The NLRP3 Inflammasome in Stress Response: Another Target for the
Promiscuous Cannabidiol

Alice      Hartmann; Carla      Vila-Verde; Francisco   S.   Guimarães; Sâmia   R.   Joca; Sabrina   F.   Lisboa
doi:10.2174/1570159X20666220411101217
Abstract

Many psychiatric patients do not respond to conventional therapy. There is a vast effort to investigate possible mechanisms involved in treatment resistance, trying to provide better treatment options, and several data points toward a possible involvement of inflammatory mechanisms. Microglia, glial, and resident immune cells are involved in complex responses in the brain, orchestrating homeostatic functions, such as synaptic pruning and maintaining neuronal activity. In contrast, microglia play a major role in neuroinflammation, neurodegeneration, and cell death. Increasing evidence implicate microglia dysfunction in neuropsychiatric disorders. The mechanisms are still unclear, but one pathway in microglia has received increased attention in the last 8 years, i.e., the NLRP3 inflammasome pathway. Stress response and inflammation, including microglia activation, can be attenuated by Cannabidiol (CBD). CBD has antidepressant, anti-stress, antipsychotic, anti-inflammatory, and other properties. CBD effects are mediated by direct or indirect modulation of many receptors, enzymes, and other targets. This review will highlight some findings for neuroinflammation and microglia involvement in stress-related psychiatric disorders, particularly addressing the NLRP3 inflammasome pathway. Moreover, we will discuss evidence and mechanisms for CBD effects in psychiatric disorders and animal models and address its potential effects on stress response via neuroinflammation and NLRP3 inflammasome modulation.
Keywords: Neuroinflammation, NLRP3 inflammasome, cannabidiol, stress, psychiatric disorders, animal models.
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Graphical Abstract

[1]
Franklin, T.C.; Xu, C.; Duman, R.S. Depression and sterile inflammation: Essential role of danger associated molecular patterns. Brain Behav. Immun.,  2018, 72, 2-13.
 [http://dx.doi.org/10.1016/j.bbi.2017.10.025] [PMID:  29102801]

[2]
Jones, K.A.; Thomsen, C. The role of the innate immune system in psychiatric disorders. Mol. Cell. Neurosci.,  2013, 53, 52-62.
 [http://dx.doi.org/10.1016/j.mcn.2012.10.002] [PMID:  23064447]

[3]
Pape, K.; Tamouza, R.; Leboyer, M.; Zipp, F. Immunoneuropsychiatry - novel perspectives on brain disorders. Nat. Rev. Neurol.,  2019, 15(6), 317-328.
 [http://dx.doi.org/10.1038/s41582-019-0174-4] [PMID:  30988501]

[4]
Troubat, R.; Barone, P.; Leman, S.; Desmidt, T.; Cressant, A.; Atanasova, B.; Brizard, B.; El Hage, W.; Surget, A.; Belzung, C.; Camus, V. Neuroinflammation and depression: A review. Eur. J. Neurosci.,  2021, 53(1), 151-171.
 [http://dx.doi.org/10.1111/ejn.14720] [PMID:  32150310]

[5]
Lasselin, J.; Schedlowski, M.; Karshikoff, B.; Engler, H.; Lekander, M.; Konsman, J.P. Comparison of bacterial lipopolysaccharide-induced sickness behavior in rodents and humans: Relevance for symptoms of anxiety and depression. Neurosci. Biobehav. Rev.,  2020, 115, 15-24.
 [http://dx.doi.org/10.1016/j.neubiorev.2020.05.001] [PMID:  32433924]

[6]
Raison, C.L.; Capuron, L.; Miller, A.H. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol.,  2006, 27(1), 24-31.
 [http://dx.doi.org/10.1016/j.it.2005.11.006] [PMID:  16316783]

[7]
Raison, C.L.; Dantzer, R.; Kelley, K.W.; Lawson, M.A.; Woolwine, B.J.; Vogt, G.; Spivey, J.R.; Saito, K.; Miller, A.H. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol. Psychiatry,  2010, 15(4), 393-403.
 [http://dx.doi.org/10.1038/mp.2009.116] [PMID:  19918244]

[8]
Wichers, M.C.; Koek, G.H.; Robaeys, G.; Verkerk, R.; Scharpé, S.; Maes, M. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol. Psychiatry,  2005, 10(6), 538-544.
 [http://dx.doi.org/10.1038/sj.mp.4001600] [PMID:  15494706]

[9]
Kappelmann, N.; Lewis, G.; Dantzer, R.; Jones, P.B.; Khandaker, G.M. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol. Psychiatry,  2018, 23(2), 335-343.
 [http://dx.doi.org/10.1038/mp.2016.167] [PMID:  27752078]

[10]
Dahl, J.; Ormstad, H.; Aass, H.C.; Malt, U.F.; Bendz, L.T.; Sandvik, L.; Brundin, L.; Andreassen, O.A. The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology,  2014, 45, 77-86.
 [http://dx.doi.org/10.1016/j.psyneuen.2014.03.019] [PMID:  24845179]

[11]
Lindqvist, D.; Wolkowitz, O.M.; Mellon, S.; Yehuda, R.; Flory, J.D.; Henn-Haase, C.; Bierer, L.M.; Abu-Amara, D.; Coy, M.; Neylan, T.C.; Makotkine, I.; Reus, V.I.; Yan, X.; Taylor, N.M.; Marmar, C.R.; Dhabhar, F.S. Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress. Brain Behav. Immun.,  2014, 42, 81-88.
 [http://dx.doi.org/10.1016/j.bbi.2014.06.003] [PMID:  24929195]

[12]
Haapakoski, R.; Mathieu, J.; Ebmeier, K.P.; Alenius, H.; Kivimäki, M. Cumulative meta-analysis of interleukins 6 and 1β tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav. Immun.,  2015, 49, 206-215.
 [http://dx.doi.org/10.1016/j.bbi.2015.06.001] [PMID:  26065825]

