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release by vascular endothelial cells (Ronco et al., 2007). Endothelin-1 is a peptide with potent vasoconstrictor properties, that is involved in the regulation of vascular tone. Its excessive production has been implicated in the pathogenesis of a variety of vascular disorders, including ischemic and hemorrhagic strokes, the Raynaud phenomenon, and myocardial ischemia. Reduced retinal blood supplies leading to chronic states of retinal hypoxia contribute to the retinal damage caused by glaucoma. These alterations have been linked to changes in endothelin metabolism, and high levels of the latter peptide have been found in the blood of patients with low-pressure glaucoma or chronic forms of simple glaucoma, compared with those found in healthy controls (Emre et al., 2005; Kim et al., 2006; Wang et al., 2006). In glaucoma, exogenous CBs could produce beneficial effects at the retinal level by increasing retinal perfusion.

The neuroprotective effects of (e)CBs might also be related to their ability to modulate inflammatory processes. In glaucoma, post-ischemic inflammation is thought to be an important factor in the induction of cell death. Experimentally induced glaucoma has been shown to be associated with massive activation of astrocytes, Muller cells, and microglia that leads to the release of factors that are toxic to the ganglion cells, including nitric oxide, glutamate, and tumor necrosis factor (Weinreb and Khaw, 2004). Experimental studies have shown that stimulation of CB1 and CB2 receptors modulates activation and migration of microglial cells, and thus inhibits the production of inflammatory cytokines and nitric oxide in models of CNS disease (Baker et al., 2003; Walter and Stella, 2004; Jackson et al., 2005).

Conclusions

The identification of plant derived, endogenous, or synthetic CBs capable of interacting with the intraocular endocannabinoid system could open new perspectives for the treatment of glaucoma. In addition to their ability to control IOP elevations caused by the disease, such agents could also produce specific neuroprotective effects at the level of RGCs, whose loss represents the final event

along with disease progression. In ophthalmology, the risk of serious systemic side effects could be substantially reduced by the use of eye drops containing (endo)cannabinoids, although topical application is complicated by the markedly low water solubility of these molecules. The recent introduction of microemulsions and cyclodextrins as vehicles has considerably increased the ability of (endo)cannabinoids to diffuse across the cornea, thus enhancing their effects on the IOP (Laine et al., 2002a, b); yet, it remains to be checked whether this administration route may allow the drugs to reach the retina and exert their neuroprotective effects.

References

Adachi, K., Kashii, S., Masai, H., Ueda, M., Morizane, C. and Kaneda, K. (1998) Mechanism of the pathogenesis of glutamate neurotoxicity in retinal ischemia. Graefe’s Arch. Clin. Exp. Ophthalmol., 236(10): 766–774.

Amantea, D., Spagnuolo, P., Bari, M., Fezza, F., Mazzei, C., Tassorelli, C., Morrone, L.A., Corasaniti, M.T., Maccarrone, M. and Bagetta, G. (2007) Modulation of the endocannabinoid system by focal brain ischemia in the rat is involved in neuroprotection afforded by 17beta-estradiol. FEBS J., 274(17): 4464–4775.

Baker, D., Pryce, G., Giovannoni, G. and Thompson, A.J. (2003) The therapeutic potential of cannabis. Lancet Neurol., 2(5): 291–298.

Baker, D., Pryce, G., Davies, W.L. and Hiley, C.R. (2006) In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol. Sci., 27(1): 1–4.

Bari, M., Spagnuolo, P., Fezza, F., Oddi, S., Pasquariello, N., Finazzi-Agro`, A. and Maccarone, M. (2006) Effect of lipid rafts on Cb2 receptor signaling and 2-arachidonoyl-glycerol metabolism in human immune cells. J. Immunol., 177(8): 4971–4980.

Bisogno, T., Delton-Vandenbroucke, I., Milone, A., Lagarde, M. and Di Marzo, V. (1999) Biosynthesis and inactivation of N-arachidonoylethanolamine (anandamide) and N-docosa- hexaenoylethanolamine in bovine retina. Arch. Biochem. Biophys., 370(2): 300–307.

