS  Google Scholar 

  • Fimiani C, Mattocks D, Cavani F, Salzet M, Deutsch DG, Pryor S, Bilfinger TV, Stefano GB (1999b) Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release. Cell Signal 11:189–193

    PubMed  CAS  Google Scholar 

  • Foster MW, McMahon TJ, Stamler JS (2003) S-nitrosylation in health and disease. Trends Mol Med 9:160–168

    PubMed  CAS  Google Scholar 

  • Fowler CJ (2004) Metabolism of the endocannabionids anandamide and 2-arachidonoyl glycerol, a review, with emphasis on the pharmacology of fatty acid amide hydrolase, a possible target for the treatment of neurodegenerative diseases and pain. Curr Med Chem Cent Nerv Sys Agents 4:161–174

    CAS  Google Scholar 

  • Fowler CJ, Holt S, Nilsson O, Jonsson KO, Tiger G, Jacobsson SO (2005) The endocannabinoid signaling system: pharmacological and therapeutic aspects. Pharmacol Biochem Behav 81:248–262

    PubMed  CAS  Google Scholar 

  • Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA, Stella N (2003) Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci 23:7767–7775

    PubMed  CAS  Google Scholar 

  • Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066

    PubMed  CAS  Google Scholar 

  • Fujimura M, Gasche Y, Morita-Fujimura Y, Massengale J, Kawase M, Chan PH (1999) Early appearance of activated matrix metalloproteinase-9 and blood–brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res 842:92–100

    PubMed  CAS  Google Scholar 

  • Galve-Roperh I, Sanchez C, Cortes ML, del Pulgar TG, Izquierdo M, Guzman M (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6:313–319

    PubMed  CAS  Google Scholar 

  • Gasche Y, Fujimura M, Morita-Fujimura Y, Copin JC, Kawase M, Massengale J, Chan PH (1999) Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood–brain barrier dysfunction. J Cereb Blood Flow Metab 19:1020–1028

    PubMed  CAS  Google Scholar 

  • Goncharov I, Weiner L, Vogel Z (2005) Δ9-Tetrahydrocannabinol increases C6 glioma cell death produced by oxidative stress. Neuroscience 134:567–574

    PubMed  CAS  Google Scholar 

  • Gonzalez-Zulueta, M, Dawson, VL, Dawson, TM (2000) Neurotoxic actions and mechanisms of nitric oxide. In: Ignarro, LJ (ed) Nitric oxide biology and pathobiology. Academic Press, San Diego, CA, pp 695–710

    Google Scholar 

  • Gow AJ, Chen Q, Hess DT, Day BJ, Ischiropoulos H, Stamler JS (2002) Basal and stimulated protein S-nitrosylation in multiple cell types and tissues. J Biol Chem 277:9637–9640

    PubMed  CAS  Google Scholar 

  • Green KA, Lund LR (2005) ECM degrading proteases and tissue remodelling in the mammary gland. Bioessays 27:894–903

    PubMed  CAS  Google Scholar 

  • Greenacre SA, Ischiropoulos H (2001) Tyrosine nitration: localisation, quantification, consequences for protein function and signal transduction. Free Radic Res 34:541–581

    PubMed  CAS  Google Scholar 

  • Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY, Lipton SA (2005) A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 25:6401–6408

    PubMed  CAS  Google Scholar 

  • Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, Smith JW, Liddington RC, Lipton SA (2002) S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297:1186–1190

    PubMed  CAS  Google Scholar 

  • Gurjar MV, DeLeon J, Sharma RV, Bhalla RC (2001) Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells. J Appl Physiol 91:1380–1386

    PubMed  CAS  Google Scholar 

  • Guzman M, Sanchez C, Galve-Roperh I (2002) Cannabinoids and cell fate. Pharmacol Ther 95:175–184

    PubMed  CAS  Google Scholar 

  • Hampson AJ, Grimaldi M, Axelrod J and Wink D (1998) Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 95:8268–8273

    PubMed  CAS  Google Scholar 

  • Hanafy KA, Krumenacker JS, Murad F (2001) NO, nitrotyrosine, and cyclic GMP in signal transduction. Med Sci Monit 7:801–819

    PubMed  CAS  Google Scholar 

  • Hansen HH, Ikonomidou C, Bittigau P, Hansen SH, Hansen HS (2001a) Accumulation of the anandamide precursor and other N-acylethanolamine phospholipids in infant rat models of in vivo necrotic and apoptotic neuronal death. J Neurochem 76:39–46

