Molecular Targets of Cannabidiol in Neurological Disorders

Neurotherapeutics

Volumn 12, Issue 4, 2015, Pages 699-730

  Ibeas Bih, Clementino ^a   Chen, Tong ^a   Nunn, Alistair V W ^b   Bazelot, Michaël ^a,c   Dallas, Mark ^a   Whalley, Benjamin J ^a  

^a UNIVERSITY OF READING   (United Kingdom)

^b Broadmind Science Ltd   (United Kingdom)

^c Porton Down Science Park   (United Kingdom)

Author keywords

Cannabidiol; cannabinoid; mechanism of action; neurological disorders; pharmacology

Indexed keywords

ADENOSINE; ADENOSINE TRIPHOSPHATASE (MAGNESIUM); ANANDAMIDE; CANNABIDIOL; CANNABINOID RECEPTOR; CERAMIDE; CYTOCHROME P450; ENDOCANNABINOID; G PROTEIN COUPLED RECEPTOR; GLYCINE RECEPTOR; LIPOXYGENASE; MULTIDRUG RESISTANCE PROTEIN; NEUROTRANSMITTER TRANSPORTER; NICOTINIC RECEPTOR; OPIATE RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PROSTAGLANDIN SYNTHASE; SEROTONIN RECEPTOR; TRANSIENT RECEPTOR POTENTIAL CHANNEL; VOLTAGE GATED CALCIUM CHANNEL; VOLTAGE GATED SODIUM CHANNEL; CANNABINOID; CELL SURFACE RECEPTOR;

ADDICTION; CHOLESTEROL METABOLISM; DRUG EFFECT; DRUG TARGETING; EPILEPSY; HUMAN; MOTOR DYSFUNCTION; MULTIDRUG RESISTANCE; NERVE DEGENERATION; NEUROLOGIC DISEASE; NONHUMAN; PAIN; PRIORITY JOURNAL; PSYCHOSIS; REVIEW; ANIMAL; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; NERVOUS SYSTEM DISEASES;

ANIMALS; CANNABINOIDS; ENDOCANNABINOIDS; GENE EXPRESSION REGULATION; HUMANS; NERVOUS SYSTEM DISEASES; RECEPTORS, CELL SURFACE;

EID: 84973926538     PISSN: 19337213     EISSN: 18787479     Source Type: Journal    
DOI: 10.1007/s13311-015-0377-3     Document Type: Review

References (290)

