Abstract
Two G protein-coupled receptors for marijuana’s psychoactive component, Δ9-tetrahydrocannabinol, have been cloned to date, the cannabinoid CB1 and CB2 receptors. These two proteins, the endogenous lipids that activate them, also known as endocannabinoids, and the proteins for the biosynthesis and inactivation of these ligands constitute the endocannabinoid system. Evidence has accumulated over the last few years suggesting that endocannabinoid-based drugs may potentially be useful to reduce the effects of neurodegeneration. In fact, exogenous and endogenous cannabinoids were shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms, such as prevention of excitotoxicity by cannabinoid CB1-mediated inhibition of glutamatergic transmission, reduction of calcium influx, anti-oxidant activity, activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, induction of phosphorylation of extracellular regulated kinases and the expression of transcription factors and neurotrophins, lowering of cerebrovasoconstriction and induction of hypothermia. The release of endocannabinoids during neuronal injury may constitute a protective response. If this neuroprotective function of cannabinoid receptor activation can be transferred to the clinic, it might represent an interesting target to develop neuroprotective agents.
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Abood M. E., Rizvi G., Sallapudi N., and McAllister S. D. (2001) Activation of the CB(1) cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci. Lett. 309, 197–201.
Andersson M., Jacobsson S. O., Jonsson K. O., Tiger G., and Fowler C. J. (2000) Neurotoxicity of glutamate in chick telencephalon neurons: reduction of toxicity by preincubation with carbachol, but not by the endogenous fatty acid amides anandamide and palmitoylethanolamide. Arch. Toxicol. 74, 161–164.
Bayewitch M., Rhee M. H., Avidor-Reiss T., Breuer A., Mechoulam R., and Vogel Z. (1996) (-)-Delta9-tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase. J. Biol. Chem. 271, 9902–9905.
Benito C., Nunez E., Tolon R. M., et al. (2003) Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J. Neurosci. 23, 11,136–11,141.
Berdyshev E. V., Schmid P. C., Krebsbach R. J., et al. (2001) Cannabinoid-receptor-independent cell signalling by N-acylethanolamines. Biochem. J. 360, 67–75.
Berger C., Schmid P., Schabitz W., Wolf M., Schwab S., and Schmid H. (2004) Massive accumlation of N-acylethanolamines after stroke. Cell signalling in acute cerebral ischemia? J. Neurochem. 88, 1159–1167.
Bisogno T., Hanus L., De Petrocellis L., et al. (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol. 134, 845–852.
Bisogno T., Howell F., Williams G., et al. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell. Biol. 163, 463–468.
Bouaboula M., Bourrie B., Rinaldi-Carmona M., Shire D., Le Fur G., and Casellas P. (1995b) Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells. J. Biol. Chem. 270, 13,973–13,980.
Bouaboula M., Poinot-Chazel C., Bourrie B., et al. (1995a) Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem. J. 312, 637–641.
Bouaboula M., Poinot-Chazel C., Marchand J., et al. (1996) Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. Eur. J. Biochem. 237, 704–711.
Braida D., Pozzi M., and Sala M. (2000) CP 55,940 protects against ischemia-induced electroencephalographic flattening and hyperlocomotion in Mongolian gerbils. Neurosci. Lett. 296, 69–72.
Braida D., Pegorini S., Arcidiacono M., Consalez G., Croci L., and Sala M. (2003) Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci. Lett. 346, 61–64.
Breivogel C. S., Griffin G., Di Marzo V., and Martin B. R. (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol. Pharmacol. 60, 155–163.
Caulfield M. P. and Brown D. A. (1992) Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br. J. Pharmacol. 106, 231–232.
Cernak I., Vink R., Natale J., et al. (2004) The dark side of endocannabinoids: a neurotoxic role for anandamide. J. Cereb. Blood Flow Metab. 24, 564–578.
Chan G. C., Hinds T. R., Impey S., and Storm D. R. (1998) Hippocampal neurotoxicity of Delta9-tetrahydrocannabinol. J. Neurosci. 18, 5322–5332.
Chemin J., Monteil A., Perez-Reyes E., Nargeot J., and Lory P. (2001) Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. Embo. J. 20, 7033–7040.
Childers S. R., Sexton T., and Roy M. B. (1994) Effects of anandamide on cannabinoid receptors in rat brain membranes. Biochem. Pharmacol. 47, 711–715.