[13]
Lamers, F.; Milaneschi, Y.; Smit, J.H.; Schoevers, R.A.; Wittenberg, G.; Penninx, B.W.J.H. Longitudinal association between depression and inflammatory markers: results from the netherlands study of depression and anxiety. Biol. Psychiatry,  2019, 85(10), 829-837.
 [http://dx.doi.org/10.1016/j.biopsych.2018.12.020] [PMID:  30819515]

[14]
Zalli, A.; Jovanova, O.; Hoogendijk, W.J.; Tiemeier, H.; Carvalho, L.A. Low-grade inflammation predicts persistence of depressive symptoms. Psychopharmacology (Berl.),  2016, 233(9), 1669-1678.
 [http://dx.doi.org/10.1007/s00213-015-3919-9] [PMID:  25877654]

[15]
Beurel, E.; Toups, M.; Nemeroff, C.B. The bidirectional relationship of depression and inflammation: double trouble. Neuron,  2020, 107(2), 234-256.
 [http://dx.doi.org/10.1016/j.neuron.2020.06.002] [PMID:  32553197]

[16]
Cattaneo, A.; Gennarelli, M.; Uher, R.; Breen, G.; Farmer, A.; Aitchison, K.J.; Craig, I.W.; Anacker, C.; Zunsztain, P.A.; McGuffin, P.; Pariante, C.M. Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology,  2013, 38(3), 377-385.
 [http://dx.doi.org/10.1038/npp.2012.191] [PMID:  22990943]

[17]
Haroon, E.; Raison, C.L.; Miller, A.H. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology,  2012, 37(1), 137-162.
 [http://dx.doi.org/10.1038/npp.2011.205] [PMID:  21918508]

[18]
Hodes, G.E.; Pfau, M.L.; Leboeuf, M.; Golden, S.A.; Christoffel, D.J.; Bregman, D.; Rebusi, N.; Heshmati, M.; Aleyasin, H.; Warren, B.L.; Lebonté, B.; Horn, S.; Lapidus, K.A.; Stelzhammer, V.; Wong, E.H.; Bahn, S.; Krishnan, V.; Bolaños-Guzman, C.A.; Murrough, J.W.; Merad, M.; Russo, S.J. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl. Acad. Sci. USA,  2014, 111(45), 16136-16141.
 [http://dx.doi.org/10.1073/pnas.1415191111] [PMID:  25331895]

[19]
Lanquillon, S.; Krieg, J.C.; Bening-Abu-Shach, U.; Vedder, H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology,  2000, 22(4), 370-379.
 [http://dx.doi.org/10.1016/S0893-133X(99)00134-7] [PMID:  10700656]

[20]
Sutcigil, L.; Oktenli, C.; Musabak, U.; Bozkurt, A.; Cansever, A.; Uzun, O.; Sanisoglu, S.Y.; Yesilova, Z.; Ozmenler, N.; Ozsahin, A.; Sengul, A. Pro- and anti-inflammatory cytokine balance in major depression: effect of sertraline therapy. Clin. Dev. Immunol.,  2007, 2007, 76396.
 [http://dx.doi.org/10.1155/2007/76396] [PMID:  18317531]

[21]
Tsao, C.W.; Lin, Y.S.; Chen, C.C.; Bai, C.H.; Wu, S.R. Cytokines and serotonin transporter in patients with major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2006, 30(5), 899-905.
 [http://dx.doi.org/10.1016/j.pnpbp.2006.01.029] [PMID:  16616982]

[22]
Tuglu, C.; Kara, S.H.; Caliyurt, O.; Vardar, E.; Abay, E. Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Psychopharmacology (Berl.),  2003, 170(4), 429-433.
 [http://dx.doi.org/10.1007/s00213-003-1566-z] [PMID:  12955291]

[23]
Köhler, O.; Benros, M.E.; Nordentoft, M.; Farkouh, M.E.; Iyengar, R.L.; Mors, O.; Krogh, J. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry,  2014, 71(12), 1381-1391.
 [http://dx.doi.org/10.1001/jamapsychiatry.2014.1611] [PMID:  25322082]

[24]
Więdłocha, M.; Marcinowicz, P.; Krupa, R.; Janoska-Jaździk, M.; Janus, M.; Dębowska, W.; Mosiołek, A.; Waszkiewicz, N.; Szulc, A. Effect of antidepressant treatment on peripheral inflammation markers - A meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2018, 80(Pt C), 217-226.
 [http://dx.doi.org/10.1016/j.pnpbp.2017.04.026] [PMID:  28445690]

[25]
Bai, S.; Guo, W.; Feng, Y.; Deng, H.; Li, G.; Nie, H.; Guo, G.; Yu, H.; Ma, Y.; Wang, J.; Chen, S.; Jing, J.; Yang, J.; Tang, Y.; Tang, Z. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: a systematic review and meta-analysis of randomised controlled trials. J. Neurol. Neurosurg. Psychiatry,  2020, 91(1), 21-32.
 [http://dx.doi.org/10.1136/jnnp-2019-320912] [PMID:  31658959]

[26]
Mansur, R.B.; Delgado-Peraza, F.; Subramaniapillai, M.; Lee, Y.; Iacobucci, M.; Rodrigues, N.; Rosenblat, J.D.; Brietzke, E.; Cosgrove, V.E.; Kramer, N.E.; Suppes, T.; Raison, C.L.; Chawla, S.; Nogueras-Ortiz, C.; McIntyre, R.S.; Kapogiannis, D. Extracellular vesicle biomarkers reveal inhibition of neuroinflammation by infliximab in association with antidepressant response in adults with bipolar depression. Cells,  2020, 9(4), E895.
 [http://dx.doi.org/10.3390/cells9040895] [PMID:  32268604]

[27]
Kaufmann, F.N.; Costa, A.P.; Ghisleni, G.; Diaz, A.P.; Rodrigues, A.L.S.; Peluffo, H.; Kaster, M.P. NLRP3 inflammasome-driven pathways in depression: Clinical and preclinical findings. Brain Behav. Immun.,  2017, 64, 367-383.
 [http://dx.doi.org/10.1016/j.bbi.2017.03.002] [PMID:  28263786]