1. Brunner TF. Marijuana in ancient Greece and Rome? The literary evidence. Bull Hist Med 1973;47:344-355.
2. Dark P. The environment of Britain in the first millennium AD. UK: Bloomsbury Academic Press, 2000.
3. Li H-L. An archaeological and historical account of cannabis in China. Econ Bot 1973;28:437-448.
4. Manniche L. An ancient Egyptian herbal. British Museum Press.
5. Mathre ML. Cannabis in medical practice: a legal, historical and pharmacological overview of the therapeutic use of marijuana. McFarland & Co Inc., Jefferson, NC. USA, 1997.
6. Mikuriya TH. Marijuana in medicine: past, present and future. Calif Med 1969;110:34-40.
7. Morningstar PJ. Thandai and chilam: traditional Hindu beliefs about the proper uses of Cannabis. J Psychoactive Drugs 1985;17:141-165.
8. Pollington S. Leechcraft: early English charms, plant lore, and healing. Anglo-Saxon Books. UK, 2000.
9. Touw M. The religious and medicinal uses of Cannabis in China, India and Tibet. J Psychoactive Drugs 1981;13:23-34.
10. Mecha M, Feliú A, Iñigo PM, Mestre L, Carrillo-Salinas FJ, Guaza C. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis 2013;59:141-150.
11. Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain 2014;18:999-1012.
12. Shrivastava A, Kuzontkoski PM, Groopman JE, Prasad A. Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther 2011;10:1161-1172.
13. Pertwee R. Handbook of cannabis. Oxford University Press.
14. Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav 2013;29:574-577.
15. GW Pharma. GW Pharmaceuticals provides update on Epidiolex® program in treatment-resistant childhood epilepsies. Available at: http://www.gwpharm.com/GW%20Pharmaceuticals%20Provides%20Update%20on%20Epidiolex%20Program%20in%20Treatment-Resistant%20Childhood%20Epilepsies.aspx. Accessed August 4, 2015.
16. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 2015;172:737-753.
17. 9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl) 2012;219:859-873.
18. Ramer R, Heinemann K, Merkord J, et al. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther 2013;12:69-82.
19. Bisogno T, Hanus L, De Petrocellis L, et al. 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 2001;134:845-852.
20. Ryberg E, Larsson N, Sjögren S, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007;152:1092-1101.
21. Ahrens J, Demir R, Leuwer M, et al. The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology 2009;83:217-222.
22. Xiong W, Cui T, Cheng K, et al. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med 2012;209:1121-1134.
23. McHugh D. GPR18 in microglia: implications for the CNS and endocannabinoid system signalling. Br J Pharmacol 2012;167:1575-1582.
24. Whyte LS, Ryberg E, Sims NA, et al. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A 2009;106:16511-16516.
25. Li K, Fichna J, Schicho R, et al. A role for O-1602 and G protein-coupled receptor GPR55 in the control of colonic motility in mice. Neuropharmacology 2013;71:255-263.
26. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 2005;30:1037-1043.
27. Mahgoub M, Keun-Hang SY, Sydorenko V, et al. Effects of cannabidiol on the function of α7-nicotinic acetylcholine receptors. Eur J Pharmacol 2013;720:310-319.
28. Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn. Schmiedebergs Arch Pharmacol 2006;372:354-361.
29. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 2008;153:199-215.
30. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 2007;150:613-623.
31. Castillo A, Tolón MR, Fernández-Ruiz J, Romero J, Martinez-Orgado J. The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis 2010;37:434-440.
32. Járai Z, Wagner JA, Varga K, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A 1999;96:14136-14141.
33. Schmuhl E, Ramer R, Salamon A, Peters K, Hinz B. Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK. Biochem Pharmacol 2014;87:489-501.
34. Yang J-N, Chen J-F, Fredholm BB. Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. Am J Physiol Heart Circ Physiol 2009;296:H1141-H1149.
35. Elmenhorst D, Meyer PT, Winz OH, et al. Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study. J. Neurosci. Off J Soc Neurosci 2007;27:2410-2415.
36. Gonca E, Darıcı F. The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors. J Cardiovasc Pharmacol Ther 2015;20:76-83.
37. Liou GI, Auchampach JA, Hillard CJ, et al. Mediation of cannabidiol anti-inflammation in the retina by equilibrative nucleoside transporter and A2A adenosine receptor. Invest Ophthalmol Vis Sci 2008;49:5526-5531.
38. Sagredo O, Ramos JA, Decio A, Mechoulam R, Fernández-Ruiz J. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. Eur J Neurosci 2007;26:843-851.
39. Lynch JW. Molecular structure and function of the glycine receptor chloride channel. Physiol Rev 2004;84:1051-1095.
40. Xiong W, Chen S-R, He L, et al. Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease. Nat Neurosci 2014;17:232-239.
41. Madar I, Lesser RP, Krauss G, et al. Imaging of delta- and mu-opioid receptors in temporal lobe epilepsy by positron emission tomography. Ann Neurol 1997;41:358-367.
42. Resstel LBM, Tavares RF, Lisboa SFS, Joca SRL, Corrêa FMA, Guimarães FS. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 2009;156:181-188.
43. Soares V de P, Campos AC, Bortoli VC de, Zangrossi H Jr, Guimarães FS, Zuardi AW. Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors. Behav Brain Res 2010;213:225-229.
44. Yang K-H, Galadari S, Isaev D, Petroianu G, Shippenberg TS, Oz M. The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J Pharmacol Exp Ther 2010;333:547-554.
45. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SRL. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 2010;159:122-128.
46. Saigal N, Bajwa AK, Faheem SS, et al. Evaluation of serotonin 5-HT1A receptors in rodent models using [18F]Mefway PET. Synapse 2013;67:596-608.
47. Austgen JR, Kline DD. Endocannabinoids blunt the augmentation of synaptic transmission by serotonin 2A receptors in the nucleus tractus solitarii (nTS). Brain Res 2013;1537:27-36.
48. Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE. WAY-100635 is a potent dopamine D4 receptor agonist. Psychopharmacology (Berl) 2006;188:244-251.