Bisogno, T., Howell, F., Williams, G., Minassi, A., Cascio, M.G., Ligresti, A., Matias, I., Schiano-Moriello, A., Paul, P., Williams, E.J., Gangadharan, U., Hobbs, C., Di Marzo, V. and Doherty, P.J. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signalling in the brain. Cell Biol., 163(3): 463–467.

Brown, B., Adams, A.J. and Haegerstrom-Portnoy, G. (1977) Pupil size after use of marijuana and alcohol. Am. J. Ophthalmol., 83(3): 350–354.

Carter-Dawson, L., Crawford, M.L., Harwerth, R.S., Smith, E.L., 3rd, Feldman, R., Shen, F.F., Mitchell, C.K. and Whitetree, A. (2002) Vitreal glutamate concentration in monkeys with experimental glaucoma. Invest. Ophthalmol. Vis. Sci., 43(8): 2633–2637.

Centonze, D., Rossi, S., Finazzi-Agro`, A., Bernardi, G. and Maccarrone, M. (2007) The (endo)cannabinoid system in multiple sclerosis and amyotrophic lateral sclerosis. Int. Rev. Neurobiol., 82: 171–186.

Chen, J., Matias, I., Dinh, T., Lu, T., Venezia, S., Nieves, A., Woodward, D.F. and Di Marzo, V. (2005) Finding of endocannabinoids in human eye tissues: implications for glaucoma. Biochem. Biophys. Res. Commun., 330(4): 1062–1067.

Chien, F.Y., Wang, R.F. and Mittag, T.W. (2003) Effects of WIN-55,212-2, a cannabinoid receptor agonist, on aqueous humor dynamic c in monkeys. Arch. Ophthalmol., 121(1): 87–90.

Collaborative Normal Tension Glaucoma Study Group. (1998) Comparison of glaucomatous progression between untreated patients with normal tension glaucoma and patients with therapeutically reduced intraocular pressure. Am. J. Ophthamol., 126: 498–505.

Cooler, P. and Gregg, J.M. (1977) Effect of delta-9-tetrahy- drocannabinol on intraocular pressure. South. Med. J., 70(8): 951–954.

Crandall, J., Matragoon, S., Khalifa, Y.M., Borlongan, C., Tsai, N.T., Caldwell, R.B. and Liou, G.I. (2007) Neuroprotective and intraocular pressure-lowering effects of ( )Delta9-tetrahydrocannabinol in a rat model of glaucoma. Ophthalmic Res., 39(2): 69–75.

Cravatt, B.F., Wright, A.T. and Kovarich, J.W. (2008) Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu. Rev. Biochem., 77: 383–414.

Davies, S.N., Pertwee, R.G. and Riedel, G. (2002) Functions of cannabinoid receptors in hippocampus. Neuropharmacology, 42(8): 993–1007.

De Petrocellis, L., Bisogno, T., Maccarrone, M., Davis, J.B., Finazzi Agro‘, A. and Di Marzo, V. (2001) The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J. Biol. Chem., 276(16): 12856–12863.

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(6507): 686–691.

Dinh, T.P., Carpenter, D., Leslie, F.M., Freund, T.F., Katona, I., Sensi, S.L., Kathuria, S. and Piomelli, D. (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl. Acad. Sci. U.S.A., 99(16): 10819–10824.

Dreyer, E.B., Zurakowsky, D., Schumer, R.A., Podos, S.M. and Lipton, S.A. (1996) Elevated glutamate in the vitreous of humans and monkeys with glaucoma. Arch. Ophthalmol., 114(3): 299–305.

El-Remessy, A.B., Khalil, I.E., Matragoon, S., AbouMohamed, G., Tsai, N.J., Roon, P., Caldwell, R.B.,

461

Caldwell, G.I., Green, K. and Liou, G.I. (2003) Neuroprotective effecs of ( )D9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity. Am. J. Pathol., 163(5): 1997–2008.

Emre, M., Orgu¨l, S., Haufschild, T., Shaw, S.G. and Flammer, J. (2005) Increased plasma endothelin-1 levels in patients with progressive open angle glaucoma. Br. J. Ophthalmol., 89(1): 60–63.