[28]
Mondelli, V.; Vernon, A.C.; Turkheimer, F.; Dazzan, P.; Pariante, C.M. Brain microglia in psychiatric disorders. Lancet Psychiatry,  2017, 4(7), 563-572.
 [http://dx.doi.org/10.1016/S2215-0366(17)30101-3] [PMID:  28454915]

[29]
Stevenson, R.; Samokhina, E.; Rossetti, I.; Morley, J.W.; Buskila, Y. Neuromodulation of glial function during neurodegeneration. Front. Cell. Neurosci.,  2020, 14, 278.
 [http://dx.doi.org/10.3389/fncel.2020.00278] [PMID:  32973460]

[30]
Da Mesquita, S.; Fu, Z.; Kipnis, J. The meningeal lymphatic system: A new player in neurophysiology. Neuron,  2018, 100(2), 375-388.
 [http://dx.doi.org/10.1016/j.neuron.2018.09.022] [PMID:  30359603]

[31]
Chen, G.Y.; Nuñez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol.,  2010, 10(12), 826-837.
 [http://dx.doi.org/10.1038/nri2873] [PMID:  21088683]

[32]
Fleshner, M.; Frank, M.; Maier, S.F. Danger signals and inflammasomes: stress-evoked sterile inflammation in mood disorders. Neuropsychopharmacology,  2017, 42(1), 36-45.
 [http://dx.doi.org/10.1038/npp.2016.125] [PMID:  27412959]

[33]
Salvador, A.F.; de Lima, K.A.; Kipnis, J. Neuromodulation by the immune system: a focus on cytokines. Nat. Rev. Immunol.,  2021, 21(8), 526-541.
 [http://dx.doi.org/10.1038/s41577-021-00508-z] [PMID:  33649606]

[34]
Liu, X.; Nemeth, D.P.; McKim, D.B.; Zhu, L.; DiSabato, D.J.; Berdysz, O.; Gorantla, G.; Oliver, B.; Witcher, K.G.; Wang, Y.; Negray, C.E.; Vegesna, R.S.; Sheridan, J.F.; Godbout, J.P.; Robson, M.J.; Blakely, R.D.; Popovich, P.G.; Bilbo, S.D.; Quan, N. Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities. Immunity,  2019, 50(2), 317-333.e6.
 [http://dx.doi.org/10.1016/j.immuni.2018.12.012] [PMID:  30683620]

[35]
Kipnis, J.; Filiano, A.J. Neuroimmunology in 2017: The central nervous system: privileged by immune connections. Nat. Rev. Immunol.,  2018, 18(2), 83-84.
 [http://dx.doi.org/10.1038/nri.2017.152] [PMID:  29279610]

[36]
Lisboa, S.F.; Gomes, F.V.; Guimaraes, F.S.; Campos, A.C. Microglial cells as a link between cannabinoids and the immune hypothesis of psychiatric disorders. Front. Neurol.,  2016, 7, 5.
 [http://dx.doi.org/10.3389/fneur.2016.00005] [PMID:  26858686]

[37]
Ginhoux, F.; Prinz, M. Origin of microglia: current concepts and past controversies. Cold Spring Harb. Perspect. Biol.,  2015, 7(8), a020537.
 [http://dx.doi.org/10.1101/cshperspect.a020537] [PMID:  26134003]

[38]
Prinz, M.; Jung, S.; Priller, J. Microglia biology: One century of evolving concepts. Cell,  2019, 179(2), 292-311.
 [http://dx.doi.org/10.1016/j.cell.2019.08.053] [PMID:  31585077]

[39]
Jurgens, H.A.; Johnson, R.W. Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation. Exp. Neurol.,  2012, 233(1), 40-48.
 [http://dx.doi.org/10.1016/j.expneurol.2010.11.014] [PMID:  21110971]

[40]
Holmes, S.E.; Hinz, R.; Conen, S.; Gregory, C.J.; Matthews, J.C.; Anton-Rodriguez, J.M.; Gerhard, A.; Talbot, P.S. Elevated translocator protein in anterior cingulate in major depression and a role for inflammation in suicidal thinking: A positron emission tomography study. Biol. Psychiatry,  2018, 83(1), 61-69.
 [http://dx.doi.org/10.1016/j.biopsych.2017.08.005] [PMID:  28939116]

[41]
Steiner, J.; Walter, M.; Gos, T.; Guillemin, G.J.; Bernstein, H.G.; Sarnyai, Z.; Mawrin, C.; Brisch, R.; Bielau, H.; Meyer zu Schwabedissen, L.; Bogerts, B.; Myint, A.M. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J. Neuroinflammation,  2011, 8(1), 94.
 [http://dx.doi.org/10.1186/1742-2094-8-94] [PMID:  21831269]

[42]
Torres-Platas, S.G.; Cruceanu, C.; Chen, G.G.; Turecki, G.; Mechawar, N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun.,  2014, 42, 50-59.
 [http://dx.doi.org/10.1016/j.bbi.2014.05.007] [PMID:  24858659]

[43]
Hori, H.; Kim, Y. Inflammation and post-traumatic stress disorder. Psychiatry Clin. Neurosci.,  2019, 73(4), 143-153.
 [http://dx.doi.org/10.1111/pcn.12820] [PMID:  30653780]

[44]
Busse, M.; Busse, S.; Myint, A.M.; Gos, T.; Dobrowolny, H.; Müller, U.J.; Bogerts, B.; Bernstein, H.G.; Steiner, J. Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses? Eur. Arch. Psychiatry Clin. Neurosci.,  2015, 265(4), 321-329.
 [http://dx.doi.org/10.1007/s00406-014-0562-0] [PMID:  25409655]

[45]
Setiawan, E.; Wilson, A.A.; Mizrahi, R.; Rusjan, P.M.; Miler, L.; Rajkowska, G.; Suridjan, I.; Kennedy, J.L.; Rekkas, P.V.; Houle, S.; Meyer, J.H. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry,  2015, 72(3), 268-275.
 [http://dx.doi.org/10.1001/jamapsychiatry.2014.2427] [PMID:  25629589]