49. Alves FHF, Crestani CC, Gomes FV, Guimarães FS, Correa FMA, Resstel LBM. Cannabidiol injected into the bed nucleus of the stria terminalis modulates baroreflex activity through 5-HT1A receptors. Pharmacol Res 2010;62:228-236.
50. Gomes FV, Alves FHF, Guimarães FS, Correa FMA, Resstel LBM, Crestani CC. Cannabidiol administration into the bed nucleus of the stria terminalis alters cardiovascular responses induced by acute restraint stress through 5-HT1A receptor. Eur. Neuropsychopharmacol 2013;23:1096-1104.
51. Sylantyev S, Jensen TP, Ross RA, Rusakov DA. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci U S A 2013;110:5193-5198.
52. Baker D, Pryce G, Davies WL, Hiley CR. In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci 2006;27:1-4.
53. Oka S, Nakajima K, Yamashita A, Kishimoto S, Sugiura T. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 2007;362:928-934.
54. O’Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA. Time-dependent vascular actions of cannabidiol in the rat aorta. Eur J Pharmacol 2009;612:61-68.
55. Usami N, Yamamoto I, Watanabe K. Generation of reactive oxygen species during mouse hepatic microsomal metabolism of cannabidiol and cannabidiol hydroxy-quinone. Life Sci 2008;83:717-724.
56. Zhou S-F, Liu J-P, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009;41:89-295.
57. Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet 2013;28:332-338.
58. Booth Depaz IM, Toselli F, Wilce PA, Gillam EMJ. Differential expression of cytochrome P450 enzymes from the CYP2C subfamily in the human brain. Drug Metab Dispos Biol Fate Chem 2015;43:353-357.
59. Wu M, Chen S, Wu X. Differences in cytochrome P450 2C19 (CYP2C19) expression in adjacent normal and tumor tissues in Chinese cancer patients. Med Sci Monit 2006;12:BR174-BR178.
60. Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos 2011;39:2049-2056.
61. Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet 2012;27:294-300.
62. Yamaori S, Kushihara M, Yamamoto I, Watanabe K. Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochem Pharmacol 2010;79:1691-1698.
63. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci 2011;88:730-736.
64. Cornicelli JA, Gilman SR, Krom BA, Kottke BA. Cannabinoids impair the formation of cholesteryl ester in cultured human cells. Arteriosclerosis 1981;1:449-454.
65. Koch M, Dehghani F, Habazettl I, Schomerus C, Korf H-W. Cannabinoids attenuate norepinephrine-induced melatonin biosynthesis in the rat pineal gland by reducing arylalkylamine N-acetyltransferase activity without involvement of cannabinoid receptors. J Neurochem 2006;98:267-278.
66. Fišar Z, Singh N, Hroudová J. Cannabinoid-induced changes in respiration of brain mitochondria. Toxicol Lett 2014;231:62-71.
67. Valvassori SS, Bavaresco DV, Scaini G, et al. Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain. Rev Bras Psiquiatr 2013;35:380-386.
68. Massi P, Valenti M, Vaccani A, et al. 5-Lipoxygenase and anandamide hydrolase (FAAH) mediate the antitumor activity of cannabidiol, a non-psychoactive cannabinoid. J Neurochem 2008;104:1091-1100.
69. Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull 2011;34:774-778.
70. Yamaori S, Okushima Y, Masuda K, et al. Structural requirements for potent direct inhibition of human cytochrome P450 1A1 by cannabidiol: role of pentylresorcinol moiety. Biol Pharm Bull 2013;36:1197-1203.
71. De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 2011;163:1479-1494.
72. Jenny M, Santer E, Pirich E, Schennach H, Fuchs D. Delta9-tetrahydrocannabinol and cannabidiol modulate mitogen-induced tryptophan degradation and neopterin formation in peripheral blood mononuclear cells in vitro. J Neuroimmunol 2009;207:75-82.
73. Takeda S, Usami N, Yamamoto I, Watanabe K. Cannabidiol-2’,6’-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor. Drug Metab Dispos Biol Fate Chem 2009;37:1733-1737.
74. Evans AT, Formukong E, Evans FJ. Activation of phospholipase A2 by cannabinoids. Lack of correlation with CNS effects. FEBS Lett 1987;211:119-122.
75. Watanabe K, Motoya E, Matsuzawa N, et al. Marijuana extracts possess the effects like the endocrine disrupting chemicals. Toxicology 2005;206:471-478.
76. Burstein S, Hunter SA, Renzulli L. Stimulation of sphingomyelin hydrolysis by cannabidiol in fibroblasts from a Niemann-Pick patient. Biochem Biophys Res Commun 1984;121:168-173.
77. Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci 2011;89:165-170.
78. Bryan HK, Olayanju A, Goldring CE, Park BK. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem. Pharmacol 2013;85:705-717.
79. Juknat A, Pietr M, Kozela E, et al. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells. PloS One 2013;8:e61462.
80. Bock J, Szabó I, Gamper N, Adams C, Gulbins E. Ceramide inhibits the potassium channel Kv1.3 by the formation of membrane platforms. Biochem. Biophys Res Commun 2003;305:890-897.
81. Cremesti AE, Goni FM, Kolesnick R. Role of sphingomyelinase and ceramide in modulating rafts: do biophysical properties determine biologic outcome? FEBS Lett 2002;531:47-53.
82. Maziere JC, Maziere C, Mora L, Routier JD, Polonovski J. In situ degradation of sphingomyelin by cultured normal fibroblasts and fibroblasts from patients with Niemann-Pick disease type A and C. Biochem Biophys Res Commun 1982;108:1101-1106.
83. Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther 2004;308:838-845.
84. Rimmerman N, Ben-Hail D, Porat Z, et al. Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death. Cell Death Dis 2013;4:e949.
85. Shoshan-Barmatz V, Mizrachi D. VDAC1: from structure to cancer therapy. Mol Cell Oncol 2012;2:164.
86. Singh N, Hroudová J, Fišar Z. Cannabinoid-induced changes in the activity of electron transport chain complexes of brain mitochondria. J Mol Neurosci 2015 Mar 29 [Epub ahead of print].
87. Escames G, León J, López LC, Acuña-Castroviejo D. Mechanisms of N-methyl-D-aspartate receptor inhibition by melatonin in the rat striatum. J Neuroendocrinol 2004;16:929-935.
88. Ozkanlar S, Kara A, Sengul E, Simsek N, Karadeniz A, Kurt N. Melatonin modulates the immune system response and inflammation in diabetic rats experimentally-induced by alloxan. Horm Metab Res 2015 May 4 [Epub ahead of print].