Fan, S.F. and Yazulla, S. (2005) Reciprocal inhibition of voltage-gated potassium currents (I K(V)) by activation of cannabinoid CB1 and dopamine D1 receptors in ON bipolar cells of goldfish retina. Vis. Neurosci., 22: 55–63.

Gilbert, G.L., Kim, H.J., Waataja, J.J. and Thayer, S.A. (2007) D9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. Brain Res., 1128: 61–69.

Glaser, S.T., Deutsch, D.G., Studholme, K.M., Zimov, S. and Yazulla, S. (2005) Endocannabinoids in the intact retina: 3 H-anandamide uptake, fatty acid amide hydrolase immunoreactivity and hydrolysis of anandamide. Vis. Neurosci., 22(6): 693–705.

Glovinsky, Y., Quigley, H.A. and Pease, M.E. (1993) Foveal ganglion cell loss is size dependent in experimental glaucoma. Invest. Ophthalmol. Vis. Sci., 34: 395–400.

Green, K. (1998) Marijuana smoking vs cannabinoids for glaucoma therapy. Arch. Ophtalmol., 116(11): 1512–1513.

Green, K., Kearse, E.C. and McIntyre, O.L. (2001) Interaction between D9-tetrahydrocannabinol and indomethacin. Ophthalmic Res., 33: 217–220.

Hampson, A.J., Bornheim, L.M., Scanziani, M., Yost, C.S., Gray, B.M., Hansen, B.M., Leonudakis, D.L. and Bicler, P.E. (1998) Dual effects of anandamide on NMDA-receptor- mediated responses and neurotransmission. J. Neurochem., 86(6): 1294–1300.

Hansen, H.S., Moesgaard, B., Hansen, H.H. and Petersen, G. (2000) N-Acylethanolamines and precursor phospholipids: relation to cell injury. Chem. Phys. Lipids, 108: 135–150.

Hare, W.A., WoldeMu¨ssie, E., Weinreb, R.N., Ton, H., Ruiz, G., Wijono, M., Feldmann, B., Zangwill, L. and Wheeler, L. (2004b) Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, II: structural measures. Invest. Ophthalmol. Vis. Sci., 45(8): 2640–2651.

He, F. and Song, Z.H. (2007) Molecular and cellular changes induced by the activation of CB2 cannabinoid receptors in trabecular meshwork cells. Mol. Vis., 13: 1348–1356.

Heijl, A., Leske, M.C., Bengtsson, B., Hyman, L. and Hussein, M. (2002) Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch. Ophthalmol., 120: 1268–1279.

Hepler, R.S. and Frank, I.R. (1971) Marihuana smoking and intraocular pressure (letter). JAMA, 217: p. 1392.

Honkanen, R.A., Baruah, S., Zimmerman, M.B., Khanna, C.L., Weaver, Y.K., Narkiewicz, J., Waziri, R., Gehrs, K.M., Weingeist, T.A., Boldt, H.C., Folk, J.C., Russell, S.R. and Kwon, Y.H. (2003) Vitreous amino acid concentrations in patients with glaucoma undergoing vitrectomy. Arch. Ophthalmol., 121(2): 183–188.

462

Hosseini, A., Lattanzio, F.A., Williams, P.B., Tibbs, D., Samudre, S.S. and Allen, R.C. (2006) Chronic topical administration of WIN-55-212-2 maintains a reduction in IOP in a rat glaucoma model without adverse effects. Exp. Eye Res., 82: 753–759.

Howlett, A.C., Barth, F., Bonner, T.I., Cabral, G., Casellas, P., Devane, W.A., Felder, C.C., Herkenham, M., Mackie, K., Martin, B.R., Mechoulam, R. and Pertwee, R.G. (2002) Classification of cannabinoid receptors. Pharmacol. Rev., 54: 161–202.

Howlett, A.C., Breivogel, C.S., Childers, S.R., Deadwyler, S.A., Hampson, R.E. and Porrino, L.J. (2004) Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology, 47: 345–358.

