Post-ischemic brain damage: The endocannabinoid system in the mechanisms of neuronal death

FEBS Journal

Volumn 276, Issue 1, 2009, Pages 2-12

  Pellegrini Giampietro, Domenico E ^a   Mannaioni, Guido ^a   Bagetta, Giacinto ^b  

^a UNIVERSITY OF FLORENCE   (Italy)

^b UNIVERSITY OF CALABRIA   (Italy)

Author keywords

2 arachidonoylglycerol; Ananadamide; Cannabinoids; CB receptors; Cerebral ischemia; Endocannabinoids; Neuroprotection; Neurotoxicity; Oxygen glucose deprivation; Stroke

Indexed keywords

CANNABINOID; CANNABINOID RECEPTOR; ENDOCANNABINOID;

BRAIN ISCHEMIA; NEUROPROTECTION; NEUROTOXICITY; NEUROTRANSMISSION; PRIORITY JOURNAL; SHORT SURVEY; STROKE;

ANIMALS; BRAIN INJURIES; BRAIN ISCHEMIA; CELL DEATH; DISEASE MODELS, ANIMAL; ENDOCANNABINOIDS; HUMANS; ISCHEMIC ATTACK, TRANSIENT; ISOENZYMES; NEURONS; NITRIC OXIDE SYNTHASE; PIPERIDINES; PYRAZOLES;

EID: 57649213243     PISSN: 1742464X     EISSN: 17424658     Source Type: Journal    
DOI: 10.1111/j.1742-4658.2008.06765.x     Document Type: Short Survey

References (105)

1. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxid/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 92, 7162 7166.
2. Gladstone DJ, Black SE Hakim AM (2002) Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33, 2123 2136.
3. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener H, Ashwood T, Wasiewski WW Emeribe U (2007) NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 357, 562 571.
4. Bliss TVP Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31 39.
5. Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT Sesma MA (1991) NMDA antagonist neurotoxicity: mechanism and prevention. Science 254, 1515 1518.
6. Grotta J (2002) Neuroprotection is unlikely to be effective in humans using current trial designs. Stroke 33, 306 307.
7. Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4, 873 884.
8. Di Marzo V (2008) Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 7, 438 455.
9. Di Marzo V Petrosino S (2007) Endocannabinoids and the regulation of their levels in health and disease. Curr Opin Lipidol 18, 129 140.
10. 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.
11. Munro S, Thomas KL Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61 65.
12. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, Decosta BR Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87, 1932 1936.
13. Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L Leon A (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.
14. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS et al. (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310, 329 332.
15. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946 1949.
16. Mechoulam R, Benshabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR et al. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50, 83 90.
17. Stella N, Schweitzer P Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773 778.
18. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A Waku K (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215, 89 97.
19. Schlicker E Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22, 565 572.
20. Mackie K Hille B (1992) Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci USA 89, 3825 3829.
21. Daniel H Crepel F (2001) Control of Ca(2+) influx by cannabinoid and metabotropic glutamate receptors in rat cerebellar cortex requires K(+) channels. J Physiol 537, 793 800.
22. Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC Piomelli D (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686 691.
23. McKinney MK Cravatt BF (2005) Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 74, 411 432.
24. Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S Piomelli D (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99, 10819 10824.
25. Scallet AC (1991) Neurotoxicology of cannabis and THC: a review of chronic exposure studies in animals. Pharmacol Biochem Behav 40, 671 676.
26. Hampson AJ, Grimaldi M, Axelrod J Wink D (1998) Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95, 8268 8273.
27. Shen M, Piser TM, Seybold VS Thayer SA (1996) Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci 16, 4322 4334.
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.
29. Jin KL, Mao XO, Goldsmith PC Greenberg DA (2000) CB1 cannabinoid receptor induction in experimental stroke. Ann Neurol 48, 257 261.
30. Louw DF, Yang FW Sutherland GR (2000) The effect of delta-9- tetrahydrocannabinol on forebrain ischemia in rat. Brain Res 857, 183 187.
31. Braida D, Pozzi M Sala M (2000) CP 55,940 protects against ischemia-induced electroencephalographic flattening and hyperlocomotion in Mongolian gerbils. Neurosci Lett 296, 69 72.
32. Mauler F, Hinz V, Augstein KH, Fassbender M Horvath E (2003) Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271. Brain Res 989, 99 111.
33. Leker RR, Gai N, Mechoulam R Ovadia H (2003) Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210. Stroke 34, 2000 2006.
34. Hayakawa K, Mishima K, Abe K, Hasebe N, Takamatsu F, Yasuda H, Ikeda T, Inui K, Egashira N, Iwasaki K et al. (2004) Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism. NeuroReport 15, 2381 2385.
35. 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.
36. Sinor AD, Irvin SM Greenberg DA (2000) Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosci Lett 278, 157 160.
37. Melis M, Pillolla G, Bisogno T, Minassi A, Petrosino S, Perra S, Muntoni AL, Lutz B, Gessa GL, Marsicano G et al. (2006) Protective activation of the endocannabinoid system during ischemia in dopamine neurons. Neurobiol Dis 24, 15 27.
38. 9- tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors. Br J Pharmacol 152, 1301 1311.
39. Degn M, Lambertsen KL, Petersen G, Meldgaard M, Artmann A, Clausen BH, Hansen SH, Finsen B, Hansen HS Lund TM (2007) Changes in brain levels of N-acylethanolamines and 2-arachidonoylglycerol in focal cerebral ischemia in mice. J Neurochem 103, 1907 1916.