89. Ramis MR, Esteban S, Miralles A, Tan D-X, Reiter RJ. Protective effects of melatonin and mitochondria-targeted antioxidants against oxidative stress: a review. Curr Med Chem 2015 Jun 18 [Epub ahead of print].
90. Sun GY, Shelat PB, Jensen MB, He Y, Sun AY, Simonyi A. Phospholipases A2 and inflammatory responses in the central nervous system. Neuromolecular Med 2010;12:133-148.
91. Arriagada E, Cid H. Search for a “toxic site” in snake venom phospholipases A2. Arch Biol Med Exp 1989;22:97-105.
92. Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients 2010;2:355-374.
93. Wheal AJ, Cipriano M, Fowler CJ, Randall MD, O’Sullivan SE. Cannabidiol improves vasorelaxation in Zucker diabetic fatty rats through cyclooxygenase activation. J Pharmacol Exp Ther 2014;351:457-466.
94. Hoyo-Becerra C, Schlaak JF, Hermann DM. Insights from interferon-α-related depression for the pathogenesis of depression associated with inflammation. Brain Behav Immun 2014;42:222-231.
95. Ross HR, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J Biol Chem 2008;283:16124-16134.
96. Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM. TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci 2008;28:6231-6238.
97. De Petrocellis L, Vellani V, Schiano-Moriello A, et al. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 2008;325:1007-1015.
98. Iannotti FA, Hill CL, Leo A, et al. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 2014;5:1131-1141
99. Ligresti A, Moriello AS, Starowicz K, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 2006;318:1375-1387.
100. Nabissi M, Morelli MB, Santoni M, Santoni G. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 2013;34:48-57.
101. De Petrocellis L, Orlando P, Moriello AS, et al. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol 2012;204:255-266.
102. Billeter AT, Hellmann JL, Bhatnagar A, Polk HC. Transient receptor potential ion channels: powerful regulators of cell function. Ann Surg 2014;259:229-235.
103. Holland ML, Allen JD, Arnold JC. Interaction of plant cannabinoids with the multidrug transporter ABCC1 (MRP1). Eur J Pharmacol 2008;591:128-131.
104. Holland ML, Lau DTT, Allen JD, Arnold JC. The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids. Br J Pharmacol 2007;152:815-824.
105. Pandolfo P, Silveirinha V, Santos-Rodrigues A dos, et al. Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum. Eur J Pharmacol 2011;655:38-45.
106. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 2006;103:7895-7900.
107. Gilbert JC, Pertwee RG, Wyllie MG. Effects of delta9-tetrahydrocannabinol and cannabidiol on a Mg2+-ATPase of synaptic vesicles prepared from rat cerebral cortex. Br J Pharmacol 1977;59:599-601.
108. Coyle JT, and Snyder SHJ. Catecholamine uptake by synaptosomes in homogenates of rat brain: Stereospecificity in different areas. Pharmacol Exp Ther 1969;170:221.
109. Whittaker VP, Michaelson IA, Kirkland RJA. The separation of synaptic vesicles from nerve-ending particles ('synaptosomes'). Biochem J 1964;90:293-303.
110. Di Marzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 1994;372:686-691.
111. Morelli MB, Offidani M, Alesiani F, et al. The effects of cannabidiol and its synergism with bortezomib in multiple myeloma cell lines. A role for transient receptor potential vanilloid type-2. Int J Cancer 2014;134:2534-2546.
112. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N, Arbel N. VDAC, a multi-functional mitochondrial protein regulating cell life and death. Mol Aspects Med 2010;31:227-285.
113. Hill AJ, Jones NA, Smith I, et al. Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se. Neurosci Lett 2014;566:269-274.
114. Vandenberg RJ, Ryan RM. Mechanisms of glutamate transport. Physiol Rev 2013;93:1621-1657.
115. Banerjee SP, Snyder SH, Mechoulam R. Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes. J Pharmacol Exp Ther 1975;194:74-81.
116. Poddar MK, Dewey WL. Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes. J Pharmacol Exp Ther 1980;214:63-67.
117. Lindamood C 3rd, Colasanti BK. Effects of delta 9-tetrahydrocannabinol and cannabidiol on sodium-dependent high affinity choline uptake in the rat hippocampus. J Pharmacol Exp Ther 1980;213:216-221.
118. Rakhshan F, Day TA, Blakely RD, Barker EL. Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL-2H3 cells. J Pharmacol Exp Ther 2000;292:960-967.
119. Watanabe K, Kayano Y, Matsunaga T, Yamamoto I, Yoshimura H. Inhibition of anandamide amidase activity in mouse brain microsomes by cannabinoids. Biol Pharm Bull 1996;19:1109-1111.
120. Di Marzo V, Melck D, De Petrocellis L, Bisogno T. Cannabimimetic fatty acid derivatives in cancer and inflammation. Prostaglandins Other Lipid Mediat 2000;61:43-61.
121. Zhu H-J, Wang J-S, Markowitz JS, et al. Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J Pharmacol Exp Ther 2006;317:850-857.
122. Szemraj J, Sobolewska B, Gulczynska E, Wilczynski J, Zylinska L. Magnesium sulfate effect on erythrocyte membranes of asphyxiated newborns. Clin Biochem 2005;38:457-464.
123. Schmidt D, Schachter SC. Drug treatment of epilepsy in adults. BMJ 2014;348:g254.
124. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014;55:791-802.
125. Shu H-F, Yu S-X, Zhang C-Q, et al. Expression of TRPV1 in cortical lesions from patients with tuberous sclerosis complex and focal cortical dysplasia type IIb. Brain Dev 2013;35:252-260.
126. Rüden EL von, Jafari M, Bogdanovic RM, Wotjak CT, Potschka H. Analysis in conditional cannabinoid 1 receptor-knockout mice reveals neuronal subpopulation-specific effects on epileptogenesis in the kindling paradigm. Neurobiol Dis 2015;73:334-347.
127. Samineni VK, Premkumar LS, Faingold CL. Post-ictal analgesia in genetically epilepsy-prone rats is induced by audiogenic seizures and involves cannabinoid receptors in the periaqueductal gray. Brain Res 2011;1389:177-182.
128. Bhaskaran MD, Smith BN. Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy. PloS One 2010;5:e10683.
129. Chen C-Y, Li W, Qu K-P, Chen C-R. Piperine exerts anti-seizure effects via the TRPV1 receptor in mice. Eur J Pharmacol 2013;714:288-294.
130. Ghazizadeh V, Nazıroğlu M. Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats. Metab Brain Dis 2014;29:787-799.