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Heck DE (2001) *NO, RSNO, ONOO−, NO+, *NOO, NOx—dynamic regulation of oxidant scavenging, nitric oxide stores, and cyclic GMP-independent cell signaling. Antioxid Redox Signal 3:249–260

    PubMed  CAS  Google Scholar 

  • Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ (1999) Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab 19:624–633

    PubMed  CAS  Google Scholar 

  • Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T, Prinz M, Priller J, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146–152

    PubMed  CAS  Google Scholar 

  • Holscher C (1997) Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity. Trends Neurosci 20:298–303

    PubMed  CAS  Google Scholar 

  • Horiguchi T, Uryu K, Giasson BI, Ischiropoulos H, LightFoot R, Bellmann C, Richter-Landsberg C, Lee VM, Trojanowski JQ (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163:1021–1031

    PubMed  CAS  Google Scholar 

  • Hou Y, Ye RD, Browning DD (2004) Activation of the small GTPase Rac1 by cGMP-dependent protein kinase. Cell Signal 16:1061–1069

    PubMed  CAS  Google Scholar 

  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202

    PubMed  CAS  Google Scholar 

  • Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ (2004) Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47(Suppl 1):345–358

    PubMed  CAS  Google Scholar 

  • Huang EP (1997) Synaptic plasticity: a role for nitric oxide in LTP. Curr Biol 7:R141–R143

    PubMed  CAS  Google Scholar 

  • Ischiropoulos H (1998) Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys 356:1–11

    PubMed  CAS  Google Scholar 

  • Ischiropoulos H, Gow A (2005) Pathophysiological functions of nitric oxide-mediated protein modifications. Toxicology 208:299–303

    PubMed  CAS  Google Scholar 

  • Jackson SJ, Diemel LT, Pryce G, Baker D (2005) Cannabinoids and neuroprotection in CNS inflammatory disease. J Neurol Sci 233:21–25

    PubMed  CAS  Google Scholar 

  • Jacobsson SO, Wallin T, Fowler CJ (2001) Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids. Relative involvement of cannabinoid and vanilloid receptors. J Pharmacol Exp Ther 299:951–959

    PubMed  CAS  Google Scholar 

  • Jaffrey SR, Erdjument-Bromage H, Ferris CD, Tempst P, Snyder SH (2001) Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol 3:193–197

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Jones JD, Norford DC, Howlett AC (2006) CB1 cannabinoid receptors mediate translocation of NO-sensitive guanylyl cyclase in neuronal cells. Symposium on the Cannabinoids 2006

  • Jurasz P, Sawicki G, Duszyk M, Sawicka J, Miranda C, Mayers I, Radomski MW (2001) Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide. Cancer Res 61:376–382

    PubMed  CAS  Google Scholar 

  • Kamisaki Y, Wada K, Bian K, Balabanli B, Davis K, Martin E, Behbod F, Lee YC, Murad F (1998) An activity in rat tissues that modifies nitrotyrosine-containing proteins. Proc Natl Acad Sci U S A 95:11584–11589

    PubMed  CAS  Google Scholar 

  • Khaspekov LG, Brenz Verca MS, Frumkina LE, Hermann H, Marsicano G, Lutz B (2004) Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Eur J Neurosci 19:1691–1698

    PubMed  Google Scholar 

  • Kim SH, Won SJ, Mao XO, Jin K, Greenberg DA (2005) Involvement of protein kinase A in cannabinoid receptor-mediated protection from oxidative neuronal injury. J Pharmacol Exp Ther 313:88–94

    PubMed  CAS  Google Scholar 

  • Kim SH, Won SJ, Mao XO, Jin K, Greenberg DA (2006) Molecular mechanisms of cannabinoid protection from neuronal excitotoxicity. Mol Pharmacol 69:691–696

    PubMed  CAS  Google Scholar 

  • Kuhn DM, Sakowski SA, Sadidi M, Geddes TJ (2004) Nitrotyrosine as a marker for peroxynitrite-induced neurotoxicity: the beginning or the end of the end of dopamine neurons? J Neurochem 89:529–536