40. Ashton JC, Rahman RM, Nair SM, Sutherland BA, Glass M Appleton I (2007) Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett 412, 114 117.
41. Zhang M, Martin BR, Adler MW, Razdan RK, Jallo JI Tuma RF (2007) Cannabinoid CB(2) receptor activation decreases cerebral infarction in a mouse focal ischemia/reperfusion model. J Cereb Blood Flow Metab 27, 1387 1396.
42. Fernandez-Lopez D, Martinez-Orgado J, Nunez E, Romero J, Lorenzo P, Moro MA Lizasoain I (2006) Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res 60, 169 173.
43. Cernak I, Vink R, Natale J, Stoica B, Lea PM, Movsesyan V, Ahmed F, Knoblach SM, Fricke ST Faden AI (2004) The "dark side" of endocannabinoids: a neurotoxic role for anandamide. J Cereb Blood Flow Metab 24, 564 578.
44. 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.
45. Amantea D, Spagnuolo P, Bari M, Fezza F, Mazzei C, Tassorelli C, Morrone LA, Corasaniti MT, Maccarrone M 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, 4464 4775.
46. 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.
47. Sommer C, Schomacher M, Berger C, Kuhnert K, Muller HD, Schwab S Schabitz WR (2006) Neuroprotective cannabinoid receptor antagonist SR141716A prevents downregulation of excitotoxic NMDA receptors in the ischemic penumbra. Acta Neuropathol 112, 277 286.
48. Pegorini S, Zani A, Braida D, Guerini-Rocco C Sala M (2006) Vanilloid VR1 receptor is involved in rimonabant-induced neuroprotection. Br J Pharmacol 147, 552 559.
49. Starowicz K, Cristino L Di Marzo V (2008) TRPV1 receptors in the central nervous system: potential for previously unforeseen therapeutic applications. Curr Pharm Des 14, 42 54.
50. Pegorini S, Braida D, Verzoni C, Guerini-Rocco C, Consalez GG, Croci L Sala M (2005) Capsaicin exhibits neuroprotective effects in a model of transient global cerebral ischemia in Mongolian gerbils. Br J Pharmacol 144, 727 735.
51. Veldhuis WB, van der Stelt M, Wadman MW, van Zadelhoff G, Maccarrone M, Fezza F, Veldink GA, Vliegenthart JFG, Bar PR, Nicolay K 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 23, 4127 4133.
52. Youssef FF, Hormuzdi SG, Irving AJ Frenguelli BG (2007) Cannabinoid modulation of neuronal function after oxygen/glucose deprivation in area CA1 of the rat hippocampus. Neuropharmacology 52, 1327 1335.
53. Zhang M, Martin BR, Adler MW, Razdan RK, Ganea D Tuma RF (2008) Modulation of the balance between cannabinoid CB(1) and CB(2) receptor activation during cerebral ischemic/reperfusion injury. Neuroscience 152, 753 760.
54. 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.
55. Pacher P Hasko G (2008) Endocannabinoids and cannabinoid receptors in ischaemia-reperfusion injury and preconditioning. Br J Pharmacol 153, 252 262.
56. Guzman M (2003) Neurons on cannabinoids: dead or alive? Br J Pharmacol 140, 439 440.
57. van der Stelt M Di Marzo V (2005) Cannabinoid receptors and their role in neuroprotection. Neuromolecular Med 7, 37 50.
58. Freund TF, Katona I Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83, 1017 1066.
59. Gerdeman G Lovinger DM (2001) CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol 85, 468 471.
60. Galante M Diana MA (2004) Group I metabotropic glutamate receptors inhibit GABA release at interneuron-Purkinje cell synapses through endocannabinoid production. J Neurosci 24, 4865 4874.
61. Nemeth B, Ledent C, Freund TF Hajos N (2008) CB1 receptor-dependent and -independent inhibition of excitatory postsynaptic currents in the hippocampus by WIN 55,212-2. Neuropharmacology 54, 51 57.
62. Domenici MR, Azad SC, Marsicano G, Schierloh A, Wotjak CT, Dodt HU, Zieglgansberger W, Lutz B Rammes G (2006) Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission. J Neurosci 26, 5794 5799.
63. Hajos N, Katona I, Naiem SS, Mackie K, Ledent C, Mody I Freund TF (2000) Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci 12, 3239 3249.
64. Katona I, Sperlagh B, Sik A, Kafalvi A, Vizi ES, Mackie K Freund TF (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19, 4544 4558.
65. Ohno-Shosaku T, Maejima T Kano M (2001) Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729 738.
66. Wilson RI Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588 592.
67. Kreitzer AC Regehr WG (2001) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29, 717 727.
68. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ 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.
69. Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F Freund TF (2004) Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 20, 441 458.
70. Alger BE, Pitler TA, Wagner JJ, Martin LA, Morishita W, Kirov SA Lenz RA (1996) Retrograde signalling in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells. J Physiol 496, 197 209.
71. Kawamura Y, Fukaya M, Maejima T, Yoshida T, Miura E, Watanabe M, Ohno-Shosaku T Kano M (2006) The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci 26, 2991 3001.
72. Hoffman AF Lupica CR (2000) Mechanisms of cannabinoid inhibition of GABA(A) synaptic transmission in the hippocampus. J Neurosci 20, 2470 2479.