131. Gonzalez-Reyes LE, Ladas TP, Chiang C-C, Durand DM. TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo. Exp Neurol 2013;250:321-332.
132. Manna SSS, Umathe SN. Involvement of transient receptor potential vanilloid type 1 channels in the pro-convulsant effect of anandamide in pentylenetetrazole-induced seizures. Epilepsy Res 2012;100:113-124.
133. Nazıroğlu M, Özkan FF, Hapil SR, Ghazizadeh V, Çiğ B. Epilepsy but not mobile phone frequency (900 MHz) induces apoptosis and calcium entry in hippocampus of epileptic rat: involvement of TRPV1 channels. J Membr Biol 2015;248:83-91.
134. Shirazi M, Izadi M, Amin M, Rezvani ME, Roohbakhsh A, Shamsizadeh A. Involvement of central TRPV1 receptors in pentylenetetrazole and amygdala-induced kindling in male rats. Neurol Sci 2014;35:1235-1241.
135. Kong W-L, Min J-W, Liu Y-L, Li J-X, He X-H, Peng B-W. Role of TRPV1 in susceptibility to PTZ-induced seizure following repeated hyperthermia challenges in neonatal mice. Epilepsy Behav 2014;31:276-280.
136. Hunt RF, Hortopan GA, Gillespie A, Baraban SC. A novel zebrafish model of hyperthermia-induced seizures reveals a role for TRPV4 channels and NMDA-type glutamate receptors. Exp Neurol 2012;237:199-206.
137. Lin Y-W, Hsieh C-L. Auricular electroacupuncture reduced inflammation-related epilepsy accompanied by altered TRPA1, pPKCα, pPKCε, and pERk1/2 signaling pathways in kainic acid-treated rats. Mediators Inflamm 2014;2014:493480.
138. Brinckmann A, Weiss C, Wilbert F, et al. Regionalized pathology correlates with augmentation of mtDNA copy numbers in a patient with myoclonic epilepsy with ragged-red fibers (MERRF-syndrome). PloS One 2010;5:e13513.
139. Jiang W, Du B, Chi Z, et al. Preliminary explorations of the role of mitochondrial proteins in refractory epilepsy: some findings from comparative proteomics. J Neurosci Res 2007;85:3160-3170.
140. Quintanilla RA, Utreras E, Cabezas-Opazo FA. Role of PPAR γ in the differentiation and function of neurons. PPAR Res 2014;2014:768594.
141. Lasoń W, Chlebicka M, Rejdak K. Research advances in basic mechanisms of seizures and antiepileptic drug action. Pharmacol Rep 2013;65:787-801.
142. Adams PJ, Snutch TP. Calcium channelopathies: voltage-gated calcium channels. Subcell Biochem 2007;45:215-251.
143. Gomora JC, Daud AN, Weiergräber M, Perez-Reyes E. Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Mol Pharmacol 2001;60:1121-1132.
144. Ceulemans B, Boel M, Leyssens K, et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 2012;53:1131-1139.
145. Theodore WH, Hasler G, Giovacchini G, et al. Reduced hippocampal 5HT1A PET receptor binding and depression in temporal lobe epilepsy. Epilepsia 2007;48:1526-1530.
146. Theodore WH, Wiggs EA, Martinez AR, et al. Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy. Epilepsia 2012;53:129-133.
147. Avila A, Nguyen L, Rigo J-M. Glycine receptors and brain development. Front Cell Neurosci 2013;7:184.
148. Harvey RJ, Carta E, Pearce BR, et al. A critical role for glycine transporters in hyperexcitability disorders. Front Mol Neurosci 2008;1:1.
149. Chu Sin Chung P, Kieffer BL. Delta opioid receptors in brain function and diseases. Pharmacol Ther 2013;140:112-120.
150. Snead OC. Opiate-induced seizures: a study of mu and delta specific mechanisms. Exp Neurol 1986;93:348-358.
151. Sagratella S, Scotti de Carolis A. In vivo and in vitro epileptogenic effects of the enkephalinergic system. Ann Ist Super Sanita 1993;29:413-418.
152. Saghazadeh A, Mastrangelo M, Rezaei N. Genetic background of febrile seizures. Rev Neurosci 2014;25:129-161.
153. Becchetti A, Aracri P, Meneghini S, Brusco S, Amadeo A. The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy. Front Physiol 2015;6:22.
154. Dias RB, Rombo DM, Ribeiro JA, Henley JM, Sebastião AM. Adenosine: setting the stage for plasticity. Trends Neurosci 2013;36:248-257.
155. Świąder MJ, Kotowski J, Łuszczki JJ. Modulation of adenosinergic system and its application for the treatment of epilepsy. Pharmacol Rep 2014;66:335-342.
156. Hedlund E, Gustafsson JA, Warner M. Cytochrome P450 in the brain; a review. Curr Drug Metab 2001;2:245-263.
157. Adibhatla RM, Hatcher JF. Altered lipid metabolism in brain injury and disorders. Subcell Biochem 2008;49:241-268.
158. Coomber B, O’Donoghue MF, Mason R. Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid. Synapse 2008;62:746-755.
159. Vilela LR, Medeiros DC, Rezende GHS, de Oliveira ACP, Moraes MFD, Moreira FA. Effects of cannabinoids and endocannabinoid hydrolysis inhibition on pentylenetetrazole-induced seizure and electroencephalographic activity in rats. Epilepsy Res 2013;104:195-202.
160. Villikka K, Kivistö KT, Mäenpää H, Joensuu H, Neuvonen PJ. Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors. Clin Pharmacol Ther 1999;66:589-593.
161. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 2015 Jun 26 [Epub ahead of print].
162. Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y. Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors. J Neurochem 2004;89:834-843.
163. Zoerner AA, Gutzki F-M, Batkai S, et al. Quantification of endocannabinoids in biological systems by chromatography and mass spectrometry: a comprehensive review from an analytical and biological perspective. Biochim Biophys Acta 2011;1811:706-723.
164. Dawbarn D, Harmar AJ, Pycock CJ. Intranigral injection of capsaicin enhances motor activity and depletes nigral 5-hydroxytryptamine but not substance P. Neuropharmacology 1981;20:341-346.
165. Hajós M, Engberg G, Nissbrandt H, Magnusson T, Carlsson A. Capsaicin-sensitive vasodilatatory mechanisms in the rat substantia nigra and striatum. J Neural Transm 1988;74:129-139.
166. Geisler S, Holmström KM, Skujat D, et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010;12:119-131.
167. Stone JM, Day F, Tsagaraki H, et al. Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume. Biol Psychiatry 2009;66:533-539.
168. Sramek JJ, Tansman M, Suri A, et al. Efficacy of buspirone in generalized anxiety disorder with coexisting mild depressive symptoms. J Clin Psychiatry 1996;57:287-291.
169. Bourin M, Nic Dhonnchadha BA. 5-HT2 receptors and anxiety. Drug Dev Res 2005;65:133-140.