    PubMed  CAS  Google Scholar 

  • Kurabayashi M, Takeyoshi I, Yoshinari D, Matsumoto K, Maruyama I, Morishita Y (2005) 2-Arachidonoylglycerol increases in ischemia–reperfusion injury of the rat liver. J Invest Surg 18:25–31

    PubMed  Google Scholar 

  • Li X, De Sarno P, Song L, Beckman JS, Jope RS (1998) Peroxynitrite modulates tyrosine phosphorylation and phosphoinositide signalling in human neuroblastoma SH-SY5Y cells: attenuated effects in human 1321N1 astrocytoma cells. Biochem J 331:599–606

    PubMed  CAS  Google Scholar 

  • Licinio J, Prolo P, McCann SM, Wong ML (1999) Brain iNOS: current understanding and clinical implications. Mol Med Today 5:225–232

    PubMed  CAS  Google Scholar 

  • Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415

    PubMed  CAS  Google Scholar 

  • Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA (2000) Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 52:375–414

    PubMed  CAS  Google Scholar 

  • Lyman WD, Sonett JR, Brosnan CF, Elkin R, Bornstein MB (1989) Δ9-Tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J Neuroimmunol 23:73–81

    PubMed  CAS  Google Scholar 

  • Maccarrone M, Bari M, Lorenzon T, Bisogno T, Di MV, Finazzi-Agro A (2000a) Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J Biol Chem 275:13484–13492

    PubMed  CAS  Google Scholar 

  • Maccarrone M, Finazzi-Agro A (2003) The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death Differ 10:946–955

    PubMed  CAS  Google Scholar 

  • Maccarrone M, Lorenzon T, Bari M, Melino G, Finazzi-Agro A (2000b) Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J Biol Chem 275:31938–31945

    PubMed  CAS  Google Scholar 

  • Manabe S, Gu Z, Lipton SA (2005) Activation of matrix metalloproteinase-9 via neuronal nitric oxide synthase contributes to NMDA-induced retinal ganglion cell death. Invest Ophthalmol Vis Sci 46:4747–4753

    PubMed  Google Scholar 

  • Marsicano G, Moosmann B, Hermann H, Lutz B, Behl C (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem 80:448–456

    PubMed  CAS  Google Scholar 

  • Matrisian LM, Wright J, Newell K, Witty JP (1994) Matrix-degrading metalloproteinases in tumor progression. Princess Takamatsu Symp 24:152–161

    PubMed  CAS  Google Scholar 

  • McCawley LJ, Matrisian LM (2000) Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6:149–156

    PubMed  CAS  Google Scholar 

  • Mechoulam R (2002) Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression. Prostaglandins Leukot Essent Fatty Acids 66:93–99

    PubMed  CAS  Google Scholar 

  • Mechoulam R, Panikashvili D, Shohami E (2002a) Cannabinoids and brain injury: therapeutic implications. Trends Mol Med 8:58–61

    PubMed  CAS  Google Scholar 

  • Mechoulam R, Spatz M, Shohami E (2002b) Endocannabinoids and neuroprotection. Sci STKE 2002:RE5

  • Molina-Holgado F, Molina-Holgado E, Guaza C (1998) The endogenous cannabinoid anandamide potentiates interleukin-6 production by astrocytes infected with Theiler's murine encephalomyelitis virus by a receptor-mediated pathway. FEBS Lett 433:139–142

    PubMed  CAS  Google Scholar 

  • Molina-Holgado F, Molina-Holgado E, Guaza C, Rothwell NJ (2002) Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures. J Neurosci Res 67:829–836

    PubMed  CAS  Google Scholar 

  • Molina-Holgado F, Pinteaux E, Moore JD, Molina-Holgado E, Guaza C, Gibson RM, Rothwell NJ (2003) Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J Neurosci 23:6470–6474

    PubMed  CAS  Google Scholar 

  • Mombouli JV, Schaeffer G, Holzmann S, Kostner GM, Graier WF (1999) Anandamide-induced mobilization of cytosolic Ca2+ in endothelial cells. Br J Pharmacol 126:1593–1600

    PubMed  CAS  Google Scholar 

  • Mukhopadhyay S, McCollum L (2003) Anandamide-mediated NO production in endothelial cells is regulated by Gi proteins: further proof of existence of a novel non-CB1 anandamide receptor in vasculature. Experimental Biology 2003 Abstracts