Clement A., Hawkins E., Lichtman A., and Cravatt B. (2003) Increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase. J. Neurosci. 23, 3916–3923.
Deadwyler S. A., Hampson R. E., Mu J., Whyte A., and Childers S. (1995) Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process. J. Pharmacol. Exp. Ther. 273, 734–743.
Deadwyler S. A., Hampson R. E., Bennett B. A., et al. (1993) Cannabinoids modulate potassium current in cultured hippocampal neurons. Receptors Channels 1, 121–134.
Di Marzo V. (1998) “Endocannabinoids” and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim. Biophys. Acta. 1392, 153–175.
Di Marzo V., Bisogno T., and De Petrocellis L. (2000a) Endocannabinoids: new targets for drug development. Curr. Pharm. Des. 6, 1361–1380.
Di Marzo V., Melck D., Bisogno T., and De Petrocellis L. (1998) Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21, 521–528.
Di Marzo V., Fontana A., Cadas H., Schinelli S., Cimino G., Schwartz J. C., and Piomelli D. (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691.
Di Marzo V., Breivogel C. S., Tao Q., et al. (2000b) Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain. J. Neurochem. 75, 2434–2444.
Dirnagl U., Iadecola C., and Moskowitz M. A. (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397.
El-Remessy A., Khalil I., Matragoon S., et al. (2003) Neuroprotective effect of (−)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-d-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am. J. Pathol. 16, 1997–2008.
Felder C. C., Briley E. M., Axelrod J., Simpson J. T., Mackie K., and Devane W. A. (1993) Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc. Natl. Acad. Sci. USA 90, 7656–7660.
Felder C. C., Joyce K. E., Briley E. M., et al. (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors Mol. Pharmacol. 48, 443–450.
Franklin A., Parmentier-Batteur S., Walter M., Greenberg D., and Stella N. (2003) Palmitoylethanolamide increases after focal cerbral ischemia and potentiates microglial cell motility. J. Neurosci. 23, 7767–7775.
Gallily R., Breuer A., and Mechoulam R. (2000) 2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-alpha production in murine macrophages, and in mice. Eur. J. Pharmacol. 406, R5–7.
Galve-Roperh I., Rueda D., Gomez D. P., Velasco G., and Guzman M. (2002) Mechanism of extracellular signal-regulated kinase activation by the CB(1) cannabinoid receptor. Mol. Pharmacol. 62, 1385–1392.
Galve-Roperh I., Sanchez C., Cortes M. L., del Pulgar T. G., Izquierdo M., and Guzman M. (2000) Antitumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat. Med. 6, 313–319.
Gebremedhin D., Lange A. R., Campbell W. B., Hillard C. J., and Harder D. R. (1999) Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current Am. J. Physiol. 276, H2085-H2093.
Gerdeman G. L., Ronesi J., and Lovinger D. M. (2002) Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat. Neurosci. 25, 25.
Glass M. and Felder C. C. (1997) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J. Neurosci. 17, 5327–5333.
Gomez Del Pulgar T., De Ceballos M. L., Guzman M., and Velasco G. (2002) Cannabinoids Protect Astrocytes from Ceramide-induced Apoptosis through the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway. J. Biol. Chem. 277, 36,527–36,533.
Gomez del Pulgar, Velasco G., and Guzman M. (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem. J. 347, 369–373.
Gonsiorek W., Lunn C., Fan X., Narula S., Lundell D., and Hipkin R. W. (2000) Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol. Pharmacol. 57(5), 1045–1050.
Grant E. R., Dubin A. E., Zhang S. P., Zivin R. A., and Zhong Z. (2002) Simultaneous intracellular calcium and sodium flux imaging in human vanilloid receptor 1 (VR1)-transfected human embryonic kidney cells: a method to resolve ionic dependence of VR1-mediated cell death. J. Pharmacol. Exp. Ther. 300, 9–17.
Guzman M., Galve-Roperh I., and Sanchez C. (2001) Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol. Sci. 22, 19–22.
Hajos N. and Freund T. (2002) Pharmacological separation of cannabinoid sensitive receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology 43, 503.
Hajos N., Ledent C., and Freund T. F. (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106, 1–4.