170. Bush A, Busst CM, Clarke B, Barnes PJ. Effect of infused adenosine on cardiac output and systemic resistance in normal subjects. Br J Clin Pharmacol 1989;27:165-171.
171. Litvin Y, Phan A, Hill MN, Pfaff DW, McEwen BS. CB1 receptor signaling regulates social anxiety and memory. Genes Brain Behav 2013;12:479-489.
172. Mohajjel Nayebi A A, Sheidaei H. Buspirone improves haloperidol-induced Parkinson disease in mice through 5-HT1A receptors. Daru 2010;18:41-45.
173. Becker CM, Hermans-Borgmeyer I, Schmitt B, Betz H. The glycine receptor deficiency of the mutant mouse spastic: evidence for normal glycine receptor structure and localization. J Neurosci 1986;6:1358-1364.
174. Henry B, Fox SH, Crossman AR, Brotchie JM. Mu- and delta-opioid receptor antagonists reduce levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease. Exp Neurol 2001;171:139-146.
175. Patsopoulos NA, Ntzani EE, Zintzaras E, Ioannidis JPA. CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis. Pharmacogenet Genomics 2005;15:151-158.
176. Liévens JC, Woodman B, Mahal A, et al. Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 2001;8:807-821.
177. Kanyó B, Argyelán M, Dibó G, et al. [Imaging of dopamine transporter with Tc99m-Trodat-SPECT in movement disorders]. Ideggyogy Sz 2003;56:231-240 (in Hungarian).
178. de Lago E, Fernández-Ruiz J, Ortega-Gutiérrez S, et al. 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 2006;16:7-18.
179. Pamplona FA, Ferreira J, Lima OM de, et al. Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc Natl Acad Sci 2012;109:21134-21139.
180. Daigle TL, Kearn CS, Mackie K. Rapid CB1 cannabinoid receptor desensitization defines the time course of ERK1/2 MAP kinase signaling. Neuropharmacology 2008;54:36-44.
181. Aso E, Sánchez-Pla A, Vegas-Lozano E, Maldonado R, Ferrer I. Cannabis-based medicine reduces multiple pathological processes in AβPP/PS1 mice. J Alzheimers Dis 2015;43:977-991.
182. Cheng D, Spiro AS, Jenner AM, Garner B, Karl T. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J Alzheimers Dis 2014;42:1383-1396.
183. Calì T, Ottolini D, Brini M. Mitochondrial Ca2+ and neurodegeneration. Cell Calcium 2012;52:73-85.
184. Currais A. Ageing and inflammation – a central role for mitochondria in brain health and disease. Ageing Res Rev 2015;21:30-42.
185. Hsieh H-L, Yang C-M. Role of redox signaling in neuroinflammation and neurodegenerative diseases. Biomed Res Int 2013;2013:484613.
186. Sosa-Ortiz AL, Acosta-Castillo I, Prince MJ. Epidemiology of dementias and Alzheimer’s disease. Arch Med Res 2012;43:600-608.
187. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992;256:184-185.
188. Latta CH, Brothers HM, Wilcock DM. Neuroinflammation in Alzheimer’s disease; a source of heterogeneity and target for personalized therapy. Neuroscience 2014;pii:S0306-4522(14)00820-3.
189. Lozano D, Gonzales-Portillo GS, Acosta S, et al. Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat 2015;11:97-106.
190. Ruhoy IS, Saneto RP. The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet 2014;7:221-234.
191. Heneka MT, Carson MJ, Khoury J El, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015;14:388-405.
192. Di Iorio G, Lupi M, Sarchione F, et al. The endocannabinoid system: a putative role in neurodegenerative diseases. Int J High Risk Behav Addict 2013;2:100-106.
193. Maroof N, Pardon MC, Kendall DA. Endocannabinoid signalling in Alzheimer’s disease. Biochem Soc Trans 2013;41:1583-1587.
194. Elmes MW, Kaczocha M, Berger WT, et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 2015;290:8711-8721.
195. Xu Y, Yan J, Zhou P, et al. Neurotransmitter receptors and cognitive dysfunction in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 2012;97:1-13.
196. Magen I, Avraham Y, Ackerman Z, Vorobiev L, Mechoulam R, Berry EM. Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation. Br J Pharmacol 2010;159:950-957.
197. Pazos MR, Mohammed N, Lafuente H, et al. Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors. Neuropharmacology 2013;71:282-291.
198. Esposito G, Scuderi C, Valenza M, et al. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PloS One 2011;6:e28668.
199. Cho H-Y, Gladwell W, Wang X, et al. Nrf2-regulated PPAR{gamma} expression is critical to protection against acute lung injury in mice. Am J Respir Crit Care Med 2010;182:170-182.
200. Juknat A, Pietr M, Kozela E, et al. Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells. Br J Pharmacol 2012;165:2512-2528.
201. Lauckner JE, Jensen JB, Chen H-Y, Lu H-C, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A 2008;105:2699-2704.
202. Henstridge CM, Balenga NAB, Ford LA, Ross RA, Waldhoer M, Irving AJ. The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB J 2009;23:183-193.
203. Fric J, Zelante T, Wong AYW, Mertes A, Yu H-B, Ricciardi-Castagnoli P. NFAT control of innate immunity. Blood 2012;120:1380-1389.
204. Vashishta A, Habas A, Pruunsild P, Zheng J-J, Timmusk T, Hetman M. Nuclear factor of activated T-cells isoform c4 (NFATc4/NFAT3) as a mediator of antiapoptotic transcription in NMDA receptor-stimulated cortical neurons. J Neurosci 2009;29:15331-15340.
205. Wu H-Y, Hudry E, Hashimoto T, et al. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 2010;30:2636-2649.
206. Abdul HM, Sama MA, Furman JL, et al. Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci 2009;29:12957-12969.
207. Deutsch SI, Burket JA, Benson AD. Targeting the α7 nicotinic acetylcholine receptor to prevent progressive dementia and improve cognition in adults with Down’s syndrome. Prog Neuropsychopharmacol Biol Psychiatry 2014;54:131-139.
208. Lombardo S, Maskos U. Role of the nicotinic acetylcholine receptor in Alzheimer’s disease pathology and treatment. Neuropharmacology 2015;96(Pt B):255-262.
209. Vaysse PJ, Gardner EL, Zukin RS. Modulation of rat brain opioid receptors by cannabinoids. J Pharmacol Exp Ther 1987;241:534-539.
210. Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid receptor function. Curr Drug Targets 2012;13:230-246.
211. Hroudová J, Singh N, Fišar Z. Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer’s disease. Biomed Res Int 2014;175062.
212. Ristow M, Schmeisser K. Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response 2014;12:288-341.