  • Mukhopadhyay S, Shim JY, Assi AA, Norford D, Howlett AC (2002) CB1 cannabinoid receptor-G protein association: a possible mechanism for differential signaling. Chem Phys Lipids 121:91–109

    PubMed  CAS  Google Scholar 

  • Mun-Bryce S, Rosenberg GA (1998a) Gelatinase B modulates selective opening of the blood–brain barrier during inflammation. Am J Physiol 274:R1203–R1211

    PubMed  CAS  Google Scholar 

  • Mun-Bryce S, Rosenberg GA (1998b) Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 18:1163–1172

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Nagayama T, Sinor A, 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 

  • Nelson EJ, Connolly J, McArthur P (2003) Nitric oxide and S-nitrosylation: excitotoxic and cell signaling mechanism. Biol Cell 95:3–8

    PubMed  CAS  Google Scholar 

  • Novaro V, Colman-Lerner A, Ortega FV, Jawerbaum A, Paz D, Lo NF, Pustovrh C, Gimeno MF, Gonzalez E (2001) Regulation of metalloproteinases by nitric oxide in human trophoblast cells in culture. Reprod Fertil Dev 13:411–420

    PubMed  CAS  Google Scholar 

  • Ohkuma S, Katsura M (2001) Nitric oxide and peroxynitrite as factors to stimulate neurotransmitter release in the CNS. Prog Neurobiol 64:97–108

    PubMed  CAS  Google Scholar 

  • Ortega-Gutierrez S, Molina-Holgado E, Arevalo-Martin A, Correa F, Viso A, Lopez-Rodriguez ML, Di Marzo, V, Guaza C (2005a) Activation of the endocannabinoid system as therapeutic approach in a murine model of multiple sclerosis. FASEB J 19:1338–1340

    PubMed  CAS  Google Scholar 

  • Ortega-Gutierrez S, Molina-Holgado E, Guaza C (2005b) Effect of anandamide uptake inhibition in the production of nitric oxide and in the release of cytokines in astrocyte cultures. Glia 52:163–168

    PubMed  Google Scholar 

  • 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 

  • Perry S, Johnson I, Mukhopadhyay S (2005) Molecular signaling mechanism of endogenous cannabinoid anandamide mediated cell migration and angiogenesis. Proc Am Soc Cell Biol

  • Pertwee RG, Ross RA (2002) Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids 66:101–121

    PubMed  CAS  Google Scholar 

  • Phillips PG, Birnby LM (2004) Nitric oxide modulates caveolin-1 and matrix metalloproteinase-9 expression and distribution at the endothelial cell/tumor cell interface. Am J Physiol Lung Cell Mol Physiol 286:L1055–L1065

    PubMed  CAS  Google Scholar 

  • Prast H, Philippu A (2001) Nitric oxide as modulator of neuronal function. Prog Neurobiol 64:51–68

    PubMed  CAS  Google Scholar 

  • Prevot V, Rialas CM, Croix D, Salzet M, Dupouy JP, Poulain P, Beauvillain JC, Stefano GB (1998) Morphine and anandamide coupling to nitric oxide stimulates GnRH and CRF release from rat median eminence: neurovascular regulation. Brain Res 790:236–244

    PubMed  CAS  Google Scholar 

  • Pryce G, Ahmed Z, Hankey DJ, Jackson SJ, Croxford JL, Pocock JM, Ledent C, Petzold A, Thompson AJ, Giovannoni G, Cuzner ML, Baker D (2003) Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126:2191–2202

    PubMed  Google Scholar 

  • Pryor WA, Squadrito GL (1995) The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am J Physiol 268:L699–L722

    PubMed  CAS  Google Scholar 

  • Ramirez BG, Blazquez C, Gomez dP, Guzman M, de Ceballos ML (2005) Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25:1904–1913

    PubMed  CAS  Google Scholar 

  • Reynolds MR, Berry RW, Binder LI (2005) Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer's disease. Biochemistry 44:1690–1700

    PubMed  CAS  Google Scholar 

  • Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29:1020–1030

    PubMed  CAS  Google Scholar 

  • Rosch S, Ramer R, Brune K, Hinz B (2006) R(+)-methanandamide and other cannabinoids induce the expression of cyclooxygenase-2 and matrix metalloproteinases in human nonpigmented ciliary epithelial cells. J Pharmacol Exp Ther 316:1219–1228