[46]
Dean, O.M.; Data-Franco, J.; Giorlando, F.; Berk, M. Minocycline: therapeutic potential in psychiatry. CNS Drugs,  2012, 26(5), 391-401.
 [http://dx.doi.org/10.2165/11632000-000000000-00000] [PMID:  22486246]

[47]
Husain, M.I.; Chaudhry, I.B.; Husain, N.; Khoso, A.B.; Rahman, R.R.; Hamirani, M.M.; Hodsoll, J.; Qurashi, I.; Deakin, J.F.; Young, A.H. Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial. J. Psychopharmacol.,  2017, 31(9), 1166-1175.
 [http://dx.doi.org/10.1177/0269881117724352] [PMID:  28857658]

[48]
Kato, T.A.; Watabe, M.; Tsuboi, S.; Ishikawa, K.; Hashiya, K.; Monji, A.; Utsumi, H.; Kanba, S. Minocycline modulates human social decision-making: possible impact of microglia on personality-oriented social behaviors. PLoS One,  2012, 7(7), e40461.
 [http://dx.doi.org/10.1371/journal.pone.0040461] [PMID:  22808165]

[49]
Soczynska, J.K.; Mansur, R.B.; Brietzke, E.; Swardfager, W.; Kennedy, S.H.; Woldeyohannes, H.O.; Powell, A.M.; Manierka, M.S.; McIntyre, R.S. Novel therapeutic targets in depression: minocycline as a candidate treatment. Behav. Brain Res.,  2012, 235(2), 302-317.
 [http://dx.doi.org/10.1016/j.bbr.2012.07.026] [PMID:  22963995]

[50]
Bassett, B.; Subramaniyam, S.; Fan, Y.; Varney, S.; Pan, H.; Carneiro, A.M.D.; Chung, C.Y. Minocycline alleviates depression-like symptoms by rescuing decrease in neurogenesis in dorsal hippocampus via blocking microglia activation/phagocytosis. Brain Behav. Immun.,  2021, 91, 519-530.
 [http://dx.doi.org/10.1016/j.bbi.2020.11.009] [PMID:  33176182]

[51]
Liu, H.Y.; Yue, J.; Hu, L.N.; Cheng, L.F.; Wang, X.S.; Wang, X.J.; Feng, B. Chronic minocycline treatment reduces the anxiety-like behaviors induced by repeated restraint stress through modulating neuroinflammation. Brain Res. Bull.,  2018, 143, 19-26.
 [http://dx.doi.org/10.1016/j.brainresbull.2018.08.015] [PMID:  30149196]

[52]
Henry, C.J.; Huang, Y.; Wynne, A.; Hanke, M.; Himler, J.; Bailey, M.T.; Sheridan, J.F.; Godbout, J.P. Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J. Neuroinflammation,  2008, 5(1), 15.
 [http://dx.doi.org/10.1186/1742-2094-5-15] [PMID:  18477398]

[53]
Miura, H.; Ando, Y.; Noda, Y.; Ozaki, N.; Isobe, K. Effects of minocycline on changes in brain tryptophan metabolism and the behavior of juvenile mice elicited by inescapable-predator stress. J. Trauma. Stress Disord. Treat.,  2013, 2(3), 7.
 [http://dx.doi.org/10.4172/2324-8947.1000107]

[54]
Wang, B.; Huang, X.; Pan, X.; Zhang, T.; Hou, C.; Su, W.J.; Liu, L.L.; Li, J.M.; Wang, Y.X. Minocycline prevents the depressive-like behavior through inhibiting the release of HMGB1 from microglia and neurons. Brain Behav. Immun.,  2020, 88, 132-143.
 [http://dx.doi.org/10.1016/j.bbi.2020.06.019] [PMID:  32553784]

[55]
Bhattacharya, A.; Drevets, W.C. Role of neuro-immunological factors in the pathophysiology of mood disorders: Implications for novel therapeutics for treatment resistant depression. Curr. Top. Behav. Neurosci.,  2017, 31, 339-356.
 [http://dx.doi.org/10.1007/7854_2016_43] [PMID:  27677784]

[56]
Schroder, K.; Tschopp, J. The inflammasomes. Cell,  2010, 140(6), 821-832.
 [http://dx.doi.org/10.1016/j.cell.2010.01.040] [PMID:  20303873]

[57]
Swanson, K.V.; Deng, M.; Ting, J.P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol.,  2019, 19(8), 477-489.
 [http://dx.doi.org/10.1038/s41577-019-0165-0] [PMID:  31036962]

[58]
Martinon, F.; Burns, K.; Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell,  2002, 10(2), 417-426.
 [http://dx.doi.org/10.1016/S1097-2765(02)00599-3] [PMID:  12191486]

[59]
He, Y.; Hara, H.; Núñez, G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci.,  2016, 41(12), 1012-1021.
 [http://dx.doi.org/10.1016/j.tibs.2016.09.002] [PMID:  27669650]

[60]
Lee, S.; Suh, G.Y.; Ryter, S.W.; Choi, A.M. Regulation and function of the nucleotide binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 inflammasome in lung disease. Am. J. Respir. Cell Mol. Biol.,  2016, 54(2), 151-160.
 [http://dx.doi.org/10.1165/rcmb.2015-0231TR] [PMID:  26418144]

[61]
Martinon, F.; Mayor, A.; Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol.,  2009, 27(1), 229-265.
 [http://dx.doi.org/10.1146/annurev.immunol.021908.132715] [PMID:  19302040]

[62]
Bauernfeind, F.G.; Horvath, G.; Stutz, A.; Alnemri, E.S.; MacDonald, K.; Speert, D.; Fernandes-Alnemri, T.; Wu, J.; Monks, B.G.; Fitzgerald, K.A.; Hornung, V.; Latz, E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol.,  2009, 183(2), 787-791.
 [http://dx.doi.org/10.4049/jimmunol.0901363] [PMID:  19570822]

[63]
Franchi, L.; Eigenbrod, T.; Núñez, G. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J. Immunol.,  2009, 183(2), 792-796.
 [http://dx.doi.org/10.4049/jimmunol.0900173] [PMID:  19542372]