213. Tapia PC. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: “Mitohormesis” for health and vitality. Med Hypotheses 2006;66:832-843.
214. Myint A-M, Kim Y-K. Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 2014;48:304-313.
215. Figueiredo-Pereira ME, Rockwell P, Schmidt-Glenewinkel T, Serrano P. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration. Front Mol Neurosci 2014;7:104.
216. Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta 2015;1851:469-484.
217. Pomponi MFL, Gambassi G, Pomponi M, Di Gioia A, Masullo C. Why docosahexaenoic acid and aspirin supplementation could be useful in women as a primary prevention therapy against Alzheimer’s disease? Ageing Res Rev 2011;10:124-131.
218. Hamelink C, Hampson A, Wink DA, Eiden LE, Eskay RL. Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. J Pharmacol Exp Ther 2005;314:780-788.
219. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 1998;95:8268-8273.
220. García-Arencibia M, González S, de Lago E, Ramos JA, Mechoulam R, Fernández-Ruiz J. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res 2007;1134:162-170.
221. Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997;236:313-322.
222. Mazur A, Lichti CF, Prather PL, et al. Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. Drug Metab Dispos Biol Fate Chem 2009;37:1496-1504.
223. Fernández-Ruiz J, Sagredo O, Pazos MR, et al. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol 2013;75:323-333.
224. Reddy PH. Is the mitochondrial outermembrane protein VDAC1 therapeutic target for Alzheimer’s disease? Biochim Biophys Acta 2013;1832:67-75.
225. Manczak M, Sheiko T, Craigen WJ, Reddy PH. Reduced VDAC1 protects against Alzheimer’s disease, mitochondria, and synaptic deficiencies. J Alzheimers Dis 2013;37:679-690.
226. Keinan N, Pahima H, Ben-Hail D, Shoshan-Barmatz V. The role of calcium in VDAC1 oligomerization and mitochondria-mediated apoptosis. Biochim Biophys Acta 2013;1833:1745-1754.
227. De Stefani D, Bononi A, Romagnoli A, et al. VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria. Cell Death Differ 2012;19:267-273.
228. Mato S, Victoria Sánchez-Gómez M, Matute C. Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes. Glia 2010;58:1739-1747.
229. Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B. Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 2009;29:2053-2063.
230. Ho KW, Ward NJ, Calkins DJ. TRPV1: a stress response protein in the central nervous system. Am J Neurodegener Dis 2012;1:1-14.
231. Luo Z, Ma L, Zhao Z, et al. TRPV1 activation improves exercise endurance and energy metabolism through PGC-1α upregulation in mice. Cell Res 2012;22:551-564.
232. Medvedeva YV, Kim M-S, Usachev YM. Mechanisms of prolonged presynaptic Ca2+ signaling and glutamate release induced by TRPV1 activation in rat sensory neurons. J Neurosci 2008;28:5295-5311.
233. Gellerich FN, Gizatullina Z, Gainutdinov T, et al. The control of brain mitochondrial energization by cytosolic calcium: the mitochondrial gas pedal. IUBMB Life 2013;65:180-190.
234. Gupta S, Sharma B. Pharmacological benefits of agomelatine and vanillin in experimental model of Huntington’s disease. Pharmacol Biochem Behav 2014;122:122-135.
235. Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA. Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 2011;1808:1380-1399.
236. Smathers RL, Petersen DR. The human fatty acid-binding protein family: evolutionary divergences and functions. Hum Genomics 2011;5:170-191.
237. Ohrfelt A, Andreasson U, Simon A, et al. Screening for new biomarkers for subcortical vascular dementia and Alzheimer’s disease. Dement Geriatr Cogn Disord Extra 2011;1:31-42.
238. Shioda N, Yabuki Y, Kobayashi Y, Onozato M, Owada Y, Fukunaga K. FABP3 protein promotes α-synuclein oligomerization associated with 1-methyl-1,2,3,6-tetrahydropiridine-induced neurotoxicity. J Biol Chem 2014;289:18957-18965.
239. Pahnke J, Fröhlich C, Krohn M, Schumacher T, Paarmann K. Impaired mitochondrial energy production and ABC transporter function-A crucial interconnection in dementing proteopathies of the brain. Mech Ageing Dev 2013;134:506-515.
240. Krohn M, Lange C, Hofrichter J, et al. Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest 2011;121:3924-3931.
241. Xiong H, Callaghan D, Jones A, et al. ABCG2 is upregulated in Alzheimer’s brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Abeta(1-40) peptides. J Neurosci 2009;29:5463-5475.
242. Martorana A, Koch G. Is dopamine involved in Alzheimer’s disease? Front Aging Neurosci 2014;6:252.
243. Caraci F, Battaglia G, Sortino MA, et al. Metabotropic glutamate receptors in neurodegeneration/neuroprotection: still a hot topic? Neurochem Int 2012;61:559-565.
244. Lund-Katz S, Phillips MC. High density lipoprotein structure-function and role in reverse cholesterol transport. Subcell Biochem 2010;51:183-227.
245. Poirier J, Miron J, Picard C, et al. Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer’s disease. Neurobiol Aging 2014;35(Suppl. 2):S3-S10.
246. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician 2008;11(2 Suppl.):S105–S120.
247. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999;83:389-400.
248. Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol 2004;143:247-250.
249. Costa B, Trovato AE, Comelli F, Giagnoni G, Colleoni M. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur J Pharmacol 2007;556:75-83.
250. Maione S, Piscitelli F, Gatta L, et al. Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. Br J Pharmacol 2011;162:584-596.
251. Ward SJ, Ramirez MD, Neelakantan H, Walker EA. Cannabidiol prevents the development of cold and mechanical allodynia in paclitaxel-treated female C57Bl6 mice. Anesth Analg 2011;113:947-950.
252. Ward SJ, McAllister SD, Kawamura R, Murase R, Neelakantan H, Walker EA. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT(1A) receptors without diminishing nervous system function or chemotherapy efficacy. Br J Pharmacol 2014;171:636-645.
253. Sałat K, Filipek B. Antinociceptive activity of transient receptor potential channel TRPV1, TRPA1, and TRPM8 antagonists in neurogenic and neuropathic pain models in mice. J Zhejiang Univ Sci B 2015;16:167-178.