    PubMed  Google Scholar 

  • Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood–brain barrier opening after reperfusion in rat brain. Stroke 29:2189–2195

    PubMed  CAS  Google Scholar 

  • Ross RA, Spengler BA, Biedler JL (1983) Coordinate morphological and biochemical interconversion of human neuroblastoma cells. J Natl Cancer Inst 71:741–747

    PubMed  CAS  Google Scholar 

  • Rothe F, Possel H, Wolf G (2002) Nitric oxide affects the phosphorylation state of microtubule-associated protein 2 (MAP-2) and neurofilament: an immunocytochemical study in the brain of rats and neuronal nitric oxide synthase (nNOS)-knockouts. Nitric Oxide 6:9–17

    PubMed  CAS  Google Scholar 

  • Rundhaug JE (2005) Matrix metalloproteinases and angiogenesis. J Cell Mol Med 9:267–285

    PubMed  CAS  Google Scholar 

  • Saeki M, Maeda S (1999) p130cas is a cellular target protein for tyrosine nitration induced by peroxynitrite. Neurosci Res 33:325–328

    PubMed  CAS  Google Scholar 

  • Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Cajal S, Guzman M (2001) Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor. Cancer Res 61:5784–5789

    PubMed  CAS  Google Scholar 

  • Sarker KP, Biswas KK, Yamakuchi M, Lee KY, Hahiguchi T, Kracht M, Kitajima I, Maruyama I (2003) ASK1-p38 MAPK/JNK signaling cascade mediates anandamide-induced PC12 cell death. J Neurochem 85:50–61

    Article  PubMed  CAS  Google Scholar 

  • Sarker KP, Maruyama I (2003) Anandamide induces cell death independently of cannabinoid receptors or vanilloid receptor 1: possible involvement of lipid rafts. Cell Mol Life Sci 60:1200–1208

    PubMed  CAS  Google Scholar 

  • Sarker KP, Obara S, Nakata M, Kitajima I, Maruyama I (2000) Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and caspase-3. FEBS Lett 472:39–44

    PubMed  CAS  Google Scholar 

  • Sawada N, Itoh H, Yamashita J, Doi K, Inoue M, Masatsugu K, Fukunaga Y, Sakaguchi S, Sone M, Yamahara K, Yurugi T, Nakao K (2001) cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem Biophys Res Commun 280:798–805

    PubMed  CAS  Google Scholar 

  • Sheng WS, Hu S, Min X, Cabral GA, Lokensgard JR, Peterson PK (2005) Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1β-stimulated human astrocytes. Glia 49:211–219

    PubMed  Google Scholar 

  • Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L, Leon A (1996a) The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proc Natl Acad Sci U S A 93:3984–3989

    PubMed  CAS  Google Scholar 

  • Skaper SD, Facci L, Romanello S, Leon A (1996b) Mast cell activation causes delayed neurodegeneration in mixed hippocampal cultures via the nitric oxide pathway. J Neurochem 66:1157–1166

    Article  PubMed  CAS  Google Scholar 

  • Soh JW, Mao Y, Liu L, Thompson WJ, Pamukcu R, Weinstein IB (2001) Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK1. J Biol Chem 276:16406–16410

    PubMed  CAS  Google Scholar 

  • Stamler JS, Lamas S, Fang FC (2001) Nitrosylation. the prototypic redox-based signaling mechanism. Cell 106:675–683

    PubMed  CAS  Google Scholar 

  • Stefano GB, Liu Y, Goligorsky MS (1996) Cannabinoid receptors are coupled to nitric oxide release in invertebrate immunocytes, microglia, and human monocytes. J Biol Chem 271:19238–19242

    PubMed  CAS  Google Scholar 

  • Stefano GB, Rialas CM, Deutsch DG, Salzet M (1998a) Anandamide amidase inhibition enhances anandamide-stimulated nitric oxide release in invertebrate neural tissues. Brain Res 793:341–345

    PubMed  CAS  Google Scholar 

  • Stefano GB, Salzet B, Rialas CM, Pope M, Kustka A, Neenan K, Pryor S, Salzet M (1997a) Morphine- and anandamide-stimulated nitric oxide production inhibits presynaptic dopamine release. Brain Res 763:63–68

    PubMed  CAS  Google Scholar 

  • Stefano GB, Salzet B, Salzet M (1997b) Identification and characterization of the leech CNS cannabinoid receptor: coupling to nitric oxide release. Brain Res 753:219–224