Jackson, S.J., Diemel, L.T., Pryce, D. and Baker, D. (2005) Cannabinoids and neuroprotection in CNS inflammatory disease. J. Neurol. Sci., 233: 21–25.

Jay, W.M. and Green, K. (1983) Multiple drop study of topically applied of 1% D9 tetrahydrocannabinol in human eye. Arch. Ophthalmol., 101: 591–593.

Jordt, S.E. and Julius, D. (2002) Molecular basis for speciesspecific sensitivity to ‘‘hot’’ chili peppers. Cell, 108(3): 421–430.

Kass, M.A., Heuer, D.K., Higginbotham, E.J., Johnson, C.A., Keltner, J.L., Miller, J.P., Parrish, R.K., 2nd., Wilson, M.R. and Goedon, M.O. (2002) The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevent the onset of primary open-angle glaucoma. Arch. Ophthalmol., 120(6): 701–713.

Kim, S.H., Kim, J.Y., Kim, D.M., Ko, H.S., Kim, S.Y., Yoo, T., Hwang, S.S. and Park, S.S. (2006) Investigations on the association between normal tension glaucoma and single nucleotide polymorphisms of the endothelin-1 and endothelin receptor genes. Mol. Vis., 12: 1016–1021.

Kim, D.J. and Thayer, S.A. (2000) Activation of CB1 cannabinoid receptors inhibits neurotransmitter release from identified synaptic sites in rat hippocampal cultures. Brain Res., 852: 398–405.

Kwon, Y.H., Rickman, D.W., Baruah, S., Zimmerman, M.B., Kim, C.S., Boldt, H.C., Russell, S.R. and Hayreh, S.S. (2005) Vitreous and retinal amino acid concentrations in experimental central retinal artery occlusion in the primate. Eye, 19(4): 455–463.

Laine, K., Jarvinen, K., Mechoulam, R., Breuer, A. and Jarvinen, T. (2002a) Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid. Invest. Ophthalmol. Vis. Sci., 43: 3216–32122.

Laine, K., Jarvinen, K., Pate, D.W., Urtti, A. and Jarvinen, T. (2002b) Effect of the enzyme inhibitor, phenylmethylsulfonyl fluoride, on the IOP profiles of topical anandamides. Invest. Ophthalmol. Vis. Sci., 43: 393–397.

Laine, K., Jarvinen, T., Savinainen, J., Laitinen, J.T., Pate, D.W. and Jarvinen, K. (2001) Effects of topical anandamidetransport inhibitors, AM404 and olvanil, on intraocular pressure in normotensive rabbits. Pharm. Res., 18: 494–499.

Lastres-Becker, I., Molina-Holgado, F., Ramos, J.A., Mechoulam, R. and Fernandez-Ruiz, J. (2005) Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol. Dis., 19: 96–107.

Lauckner, J.E., Jensen, J.B., Chen, H.Y., Lu, H.C., Hille, B. and Mackie, K. (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc. Natl. Acad. Sci., 105: 2699–2704.

Ligresti, A., Cascio, M.G. and Di Marzo, V. (2005) Endocannabinoid metabolic pathways and enzymes. Curr. Drug Targets CNS Neurol. Disord., 4: 615–623.

Lipton, S.A. (2003) Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. Surv. Ophthalmol., 48(Suppl 1): S38–S46.

Lograno, M.D. and Romano, M.R. (2004) Cannabinoid agonists induce contractile responses through Gi/o-depen- dent activation of phospholipase C in the bovine ciliary muscle. Eur. J. Pharmacol., 494: 55–62.

Louzada-Ju´nior, P., Dias, J.J., Santos, W.F., Lachat, J.J., Bradford, H.F. and Coutinho-Netto, J. (1992) Glutamate release in experimental ischaemia of the retina: an approach using microdialysis. J. Neurochem., 59(1): 358–363.

Lucas, D.R. and Newhouse, J.P. (1957) The toxic effect of sodium L-glutamate on the inner layers of the retina. Am. Med. Assoc. Arch. Ophthalmol., 58.: 193–201.

Maccarrone, M., Battista, N. and Centonze, D. (2007) The endocannabinoid pathway in Huntington’s disease: a comparison with other neurodegenerative diseases. Prog. Neurobiol., 81: 349–379.