Hampson A. J., Grimaldi M., Axelrod J., and Wink D. (1998a) Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc. Natl. Acad. Sci. USA 95, 8268–8273.
Hampson A. J., Bornheim L. M., Scanziani M., et al. (1998b) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J. Neurochem. 70, 671–676.
Hampson R. E., Foster T C., and Deadwyler S. A. (1989) Effects of delta-9-tetrahydrocannabinol on sensory evoked hippocampal activity in the rat: principal components analysis and sequential dependency. J. Pharmacol. Exp. Ther. 251, 870–877.
Hansen H. H., Ikonomidou C., Bittigau P., Hansen S. H., and Hansen H. S. (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.
Hansen H. H., Azcoitia I., Pons S., et al. (2002) Blockade of cannabinoid CB(1) receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity. J. Neurochem. 82, 154–158.
Hansen H. H., Schmid P. C., Bittigau P., et al. (2001b) Anandamide, butnot2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J. Neurochem. 78, 1415–1427.
Hansen H. S., Lauritzen L., Strand A. M., Vinggaard A. M., Frandsen A., and Schousboe A. (1997) Characterization of glutamate-induced formation of N-acylphosphatidylethanolamine and N-acylethanolamine in cultured neocortical neurons. J. Neurochem. 69, 753–761.
Hanus L., Abu-Lafi S., Fride E., et al. (2001) 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. USA 98, 3662–3665.
Henry D. J. and Chavkin C. (1995) Activation of inwardly rectifying potassium channels (GIRK1) by co-expressed rat brain cannabinoid receptors in Xenopus oocytes. Neurosci. Lett. 186, 91–94.
Herkenham M., Lynn A. B., Johnson M. R., Melvin L. S., de Costa B. R., and Rice K. C. (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci. 11, 563–583.
Herkenham M., Lynn A. B., Little M. D., et al. (1990) Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA 87, 1932–1936.
Howlett A. C., and Mukhopadhyay S. (2000) Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem. Phys. Lipids 108, 53–70.
Howlett A. C. Barth F., Bonner T. I., et al. (2002) International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors Pharmacol. Rev. 54, 161–202.
Howlett A. C. (1995) Pharmacology of cannabinoid receptors Annu. Rev. Pharmacol. Toxicol. 35, 607–634.
Huang S. M., Bisogno T., Trevisani M., et al. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl. Acad. Sci. USA 99, 8400–8405.
Jacobsson S. O., Wallin T., and Fowler C. J. (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.
Jin K. L., Mao X. O., Goldsmith P. C., and Greenberg D. A. (2000) CB1 cannabinoid receptor induction in experimental stroke. Ann Neurol 48, 257–261.
Kermer P., Klocker N., and Bahr M. (1999) Neuronal death after brain injury. Models, mechanisms, and therapeutic strategies in vivo. Cell Tissue Res. 298, 383–395.
Khaspekov L., Brenz Verca M., Frumkina L. E., Hermann H., Marsicano G., and Lutz B. (2004) Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Eur. J. Neurosci. 19, 1691–1698.
Kreitzer A. C. and Regehr W. G. (2001) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron. 29, 717–727.
Leker R., Gai N., Mechoulam R., and Ovadia H. (2003) Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210. Stroke 34, 2000–2006.
Lipton S. (2003) Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. Surv. Ophthalmol. Suppl. 1, S38–46.
Liu J., Gao B., Mirshahi F., et al. (2000) Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem. J. 346, 835–840.
Louw D. F., Yang F. W., and Sutherland G. R. (2000) The effect of delta-9-tetrahydrocannabinol on forebrain ischemia in rat. Brain Res. 857, 183–187.
Lutz B. (2004) On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures. Biochem. Pharmacol. 68:1691–1698.
Maccarrone M., Lorenzon T., Bari M., Melino G., and Finazzi-Agro A. (2000) Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J. Biol. Chem. 275, 31,938–31,945.
Mackie K., Devane W. A., and Hille B. (1993) Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol. Pharmacol. 44, 498–503.
Mackie K. and Hille B. (1992) Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc. Natl. Acad. Sci. USA 89, 3825–3829.
Mackie K., Lai Y., Westenbroek R., and Mitchell R. (1995) Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J. Neurosci. 15(10), 6552–6561.
Maingret F., Patel A. J., Lazdunski M., and Honore E. (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1. Embo. J. 20, 47–54.