    PubMed  CAS  Google Scholar 

  • Stefano GB, Salzet M, Magazine HI, Bilfinger TV (1998b) Antagonism of LPS and IFN-γ induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase. J Cardiovasc Pharmacol 31:813–820

    PubMed  CAS  Google Scholar 

  • Upchurch GR, Jr., Ford JW, Weiss SJ, Knipp BS, Peterson DA, Thompson RW, Eagleton MJ, Broady AJ, Proctor MC, Stanley JC (2001) Nitric oxide inhibition increases matrix metalloproteinase-9 expression by rat aortic smooth muscle cells in vitro. J Vasc Surg 34:76–83

    PubMed  Google Scholar 

  • van der Stelt M, Di Marzo V (2005) Cannabinoid receptors and their role in neuroprotection. Neuromolecular Med 7:37–50

    PubMed  Google Scholar 

  • van der Stelt M, Hansen HH, Veldhuis WB, Bar PR, Nicolay K, Veldink GA, Vliegenthart JF, Hansen HS (2003) Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases. Neurotox Res 5:183–200

    Article  PubMed  Google Scholar 

  • Velasco G, Galve-Roperh I, Sanchez C, Blazquez C, Guzman M (2004) Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology 47:315–323

    PubMed  CAS  Google Scholar 

  • Wagner JA, Hu K, Bauersachs J, Karcher J, Wiesler M, Goparaju SK, Kunos G, Ertl G (2001) Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 38:2048–2054

    PubMed  CAS  Google Scholar 

  • Waksman Y, Olson JM, Carlisle SJ, Cabral GA (1999) The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J Pharmacol Exp Ther 288:1357–1366

    PubMed  CAS  Google Scholar 

  • Wiendl H, Hohlfeld R (2002) Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials. BioDrugs 16:183–200

    PubMed  CAS  Google Scholar 

  • Wilkinson JD, Whalley BJ, Baker D, Pryce G, Constanti A, Gibbons S, Williamson EM (2003) Medicinal cannabis: is Δ9-tetrahydrocannabinol necessary for all its effects? J Pharm Pharmacol 55:1687–1694

    PubMed  CAS  Google Scholar 

  • Woessner JF, Jr. (1999) Matrix metalloproteinase inhibition. From the Jurassic to the third millennium. Ann N Y Acad Sci 878:388–403

    PubMed  CAS  Google Scholar 

  • Wykes V, Bellamy TC, Garthwaite J (2002) Kinetics of nitric oxide-cyclic GMP signaling in CNS cells and its possible regulation by cyclic GMP. J Neurochem 83:37–47

    PubMed  CAS  Google Scholar 

  • Yamazaki M, Chiba K, Mohri T, Hatanaka H (2001) Activation of the mitogen-activated protein kinase cascade through nitric oxide synthesis as a mechanism of neuritogenic effect of genipin in PC12h cells. J Neurochem 79:45–54

    PubMed  CAS  Google Scholar 

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Correspondence to Allyn C. Howlett.

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Support: National Institute on Drug Abuse U24-DA12385 (S.M. and D.C.N.), R01-DA03690 and K05-00182 (A.C.H.), the American Heart Association Beginning Grant in Aid (S.M.), National Institute of General Medical Sciences S06 GM08049 (D.C.N.), and the National Center on Minority Health and Health Disparities P20-MD00175 (D.C.N. and A.C.H.).

Meeting: Mechanisms of Toxicity, Toxicokinetics, and Medical Consequences of Drugs, Substances of Abuse and AIDS. Date: November 4–5, 2005. Place: Nashville, TN. A Satellite Meeting to the American Association of Pharmaceutical Scientists (AAPS). Co-Sponsors: DDD Section, Drug Metabolism Focus Group (DFG). Sponsored by the AIDS Office, NIDA Chairs: Rao S. Rapaka, Ph.D., NIDA/NIH, and Ho-Leung Fung, Ph.D., SUNY, Buffalo, NY.

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Howlett, A.C., Mukhopadhyay, S. & Norford, D.C. Endocannabinoids and Reactive Nitrogen and Oxygen Species in Neuropathologies. Jrnl Neuroimmune Pharm 1, 305–316 (2006). https://doi.org/10.1007/s11481-006-9022-6

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