Maccarrone, M., Rossi, S., Bari, M., De Chiara, V., Fezza, F., Musella, A., Gasperi, V., Prosperetti, C., Bernardi, G., Finazzi-Agro`, A., Cravatt, B.F. and Centonze, D. (2008) Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat. Neurosci., 11: 152–159.

Maihofner, C., Schlotzer-Schrehardt, U., Guhring, H., Zeilhofer, H.U., Naumann, G.O.H., Pahl, A., Mardin, C., Tamm, E.R. and Brune, K. (2001) Expression of ciclooxigenase-1 and -2 in normal and glaucomatous human eyes. Invest. Ophthalmol. Vis. Sci., 42: 2616–2624.

Marinelli, S., Di Marzo, V., Berretta, N., Matias, I., Maccarrone, M., Bernardi, G. and Mercuri, N.B. (2003) Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J. Neurosci., 23(8): 3136–3144.

Marsicano, G., Goodenough, S., Monory, K., Hermann, H., Eder, M., Cannich, A., Azad, S.C., Cascio, M.G., Gutierrez, S.O. and V. Stelt, O. (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science, 302: 84–88.

Matsuda, S., Kanemitsu, N., Nakamura, A., Mimura, Y., Ueda, N., Kurahashi, Y. and Yamamoto, S. (1997) Metabolism of anandamide, an endogenous cannabinoid receptor ligand, in porcine ocular tissues. Exp. Eye Res., 64(5): 707–711.

McIntosh, B.T., Hudson, B., Yegorova, S., Jollimore, C.A.B. and Kelly, M.E.M. (2007) Agonist-dependent cannabinoid receptor signalling in human trabecular meshwork k cells. Br. J. Pharmacol., 152: 1111–1120.

McKinney, M.K. and Cravatt, B.F. (2005) Structure and function of fatty acid amide hydrolase. Annu. Rev. Biochem., 74: 411–432.

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

Muller, A., Villain, M. and Bonne, C. (1997) The release of amino acids from ischemic retina. Exp Eye Res., 64(2): 291–293.

Nagayama, T., Sinor, A.D., Simon, R.P., Chen, J., Graham, S.H., Jin, K. and Greenberg, D.A. (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J. Neurosci., 19: 2987–2995.

Njie, Y.F., Kumar, A., Qiao, Z., Zhong, L. and Song, Z.H. (2006) Noladin ether acts on trabecular meshwork cannabinoid (CB1) receptors to enhance aqueous humor outflow facility. Invest. Ophthalmol. Vis. Sci., 47: 1999–2005.

Nucci, C., Cerulli, A., Turtoro, A., Tartaglione, R., Morrone, LA., Bagetta, G. and Corasaniti, M.T. (2005a) Apoptosis and glaucoma: new insight from basic research to the development of novel strategies for neuroprotection. In: Reece S.M. (Ed.), Focus on Glaucoma Research. Nova Science Publisher, New York, USA, pp. 1–26.

Nucci, C., Gasperi, V., Tartaglione, R., Cerulli, A., Terrinoni, A., Bari, M., De Simone, C., Finazzi Agro`, A., Morrone, L.A., Corasaniti, M.T., Bagetta, G. and Maccarrone, M. (2007b) Involvement of the endocannabinoid system in retinal damage following high intraocular pressureinduced ischemia in rat. Invest. Ophthalmol. Vis. Sci., 48: 2997–3002.

Nucci, C., Tartaglione, R., Cerulli, A., Mancino, R., Spano`, A., Cavaliere, F., Rombola`, L., Bagetta, G., Corasaniti, M.T. and Morrone, L.A. (2007a) Retinal damage caused by high intraocular pressure (IOP)-induced transient ischemia is prevented by coenzyme Q10 in rat. Int. Rev. Neurobiol., 82: 397–406.

Nucci, C., Tartaglione, R., Rombola, L., Morrone, L.A., Fazzi, E. and Bagetta, G. (2005b) Neurochemical evidence to implicate elevated glutamate in the mechanisms of high intraocular pressure (IOP)-induced retinal ganglion cell death in rat. Neurotoxicology, 26: 935–941.