Marsicano G., Moosmann B., Hermann H., Lutz B., and Behl C. (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J. Neurochem. 80, 448–456.
Marsicano G., Goodenough S., Monory K., et al. (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88.
Martinez-Orgado J., Fernandez-Frutos B., Gonzalez R., et al. (2003) Neuroprotection by the cannabinoid agonist WIN-55212 in an in vivo newborn rat model of acute severe asphyxia. Brain Res. Mol. 114, 132–139.
Matsuda L. A., Lolait S. J., Brownstein M. J., Young A. C., and Bonner T. I. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564.
Mauler F., Mittendorf J., Horvath E., and De Vry J. (2002) Characterization of the diarylether sulfonylester (−)-(R)-3-(2- hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties. J. Pharmacol. Exp. Ther. 302, 359–368.
McAllister S. D., Griffin G., Satin L. S., and Abood M. E. (1999) Cannabinoid receptors can activate and inhibit G protein-coupled inwardly rectifying potassium channels in a xenopus oocyte expression system J. Pharmacol. Exp. Ther. 291, 618–626.
Mechoulam R., Panikashvili D., and Shohami E. (2002) Cannabinoids and brain injury: therapeutic implications. Trends Mol. Med. 8, 58–61.
Molina-Holgado E., Vela J., Arevalo-Martin A., et al. (2002) Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J. Neurosci. 22, 9742–9753.
Molina-Holgado F., Pinteaux E., Moore J., et al. (2003) Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J. Neurosci. 23, 6470–6474.
Molina-Holgado F., Pinteaux E., Heenan L., Moore J. D., Rothwell N. J., and Gibson R. M. Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase/AKT signaling Mol. Cell Neurosci., in press.
Munro S., Thomas K. L., and Abu-Shaar M. (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65.
Muthian S., Rademacher D. J., Roelke C. T., Gross G. J., and Hillard C. (2004) Anandamide content is increased and Cb1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia. Neurosci. 129, 743–750.
Nagayama T., Sinor A. D., Simon R. P., et al. (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J. Neurosci. 19, 2987–2995.
Netzeband J. G., Conroy S. M., Parsons K. L., and Gruol D. L. (1999) Cannabinoids enhance NMDA-elicited Ca2+ signals in cerebellar granule neurons in culture. J. Neurosci. 19, 8765–8777.
Nicotera P., Leist M., and Manzo L. (1999) Neuronal cell death: a demise with different shapes. Trends Pharmacol. Sci. 20, 46–51.
Ohno-Shosaku T., Maejima T., and Kano M. (2001) Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron. 29, 729–738.
Okamoto Y., Morishita J., Tsuboi K., Tonai T., and Ueda N. (2004), Molecular characterization of a phospholipase D generating anandamide and Its congeners. J. Biol. Chem. 279, 5298–5305
Pan X., Ikeda S. R., and Lewis D. L. (1996) Rat brain cannabinoid receptor modulates N-type Ca2+ channels in a neuronal expression system Mol. Pharmacol. 49, 707–714.
Panikashvili D., Simeonidou C., Ben-Shabat S., et al. (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–531.
Parmentier-Batteur S., Jin K., Mao X., Xie L., and Greenberg D. (2002) Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J. Neurosci. 22, 9771–9775.
Pinto J. C., Potie F., Rice K. C., et al. (1994) Cannabinoid receptor binding and agonist activity of amides and esters of arachidonic acid Mol. Pharmacol. 46, 516–522.
Porter A. C., Sauer J. M., Knierman M. D., et al. (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther. 301, 1020–1024.
Priller J., Briley E. M., Mansouri J., Devane W. A., Mackie K., and Felder C. C. (1995) Mead ethanolamide, a novel eicosanoid, is an agonist for the central (CB1) and peripheral (CB2) cannabinoid receptors Mol. Pharmacol. 48, 288–292.
Rhee M. H., Bayewitch M., Avidor-Reiss T., Levy R., and Vogel Z. (1998) Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes J. Neurochem. 71, 1525–1534.
Robbe D., Kopf M., Remaury A., Bockaert J., and Manzoni O. J. (2002) Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc. Natl. Acad. Sci. USA 99, 8384–8388.
Rueda D., Galve-Roperh I., Haro A., and Guzman M. (2000) The CB(1) cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase Mol. Pharmacol. 58, 814–820.