[64]
Harder, J.; Franchi, L.; Muñoz-Planillo, R.; Park, J.H.; Reimer, T.; Núñez, G. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. J. Immunol.,  2009, 183(9), 5823-5829.
 [http://dx.doi.org/10.4049/jimmunol.0900444] [PMID:  19812205]

[65]
Xing, Y.; Yao, X.; Li, H.; Xue, G.; Guo, Q.; Yang, G.; An, L.; Zhang, Y.; Meng, G. Cutting Edge: TRAF6 Mediates TLR/IL-1R Signaling-Induced Nontranscriptional Priming of the NLRP3 Inflammasome. J. Immunol.,  2017, 199(5), 1561-1566.
 [http://dx.doi.org/10.4049/jimmunol.1700175] [PMID:  28739881]

[66]
Barry, R.; John, S.W.; Liccardi, G.; Tenev, T.; Jaco, I.; Chen, C.H.; Choi, J.; Kasperkiewicz, P.; Fernandes-Alnemri, T.; Alnemri, E.; Drag, M.; Chen, Y.; Meier, P. SUMO-mediated regulation of NLRP3 modulates inflammasome activity. Nat. Commun.,  2018, 9(1), 3001.
 [http://dx.doi.org/10.1038/s41467-018-05321-2] [PMID:  30069026]

[67]
Guo, C.; Xie, S.; Chi, Z.; Zhang, J.; Liu, Y.; Zhang, L.; Zheng, M.; Zhang, X.; Xia, D.; Ke, Y.; Lu, L.; Wang, D. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity,  2016, 45(4), 802-816.
 [http://dx.doi.org/10.1016/j.immuni.2016.09.008] [PMID:  27692610]

[68]
Han, S.; Lear, T.B.; Jerome, J.A.; Rajbhandari, S.; Snavely, C.A.; Gulick, D.L.; Gibson, K.F.; Zou, C.; Chen, B.B.; Mallampalli, R.K. Lipopolysaccharide primes the NALP3 inflammasome by inhibiting its ubiquitination and degradation mediated by the SCFFBXL2 E3 ligase. J. Biol. Chem.,  2015, 290(29), 18124-18133.
 [http://dx.doi.org/10.1074/jbc.M115.645549] [PMID:  26037928]

[69]
Juliana, C.; Fernandes-Alnemri, T.; Kang, S.; Farias, A.; Qin, F.; Alnemri, E.S. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J. Biol. Chem.,  2012, 287(43), 36617-36622.
 [http://dx.doi.org/10.1074/jbc.M112.407130] [PMID:  22948162]

[70]
Py, B.F.; Kim, M.S.; Vakifahmetoglu-Norberg, H.; Yuan, J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell,  2013, 49(2), 331-338.
 [http://dx.doi.org/10.1016/j.molcel.2012.11.009] [PMID:  23246432]

[71]
Rodgers, M.A.; Bowman, J.W.; Fujita, H.; Orazio, N.; Shi, M.; Liang, Q.; Amatya, R.; Kelly, T.J.; Iwai, K.; Ting, J.; Jung, J.U. The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J. Exp. Med.,  2014, 211(7), 1333-1347.
 [http://dx.doi.org/10.1084/jem.20132486] [PMID:  24958845]

[72]
Song, H.; Liu, B.; Huai, W.; Yu, Z.; Wang, W.; Zhao, J.; Han, L.; Jiang, G.; Zhang, L.; Gao, C.; Zhao, W. The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation by promoting proteasomal degradation of NLRP3. Nat. Commun.,  2016, 7(1), 13727.
 [http://dx.doi.org/10.1038/ncomms13727] [PMID:  27929086]

[73]
Song, N.; Liu, Z.S.; Xue, W.; Bai, Z.F.; Wang, Q.Y.; Dai, J.; Liu, X.; Huang, Y.J.; Cai, H.; Zhan, X.Y.; Han, Q.Y.; Wang, H.; Chen, Y.; Li, H.Y.; Li, A.L.; Zhang, X.M.; Zhou, T.; Li, T. NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation. Mol. Cell,  2017, 68(1), 185-197.e6.
 [http://dx.doi.org/10.1016/j.molcel.2017.08.017] [PMID:  28943315]

[74]
Stutz, A.; Kolbe, C.C.; Stahl, R.; Horvath, G.L.; Franklin, B.S.; van Ray, O.; Brinkschulte, R.; Geyer, M.; Meissner, F.; Latz, E. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J. Exp. Med.,  2017, 214(6), 1725-1736.
 [http://dx.doi.org/10.1084/jem.20160933] [PMID:  28465465]

[75]
Zhang, Z.; Meszaros, G.; He, W.T.; Xu, Y.; de Fatima Magliarelli, H.; Mailly, L.; Mihlan, M.; Liu, Y.; Puig Gámez, M.; Goginashvili, A.; Pasquier, A.; Bielska, O.; Neven, B.; Quartier, P.; Aebersold, R.; Baumert, T.F.; Georgel, P.; Han, J.; Ricci, R. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J. Exp. Med.,  2017, 214(9), 2671-2693.
 [http://dx.doi.org/10.1084/jem.20162040] [PMID:  28716882]

[76]
Jo, E.K.; Kim, J.K.; Shin, D.M.; Sasakawa, C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell. Mol. Immunol.,  2016, 13(2), 148-159.
 [http://dx.doi.org/10.1038/cmi.2015.95] [PMID:  26549800]

[77]
Kelley, N.; Jeltema, D.; Duan, Y.; He, Y. The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int. J. Mol. Sci.,  2019, 20(13), E3328.
 [http://dx.doi.org/10.3390/ijms20133328] [PMID:  31284572]

[78]
Sutterwala, F.S.; Haasken, S.; Cassel, S.L. Mechanism of NLRP3 inflammasome activation. Ann. N. Y. Acad. Sci.,  2014, 1319(1), 82-95.
 [http://dx.doi.org/10.1111/nyas.12458] [PMID:  24840700]