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.

Oltmanns, M.H., Samudre, S.S., Castillo, I.G., Hosseni, A., Lichtman, A.H., Allen, R.C., Lattanzio, F.A. and Williams, P.B. (2008) Topical WIN 55212-2 alleviates intraocular hypertension in rats through a CB1 receptor-mediated mechanism of actionJ. Ocul. Pharmacol., Jan 17 Epub ahead of print.

Osborne, N.N., Casson, R.J., Wood, J.P.M., Childlow, G., Graham, M. and Melena, J. (2004) Retinal ischemia:

463

mechanisms of damage and potential therapeutic strategies. Prog. Retin. Eye Res., 23: 91–147.

Osborne, N.N., Ugarte, M., Chao, M., Chidlow, G., Bae, J.H., Wood, J.P. and Nash, M.S. (1999) Neuroprotection in relation to retinal ischemia and relevance to glaucoma. Surv. Ophthalmol., 43: S102–S128.

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

Pate, D.W., Ja¨rvinen, K., Urtii, A., Jarho, P., Fich, M., Mahadevan, V. and Jarvinen, T. (1996) Effects of topical anandamides on intraocular pressure in normotensive rabbits. Life Sci., 58: 1849–1860.

Pate, D.W., Jarvinen, K., Urtti, A., Jarho, P., Mahadevan, V. and Jarvinen, T. (1997) Effects of topical alpha-substituted anandamides on intraocular pressure in normotensive rabbits. Pharm. Res., 14: 1738–1743.

Pate, D.W., Ja¨rvinen, K., Urtti, A., Mahadevan, V. and Jarvinen, T. (1998) Effect of the CB1 receptor antagonist SR 141716A on cannabinoids induced ocular hypotension in normotensive rabbits. Life Sci., 63: 2181–2188.

Perez-Reyez, M., Wagner, D., Wall, M.E. and Davis, K.H. (1976) Intravenous administration of cannabinoids and intraocular pressure. In: Braude M.C. and Szara S. (Eds.), The Pharmacology of Marihuana. Raven Press, New York, NY, pp. 832–839.

Pertwee, R.G. and Ross, R.A. (2002) Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids, 66(2-3): 101–121.

Piomelli, D. (2003) The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci., 4(11): 873–884.

Plange, N., Arend, K.O., Kaup, M., Doehmen, B. and Adams, H. (2007) Dronabinol and retinal hemodynamics in human. Am. J. Ophthalmol., 143.: 173–174.

Porcella, A., Maxia, C.H., Gessa, G.L. and Pani, L. (2001) The synthetic cannabinoids WIN-55,212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies. Eur. J. Neurosci., 13: 409–412.

Pryce, G., Ahmed, Z., Hankey, D.J., Jackson, S.J., Croxford, J.L., Pocock, J.M., Ledent, C., Petzold, A., Thompson, A.J., Giovannoni, G., Cuzner, M.L. and Maker, D. (2003) Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain, 126: 2191–2202.

Ramirez, B.G., Blazquez, C., Gomez, D.P., Guzman, M. and De Ceballos, M.L. (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci., 25: 1904–1913.

Romano, M.R. and Lograno, M.D. (2006) Cannabinoid agonists induce relaxation in the bovine ophthalmic artery: evidences for CB1 receptors, nitric oxide and potassium channels. Br. J. Pharmacol., 147(8): 917–925.

Ronco, A.M., Llanos, M., Tamayo, D. and Hirsch, S. (2007) Anandamide inhibits endothelin-1 production by human cultured endothelial cells: a new vascular action of this endocannabinoid. Pharmacology, 79(1): 12–16.

464

Rosch, S., Ramer, R., Brune, K. and 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(3): 1219–1228.

Samy, C.N., Lui, C.J., Kaiser, P.K., Lipton, S.A. and Dreyer, E.B. (1994) Toxicity of chronic glutamate administration to the retina. Invest. Ophthalmol. Vis. Sci., 35: p. 497.