73. Chevaleyre V Castillo PE (2003) Heterosynaptic LTD of hippocampal GABAergic synapses. A novel role of endocannabinoids in regulating excitability. Neuron 38, 461 472.
74. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M et al. (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84 88.
75. Monory K, Massa F, Egertova M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M et al. (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455 466.
76. Chen K, Ratzliff A, Hilgenberg L, Gulyas A, Freund TF, Smith M, Dinh TP, Piomelli D, Mackie K Soltesz I (2003) Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 39, 599 611.
77. Chen K, Neu A, Howard AL, Foldy C, Echegoyen J, Hilgenberg L, Smith M, Mackie K Soltesz I (2007) Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures. J Neurosci 27, 46 58.
78. Navarrete M Araque A (2008) Endocannabinoids mediate neuron-astrocyte communication. Neuron 57, 883 893.
79. Gebremedhin D, Lange AR, Campbell WB, Hillard CJ Harder DR (1999) Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol 276, H2085 H2093.
80. Wagner JA, Jarai Z, Batkai S Kunos G (2001) Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB1 receptors. Eur J Pharmacol 423, 203 210.
81. Hillard CJ (2000) Endocannabinoids and vascular function. J Pharmacol Exp Ther 294, 27 32.
82. Mathew RJ, Wilson WH Davis R (2003) Postural syncope after marijuana: a transcranial Doppler study of the hemodynamics. Pharmacol Biochem Behav 75, 309 318.
83. MacGregor DG, Carswell HVO, Graham DI, McCulloch J Macrae IM (2000) Impaired cerebral autoregulation 24 h after induction of transient unilateral focal ischaemia in the rat. Eur J Neurosci 12, 58 66.
84. Golech SA, McCarron RM, Chen Y, Bembry J, Lenz F, Mechoulam R, Shohami E Spatz M (2004) Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res Mol Brain Res 132, 87 92.
85. McCollum L, Howlett AC Mukhopadhyay S (2007) Anandamide-mediated CB1/CB2 cannabinoid receptor-independent nitric oxide production in rabbit aortic endothelial cells. J Pharmacol Exp Ther 321, 930 937.
86. Ellis EF, Moore SF Willoughby KA (1995) Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin. Am J Physiol 269, H1859 H1864.
87. Poblete IM, Orliac ML, Briones R, Adler-Graschinsky E Huidobro-Toro JP (2005) Anandamide elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed. J Physiol 568, 539 551.
88. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452 457.
89. Rawls SM, Cabassa J, Geller EB Adler MW (2002) CB1 receptors in the preoptic anterior hypothalamus regulate win 55212-2 [(4,5-dihydro-2-methyl-4(4- morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij] quinolin-6-one]-induced hypothermia. J Pharmacol Exp Ther 301, 963 968.
90. Chan GCK, Hinds TR, Impey S Storm DR (1998) Hippocampal neurotoxicity of Delta(9)-tetrahydrocannabinol. J Neurosci 18, 5322 5332.
91. Gomez del Pulgar T, Velasco G Guzman M (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem J 347, 369 373.
92. Ozaita A, Puighermanal E Maldonado R (2007) Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain. J Neurochem 102, 1105 1114.
93. Molina-Holgado E, Vela JM, Arevalo-Martin A, Almazan G, Molina-Holgado F, Borrell J Guaza C (2002) Cannabinoids promote oligodendrocyte progenitor survival: Involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci 22, 9742 9753.
94. Molina-Holgado F, Pinteaux E, Heenan L, Moore JD, Rothwell NJ Gibson RM (2005) Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase/AKT signaling. Mol Cell Neurosci 28, 189 194.
95. 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.
96. Chen YQ Buck J (2000) Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism. J Pharmacol Exp Ther 293, 807 812.
97. 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.
98. Berdyshev EV, Schmid PC, Krebsbach RJ, Hillard CJ, Huang CS, Chen NY, Dong ZG Schmid HHO (2001) Cannabinoid-receptor-independent cell signalling by N-acylethanolamines. Biochem J 360, 67 75.
99. Maccarrone M, Lorenzon T, Bari M, Melino G 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, 31938 31945.
100. Grant ER, Dubin AE, Zhang SP, Zivin RA 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.
101. Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B Mackie K (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci USA 105, 2699 2704.
102. Bisogno T Di Marzo V (2008) The role of the endocannabinoid system in Alzheimer's disease: facts and hypotheses. Curr Pharm Des 14, 2299 3305.
103. Kim SR, Chung YC, Chung ES, Park KW, Won SY, Bok E, Park ES Jin BK (2007) Roles of transient receptor potential vanilloid subtype 1 and cannabinoid type 1 receptors in the brain: neuroprotection versus neurotoxicity. Mol Neurobiol 35, 245 254.
104. Bahr BA, Karanian DA, Makanji SS Makriyannis A (2006) Targeting the endocannabinoid system in treating brain disorders. Expert Opin Investig Drugs 15, 351 365.
105. 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.