Sagan S., Venance L., Torrens Y., Cordier J., Glowinski J., and Giaume C. (1999) Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-protein-coupled receptors distinct from CB1 cannabinoid receptors in cultured astrocytes. Eur. J. Neurosci. 11, 691–699.
Sanchez C., de Ceballos M. L., del Pulgar T. G., et al. (2001) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor Cancer Res. 61, 5784–5789.
Sanchez C., Galve-Roperh I., Rueda D., and Guzman M. (1998) Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes Mol. Pharmacol. 54, 834–843.
Schlicker E. and Kathmann M. (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22, 565–572.
Shen M. and Thayer S. A. (1998a) Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol. Pharmacol. 54, 459–462.
Shen M. and Thayer S. A. (1998b) The cannabinoid agonist Win55, 212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons. Brain Res. 783, 77–84.
Sinor A. D., Irvin S. M., and Greenberg D. A. (2000) Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci. Lett. 278, 157–160.
Skaper S. D., Buriani A., Dal Toso R., et al. (1996) 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. USA 93, 3984–3989.
Slipetz D. M., O’Neill G. P., Favreau L., et al. (1995) Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase Mol. Pharmacol. 48, 352–361.
Smart D. and Jerman J. C. (2000) Anandamide: an endogenous activator of the vanilloid receptor. Trends Pharmacol. Sci. 21, 134.
Sugiura T., Kodaka T., Kondo S., et al. (1997b) Is the cannabinoid CB1 receptor a 2-arachidonoylglycerol receptor? Structural requirements for triggering a Ca2+ transient in NG108-15 cells J. Biochem. (Tokyo) 122, 890–895.
Sugiura T., Kodaka T., Kondo S., et al. (1996) 2-Arachidonoylglycerol, a putative endogenous cannabinoid receptor ligand, induces rapid, transient elevation of intracellular free Ca2+ in neuroblastoma × glioma hybrid NG108-15 cells Biochem. Biophys. Res. Commun. 229, 58–64.
Sugiura T., Kodaka T., Kondo S., et al. (1997a) Inhibition by 2-arachidonoylglycerol, a novel type of possible neuromodulator, of the depolarization-induced increase in intracellular free calcium in neuroblastoma × glioma hybrid NG108-15 cells Biochem. Biophys. Res. Commun. 233, 207–210.
Sugiura T., Kodaka T., Nakane S., et al. (1999) Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds J. Biol. Chem. 274, 2794–2801.
Sugiura T., Yoshinaga N., Kondo S., Waku K., and Ishima Y. (2000) Generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in picrotoxinin-administered rat brain. Biochem. Biophys. Res. Commun. 271, 654–658.
Tsou K., Brown S., Sanudo-Pena M. C., Mackie K., and Walker J. M. (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83, 393–411.
van der Stelt M., Veldhuis W. B., Bar P. R., Veldink G. A., Vliegenthart J. F., and Nicolay K. (2001a) Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J. Neurosci. 21, 6475–6479.
van der Stelt M., Veldhuis W. B., Maccarrone M., et al. (2002) Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol. Neurobiol. 26, 317–346.
van der Stelt M., Veldhuis W. B., van Haaften G. W., et al. (2001b) Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J. Neurosci. 21, 8765–8771.
Veldhuis W., Van der Stelt M., Wadman M., et al. (2003) Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J. Neurosci. in press.
Vogel Z., Barg J., Levy R., Saya D., Heldman E., and Mechoulam R. (1993) Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase J. Neurochem. 61, 352–355.
Walter L. and Stella N. (2004) Cannabinoids and neuroinflammation Br. J. Pharmacol. 141, 775–785.
Wartmann M., Campbell D., Subramanian A., Burstein S. H., and Davis R. J. (1995) The MAP kinase signal transduction pathway is activated by the endogenous cannabinoid anandamide FEBS Lett 359, 133–136.
Wilson R. I. and Nicoll R. A. (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592.
Zygmunt P. M., Petersson J., Andersson D. A., et al. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457.
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van der Stelt, M., Di Marzo, V. Cannabinoid receptors and their role in neuroprotection. Neuromol Med 7, 37–50 (2005). https://doi.org/10.1385/NMM:7:1-2:037
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DOI: https://doi.org/10.1385/NMM:7:1-2:037