Sappington, R.M. and Calkins, D. (2008) TRPV1 contributes to microglia-derived IL-6 and NF{kappa}B translocation with elevated hydrostatic pressure. Invest. Ophthalmol. Vis. Sci.

Sawzdargo, M., Nguyen, T., Lee, D.K., Lynch, K.R., Cheng, R., Heng, H.H., George, S.R. and O’Dowd, B.F. (1999) Identification and cloning of three novel human G proteincoupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brian Res. Mol. Brain Res., 64: p. 193.

Shen, M. and Thayer, S.A. (1998) The cannabinoid agonist win 55,212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons. Brain Res., 783: 77–84.

Shen, M. and Thayer, S.A. (1999) D9-tetrahydrocannabinol act as a partial agonist to modulate glutamatergic synaptic transmission between rat hippocampal neurons in culture. Mol. Pharmacol., 55: 459–462.

Sisk, D.R. and Kuwabara, T. (1985) Histologic changes in the inner retina of albino rats following intravitreal injection of monosodium L-glutamate. Graefes Arch. Clin. Exp. Ophthalmol., 223: 250–258.

Song, Z.H. and Slowey, C.A. (2000) Involvement of cannabinoids receptors in the intraocular pressure lowering effects of WIN-55,212-2. Pharmacol. Exp. Ther., 292: 136–139.

Starowicz, K., Nigam, S. and Di Marzo, V. (2007) Biochemistry and pharmacology of endovanilloids. Pharmacol. Ther., 114: 13–33.

Straiker, A., Maguire, G., Makie, K. and Lindsey, J (1999) Localization of cannabinoid CB1 receptors in the human anterior eye and retina. Invest. Ophthalmol. Vis. Sci., 40: 2442–2448.

Struik, M.L., Yazulla, S. and Kamermans, M. (2006) Cannabinoid agonist WIN 55212-2 speeds up the cone

response to light offset in goldfish retina. Vis. Neurosci., 23: 285–293.

Sucher, N.J., Lipton, S.A. and Dreyer, E.B. (1997) Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res., 37: 3483–3493.

Tomida, I., Azuara-Blanco, A., House, H., Flint, M., Pertwee, R.G. and Robson, P.J. (2006) Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J. Glaucoma, 15: 349–353.

Tomida, I., Pertwee, R.G. and Azuara-Blanco, A. (2004) Cannabinoids and glaucoma. Br. J. Ophthalmol., 88: 708–713.

Tsuboi, K., Sun, Y.X., Okamoto, Y., Araki, N., Tonai, T. and Ueda, N.J. (2005) Molecular characterization of N-acyletha- nolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. Biol. Chem., 280(12): 11082–11092.

Twitchell, W., Brown, S. and Mackie, K. (1997) Cannabinoid inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol., 78: 43–50.

van der Stelt, M. and Di Marzo, V. (2005) Cannabinoid receptors and their role in neuroprotection. Neuromolecular Med., 7(1–2): 37–50.

Walter, L. and Stella, N. (2004) Cannabinoids and neuroinflammation. Br. J. Pharmacol., 141: 775–785.

Wang, L., Fortune, B., Cull, G., Dong, J. and Cioffi, G.A. (2006) Endothelin B receptor in human glaucoma and experimentally induced optic nerve damage. Arch. Ophthalmol., 124(5): 717–724.

Wei, B.Q., Mikkelsen, T.S., McKinney, M.K., Lander, E.S. and Cravatt, B.F. (2006) A second fatty acid amide hydrolase with variable distribution among placental mammals. J. Biol. Chem., 281(48): 36569–36578.

Weinreb, R.N. and Khaw, P.T. (2004) Primary open-angle glaucoma. Lancet, 363: 1711–1720.

Weinreb, R.N. and Lindsay, J.D. (2002) Metalloproteinase gene transcription in human ciliary muscle cells with latanoprost. Invest. Ophthalmol. Vis. Sci., 43: 716–722.

Yazulla, S. and Studholme, K.M. (2004) Vanilloid receptor like 1 (VRL1) immunoreactivity in mammalian retina: colocalization with somatostatin and purinergic P2 1 receptors. J. Comp. Neurol., 474(3): 407–418.