254. Costa B, Siniscalco D, Trovato AE, et al. AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. Br J Pharmacol 2006;148:1022-1032.
255. Lehto SG, Weyer AD, Zhang M, et al. AMG2850, a potent and selective TRPM8 antagonist, is not effective in rat models of inflammatory mechanical hypersensitivity and neuropathic tactile allodynia. Naunyn Schmiedebergs Arch Pharmacol 2015;388:465-476.
256. Baddack U, Frahm S, Antolin-Fontes B, et al. Suppression of peripheral pain by blockade of Cav2.2 channels in nociceptors induces RANKL and impairs recovery from inflammatory arthritis. Arthritis Rheumatol 2015;67:1657-1667.
257. Jayamanne A, Jeong HJ, Schroeder CI, Lewis RJ, Christie MJ, Vaughan CW. Spinal actions of ω-conotoxins, CVID, MVIIA and related peptides in a rat neuropathic pain model. Br J Pharmacol 2013;170:245-254.
258. Gao X, Lu Q, Chou G, et al. Norisoboldine attenuates inflammatory pain via the adenosine A1 receptor. Eur J Pain 2014;18:939-948.
259. Li L, Hao JX, Fredholm BB, Schulte G, Wiesenfeld-Hallin Z, Xu XJ. Peripheral adenosine A2A receptors are involved in carrageenan-induced mechanical hyperalgesia in mice. Neuroscience 2010;170:923-928.
260. Fornal CA, Metzler CW, Gallegos RA, Veasey SC, McCreary AC, Jacobs BL. WAY-100635, a potent and selective 5-hydroxytryptamine1A antagonist, increases serotonergic neuronal activity in behaving cats: comparison with (S)-WAY-100135. J Pharmacol Exp Ther 1996;278:752-762.
261. Staton PC, Hatcher JP, Walker DJ, et al. The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. Pain 2008;139:225-236.
262. Terrando N, Yang T, Ryu JK, et al. Stimulation of the alpha 7 nicotinic acetylcholine receptor protects against neuroinflammation after tibia fracture and endotoxemia in mice. Mol Med 2015;20:667-675.
263. AlSharari SD, Freitas K, Damaj MI. Functional role of alpha7 nicotinic receptor in chronic neuropathic and inflammatory pain: Studies in transgenic mice. Biochem Pharmacol 2013;86:1201-1207.
264. Gong S, Liang Q, Zhu Q, et al. Nicotinic acetylcholine receptor α7 subunit is involved in the cobratoxin-induced antinociception in an animal model of neuropathic pain. Toxicon 2015;93:31-36.
265. Papke RL, Bagdas D, Kulkarni AR, et al. The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor. Neuropharmacology 2015;91:34-42.
266. Hasani R Al-, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 2011;115:1363-1381.
267. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain 2015;156:569-576.
268. Zahari Z, Ismail R. Influence of Cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics. Drug Metab Pharmacokinet 2014;29:29-43.
269. Campos AC, Guimarães FS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1517-1521.
270. Moussaieff A, Rimmerman N, Bregman T, et al. Incensole acetate, an incense component, elicits psychoactivity by activating TRPV3 channels in the brain. FASEB J 2008;22:3024-3034.
271. Uslaner JM, Smith SM, Huszar SL, et al. T-type calcium channel antagonism produces antipsychotic-like effects and reduces stimulant-induced glutamate release in the nucleus accumbens of rats. Neuropharmacology 2012;62:1413-1421.
272. Gangarossa G, Laffray S, Bourinet E, Valjent E. T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants. Front Behav Neurosci 2014;8:92.
273. Price DL, Bonhaus DW, McFarland K. Pimavanserin, a 5-HT2A receptor inverse agonist, reverses psychosis-like behaviors in a rodent model of Alzheimer’s disease. Behav Pharmacol 2012;23:426-433.
274. Zhang CG, Kim S-J. Taurine induces anti-anxiety by activating strychnine-sensitive glycine receptor in vivo. Ann Nutr Metab 2007;51:379-386.
275. Randall-Thompson JF, Pescatore KA, Unterwald EM. A role for delta opioid receptors in the central nucleus of the amygdala in anxiety-like behaviors. Psychopharmacology 2010;212:585-595.
276. Rahimi A, Hajizadeh Moghaddam A, Roohbakhsh A. Central administration of GPR55 receptor agonist and antagonist modulates anxiety-related behaviors in rats. Fundam Clin Pharmacol 2015;29:185-190.
277. Maximino C, Lima MG, Olivera KRM, Picanço-Diniz DLW, Herculano AM. Adenosine A1, but not A2, receptor blockade increases anxiety and arousal in Zebrafish. Basic Clin Pharmacol Toxicol 2011;109:203-207.
278. Shen H-Y, Singer P, Lytle N, et al. Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia. J Clin Invest 2012;122:2567-2577.
279. Müller N. COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr Opin Investig Drugs 2010;11:31-42.
280. Hill MN, Kumar SA, Filipski SB, et al. Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Mol Psychiatry 2013;18:1125-1135.
281. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2012;2:e94.
282. Stangherlin EC, Nogueira CW. Diphenyl ditelluride induces anxiogenic-like behavior in rats by reducing glutamate uptake. Biol Trace Elem Res 2014;158:392-398.
283. Morgan CJA, Das RK, Joye A, Curran HV, Kamboj SK. Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings. Addict Behav 2013;38:2433-2436.
284. Ren Y, Whittard J, Higuera-Matas A, Morris CV, Hurd YL. Cannabidiol, a nonpsychotropic component of cannabis, inhibits cue-induced heroin seeking and normalizes discrete mesolimbic neuronal disturbances. J Neurosci 2009;29:14764-14769.
285. Adamczyk P, Miszkiel J, McCreary AC, Filip M, Papp M, Przegaliński E. The effects of cannabinoid CB1, CB2 and vanilloid TRPV1 receptor antagonists on cocaine addictive behavior in rats. Brain Res 2012;1444:45-54.
286. Heng L-J, Huang B, Guo H, et al. Blocking TRPV1 in nucleus accumbens inhibits persistent morphine conditioned place preference expression in rats. PloS One 2014;9:e104546.
287. Shapovalov G, Gkika D, Devilliers M, et al. Opiates modulate thermosensation by internalizing cold receptor TRPM8. Cell Rep 2013;4:504-515.
288. Tyndale RF, Droll KP, Sellers EM. Genetically deficient CYP2D6 metabolism provides protection against oral opiate dependence. Pharmacogenetics 1997;7:375-379.
289. Miksys S, Rao Y, Hoffmann E, Mash DC, Tyndale RF. Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics. J Neurochem 2002;82:1376-1387.
290. Tournier N, Chevillard L, Megarbane B, Pirnay S, Scherrmann J-M, Declèves X. Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). Int J Neuropsychopharmacol 2010;13:905-915.