[79]
Perregaux, D.; Gabel, C.A. Interleukin-1 beta maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J. Biol. Chem.,  1994, 269(21), 15195-15203.
 [http://dx.doi.org/10.1016/S0021-9258(17)36591-2] [PMID:  8195155]

[80]
Shimada, K.; Crother, T.R.; Karlin, J.; Dagvadorj, J.; Chiba, N.; Chen, S.; Ramanujan, V.K.; Wolf, A.J.; Vergnes, L.; Ojcius, D.M.; Rentsendorj, A.; Vargas, M.; Guerrero, C.; Wang, Y.; Fitzgerald, K.A.; Underhill, D.M.; Town, T.; Arditi, M. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity,  2012, 36(3), 401-414.
 [http://dx.doi.org/10.1016/j.immuni.2012.01.009] [PMID:  22342844]

[81]
Halle, A.; Hornung, V.; Petzold, G.C.; Stewart, C.R.; Monks, B.G.; Reinheckel, T.; Fitzgerald, K.A.; Latz, E.; Moore, K.J.; Golenbock, D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol.,  2008, 9(8), 857-865.
 [http://dx.doi.org/10.1038/ni.1636] [PMID:  18604209]

[82]
Freeman, L.; Guo, H.; David, C.N.; Brickey, W.J.; Jha, S.; Ting, J.P. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J. Exp. Med.,  2017, 214(5), 1351-1370.
 [http://dx.doi.org/10.1084/jem.20150237] [PMID:  28404595]

[83]
Dostert, C.; Guarda, G.; Romero, J.F.; Menu, P.; Gross, O.; Tardivel, A.; Suva, M.L.; Stehle, J.C.; Kopf, M.; Stamenkovic, I.; Corradin, G.; Tschopp, J. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One,  2009, 4(8), e6510.
 [http://dx.doi.org/10.1371/journal.pone.0006510] [PMID:  19652710]

[84]
Duewell, P.; Kono, H.; Rayner, K.J.; Sirois, C.M.; Vladimer, G.; Bauernfeind, F.G.; Abela, G.S.; Franchi, L.; Nuñez, G.; Schnurr, M.; Espevik, T.; Lien, E.; Fitzgerald, K.A.; Rock, K.L.; Moore, K.J.; Wright, S.D.; Hornung, V.; Latz, E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature,  2010, 464(7293), 1357-1361.
 [http://dx.doi.org/10.1038/nature08938] [PMID:  20428172]

[85]
Martinon, F.; Pétrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature,  2006, 440(7081), 237-241.
 [http://dx.doi.org/10.1038/nature04516] [PMID:  16407889]

[86]
Mulay, S.R.; Kulkarni, O.P.; Rupanagudi, K.V.; Migliorini, A.; Darisipudi, M.N.; Vilaysane, A.; Muruve, D.; Shi, Y.; Munro, F.; Liapis, H.; Anders, H.J. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion. J. Clin. Invest.,  2013, 123(1), 236-246.
 [http://dx.doi.org/10.1172/JCI63679] [PMID:  23221343]

[87]
Muñoz-Planillo, R. Kuffa, P.; Martínez-Colón, G.; Smith, B.L.; Rajendiran, T.M.; Núñez, G. K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity,  2013, 38(6), 1142-1153.
 [http://dx.doi.org/10.1016/j.immuni.2013.05.016] [PMID:  23809161]

[88]
Kankkunen, P.; Teirilä, L.; Rintahaka, J.; Alenius, H.; Wolff, H.; Matikainen, S. (1,3)-beta-glucans activate both dectin-1 and NLRP3 inflammasome in human macrophages. J. Immunol.,  2010, 184(11), 6335-6342.
 [http://dx.doi.org/10.4049/jimmunol.0903019] [PMID:  20421639]

[89]
Lamkanfi, M.; Malireddi, R.K.; Kanneganti, T.D. Fungal zymosan and mannan activate the cryopyrin inflammasome. J. Biol. Chem.,  2009, 284(31), 20574-20581.
 [http://dx.doi.org/10.1074/jbc.M109.023689] [PMID:  19509280]

[90]
Franchi, L.; Eigenbrod, T.; Muñoz-Planillo, R.; Ozkurede, U.; Kim, Y.G.; Arindam, C.; Gale, M., Jr; Silverman, R.H.; Colonna, M.; Akira, S.; Núñez, G. Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. J. Immunol.,  2014, 193(8), 4214-4222.
 [http://dx.doi.org/10.4049/jimmunol.1400582] [PMID:  25225670]

[91]
Sha, W.; Mitoma, H.; Hanabuchi, S.; Bao, M.; Weng, L.; Sugimoto, N.; Liu, Y.; Zhang, Z.; Zhong, J.; Sun, B.; Liu, Y.J. Human NLRP3 inflammasome senses multiple types of bacterial RNAs. Proc. Natl. Acad. Sci. USA,  2014, 111(45), 16059-16064.
 [http://dx.doi.org/10.1073/pnas.1412487111] [PMID:  25355909]

[92]
Katsnelson, M.A.; Rucker, L.G.; Russo, H.M.; Dubyak, G.R.K. K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling. J. Immunol.,  2015, 194(8), 3937-3952.
 [http://dx.doi.org/10.4049/jimmunol.1402658] [PMID:  25762778]

[93]
Pétrilli, V.; Papin, S.; Dostert, C.; Mayor, A.; Martinon, F.; Tschopp, J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ.,  2007, 14(9), 1583-1589.
 [http://dx.doi.org/10.1038/sj.cdd.4402195] [PMID:  17599094]

[94]
Rühl, S.; Broz, P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur. J. Immunol.,  2015, 45(10), 2927-2936.
 [http://dx.doi.org/10.1002/eji.201545772] [PMID:  26173909]

[95]
Walev, I.; Reske, K.; Palmer, M.; Valeva, A.; Bhakdi, S. Potassium-inhibited processing of IL-1 beta in human monocytes. EMBO J.,  1995, 14(8), 1607-1614.
 [http://dx.doi.org/10.1002/j.1460-2075.1995.tb07149.x] [PMID:  7737113]

[96]
Domingo-Fernández, R.; Coll, R.C.; Kearney, J.; Breit, S.; O’Neill, L.A.J. The intracellular chloride channel proteins CLIC1 and CLIC4 induce IL-1β transcription and activate the NLRP3 inflammasome. J. Biol. Chem.,  2017, 292(29), 12077-12087.
 [http://dx.doi.org/10.1074/jbc.M117.797126] [PMID:  28576828]

[97]
Tang, T.; Lang, X.; Xu, C.; Wang, X.; Gong, T.; Yang, Y.; Cui, J.; Bai, L.; Wang, J.; Jiang, W.; Zhou, R. CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nat. Commun.,  2017, 8(1), 202.
 [http://dx.doi.org/10.1038/s41467-017-00227-x] [PMID:  28779175]

[98]
Brough, D.; Le Feuvre, R.A.; Wheeler, R.D.; Solovyova, N.; Hilfiker, S.; Rothwell, N.J.; Verkhratsky, A. Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1 beta and IL-1 alpha from murine macrophages. J. Immunol.,  2003, 170(6), 3029-3036.
 [http://dx.doi.org/10.4049/jimmunol.170.6.3029] [PMID:  12626557]

[99]
Lee, G.S.; Subramanian, N.; Kim, A.I.; Aksentijevich, I.; Goldbach-Mansky, R.; Sacks, D.B.; Germain, R.N.; Kastner, D.L.; Chae, J.J. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature,  2012, 492(7427), 123-127.
 [http://dx.doi.org/10.1038/nature11588] [PMID:  23143333]

[100]
Murakami, T.; Ockinger, J.; Yu, J.; Byles, V.; McColl, A.; Hofer, A.M.; Horng, T. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc. Natl. Acad. Sci. USA,  2012, 109(28), 11282-11287.
 [http://dx.doi.org/10.1073/pnas.1117765109] [PMID:  22733741]

[101]
Rossol, M.; Pierer, M.; Raulien, N.; Quandt, D.; Meusch, U.; Rothe, K.; Schubert, K.; Schöneberg, T.; Schaefer, M.; Krügel, U.; Smajilovic, S.; Bräuner-Osborne, H.; Baerwald, C.; Wagner, U. Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors. Nat. Commun.,  2012, 3(1), 1329.
 [http://dx.doi.org/10.1038/ncomms2339] [PMID:  23271661]

[102]
Chu, J.; Thomas, L.M.; Watkins, S.C.; Franchi, L.; Núñez, G.; Salter, R.D. Cholesterol-dependent cytolysins induce rapid release of mature IL-1beta from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner. J. Leukoc. Biol.,  2009, 86(5), 1227-1238.
 [http://dx.doi.org/10.1189/jlb.0309164] [PMID:  19675207]

[103]
Hornung, V.; Bauernfeind, F.; Halle, A.; Samstad, E.O.; Kono, H.; Rock, K.L.; Fitzgerald, K.A.; Latz, E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat. Immunol.,  2008, 9(8), 847-856.
 [http://dx.doi.org/10.1038/ni.1631] [PMID:  18604214]

[104]
Orlowski, G.M.; Colbert, J.D.; Sharma, S.; Bogyo, M.; Robertson, S.A.; Rock, K.L. Multiple cathepsins promote Pro-IL-1β synthesis and NLRP3-mediated IL-1β activation. J. Immunol.,  2015, 195(4), 1685-1697.
 [http://dx.doi.org/10.4049/jimmunol.1500509] [PMID:  26195813]

[105]
Bauernfeind, F.; Bartok, E.; Rieger, A.; Franchi, L.; Núñez, G.; Hornung, V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J. Immunol.,  2011, 187(2), 613-617.
 [http://dx.doi.org/10.4049/jimmunol.1100613] [PMID:  21677136]

[106]
Dostert, C.; Pétrilli, V.; Van Bruggen, R.; Steele, C.; Mossman, B.T.; Tschopp, J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science,  2008, 320(5876), 674-677.
 [http://dx.doi.org/10.1126/science.1156995] [PMID:  18403674]

[107]
Lawlor, K.E.; Vince, J.E. Ambiguities in NLRP3 inflammasome regulation: is there a role for mitochondria? Biochim. Biophys. Acta,  2014, 1840(4), 1433-1440.
 [http://dx.doi.org/10.1016/j.bbagen.2013.08.014] [PMID:  23994495]

[108]
Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature,  2011, 469(7329), 221-225.
 [http://dx.doi.org/10.1038/nature09663] [PMID:  21124315]

[109]
Surprenant, A.; Rassendren, F.; Kawashima, E.; North, R.A.; Buell, G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science,  1996, 272(5262), 735-738.
 [http://dx.doi.org/10.1126/science.272.5262.735] [PMID:  8614837]

[110]
Di, A.; Xiong, S.; Ye, Z.; Malireddi, R.K.S.; Kometani, S.; Zhong, M.; Mittal, M.; Hong, Z.; Kanneganti, T.D.; Rehman, J.; Malik, A.B. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation. Immunity,  2018, 49(1), 56-65.e4.
 [http://dx.doi.org/10.1016/j.immuni.2018.04.032] [PMID:  29958799]

[111]
Biasizzo, M.; Kopitar-Jerala, N. Interplay between NLRP3 inflammasome and autophagy. Front. Immunol.,  2020, 11, 591803.
 [http://dx.doi.org/10.3389/fimmu.2020.591803] [PMID:  33163006]

[112]
Saitoh, T.; Akira, S. Regulation of inflammasomes by autophagy. J. Allergy Clin. Immunol.,  2016, 138(1), 28-36.
 [http://dx.doi.org/10.1016/j.jaci.2016.05.009] [PMID:  27373323]

[113]
Zheng, D.; Liwinski, T.; Elinav, E. Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discov.,  2020, 6(1), 36.
 [http://dx.doi.org/10.1038/s41421-020-0167-x] [PMID:  32550001]

[114]
Alirezaei, M.; Kemball, C.C.; Whitton, J.L. Autophagy, inflammation and neurodegenerative disease. Eur. J. Neurosci.,  2011, 33(2), 197-204.
 [http://dx.doi.org/10.1111/j.1460-9568.2010.07500.x] [PMID:  21138487]

[115]
Houtman, J.; Freitag, K.; Gimber, N.; Schmoranzer, J.; Heppner, F.L.; Jendrach, M. Beclin1-driven autophagy modulates the inflammatory response of microglia via NLRP3. EMBO J.,  2019, 38(4), e99430.
 [http://dx.doi.org/10.15252/embj.201899430] [PMID:  30617086]

[116]
Jiang, P.; Mizushima, N. Autophagy and human diseases. Cell Res.,  2014, 24(1), 69-79.
 [http://dx.doi.org/10.1038/cr.2013.161] [PMID:  24323045]

[117]
Mizushima, N.; Levine, B. Autophagy in human diseases. N. Engl. J. Med.,  2020, 383(16), 1564-1576.
 [http://dx.doi.org/10.1056/NEJMra2022774] [PMID:  33053285]

[118]
Pierone, B.C.; Pereira, C.A.; Garcez, M.L.; Kaster, M.P. Stress and signaling pathways regulating autophagy: From behavioral models to psychiatric disorders. Exp. Neurol.,  2020, 334, 113485.
 [http://dx.doi.org/10.1016/j.expneurol.2020.113485] [PMID:  32987001]

[119]
Iwata, M.; Ota, K.T.; Duman, R.S. The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav. Immun.,  2013, 31, 105-114.
 [http://dx.doi.org/10.1016/j.bbi.2012.12.008] [PMID:  23261775]

[120]
Mangan, M.S.J.; Olhava, E.J.; Roush, W.R.; Seidel, H.M.; Glick, G.D.; Latz, E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov.,  2018, 17(8), 588-606.
 [http://dx.doi.org/10.1038/nrd.2018.97] [PMID:  30026524]

[121]
Meyers, A.K.; Zhu, X. The NLRP3 inflammasome: Metabolic regulation and contribution to inflammaging. Cells,  2020, 9(8), E1808.
 [http://dx.doi.org/10.3390/cells9081808] [PMID:  32751530]

[122]
Pereira, C.F.; Santos, A.E.; Moreira, P.I.; Pereira, A.C.; Sousa, F.J.; Cardoso, S.M.; Cruz, M.T. Is Alzheimer’s disease an inflammasomopathy? Ageing Res. Rev.,  2019, 56, 100966.
 [http://dx.doi.org/10.1016/j.arr.2019.100966] [PMID:  31577960]

[123]
Pirzada, R.H.; Javaid, N.; Choi, S. The roles of the NLRP3 inflammasome in neurodegenerative and metabolic diseases and in relevant advanced therapeutic interventions. Genes (Basel),  2020, 11(2), E131.
 [http://dx.doi.org/10.3390/genes11020131] [PMID:  32012695]

[124]
Shao, B.Z.; Xu, Z.Q.; Han, B.Z.; Su, D.F.; Liu, C. NLRP3 inflammasome and its inhibitors: a review. Front. Pharmacol.,  2015, 6, 262.
 [http://dx.doi.org/10.3389/fphar.2015.00262] [PMID:  26594174]

[125]
Tong, Y.; Wang, Z.; Cai, L.; Lin, L.; Liu, J.; Cheng, J. NLRP3 inflammasome and its central role in the cardiovascular diseases. Oxid. Med. Cell. Longev.,  2020, 2020, 4293206.
 [http://dx.doi.org/10.1155/2020/4293206] [PMID:  32377298]

[126]
Zahid, A.; Li, B.; Kombe, A.J.K.; Jin, T.; Tao, J. Pharmacological inhibitors of the NLRP3 inflammasome. Front. Immunol.,  2019, 10, 2538.
 [http://dx.doi.org/10.3389/fimmu.2019.02538] [PMID:  31749805]

[127]
Zhou, W.; Chen, C.; Chen, Z.; Liu, L.; Jiang, J.; Wu, Z.; Zhao, M.; Chen, Y. NLRP3: A novel mediator in cardiovascular disease. J. Immunol. Res.,  2018, 2018, 5702103.
 [http://dx.doi.org/10.1155/2018/5702103] [PMID:  29850631]

[128]
Gordon, R.; Albornoz, E.A.; Christie, D.C.; Langley, M.R.; Kumar, V.; Mantovani, S.; Robertson, A.A.B.; Butler, M.S.; Rowe, D.B.; O’Neill, L.A.; Kanthasamy, A.G.; Schroder, K.; Cooper, M.A.; Woodruff, T.M. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci. Transl. Med.,  2018, 10(465), eaah4066.
 [http://dx.doi.org/10.1126/scitranslmed.aah4066] [PMID:  30381407]

[129]
Walsh, J.G.; Muruve, D.A.; Power, C. Inflammasomes in the CNS. Nat. Rev. Neurosci.,  2014, 15(2), 84-97.
 [http://dx.doi.org/10.1038/nrn3638] [PMID:  24399084]

[130]
Wong, M.L.; Inserra, A.; Lewis, M.D.; Mastronardi, C.A.; Leong, L.; Choo, J.; Kentish, S.; Xie, P.; Morrison, M.; Wesselingh, S.L.; Rogers, G.B.; Licinio, J. Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition. Mol. Psychiatry,  2016, 21(6), 797-805.
 [http://dx.doi.org/10.1038/mp.2016.46] [PMID:  27090302]

[131]
Alcocer-Gómez, E.; de Miguel, M.; Casas-Barquero, N.; Núñez-Vasco, J.; Sánchez-Alcazar, J.A.; Fernández-Rodríguez, A.; Cordero, M.D. NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav. Immun.,  2014, 36, 111-117.
 [http://dx.doi.org/10.1016/j.bbi.2013.10.017] [PMID:  24513871]

[132]
Pan, Y.; Chen, X.Y.; Zhang, Q.Y.; Kong, L.D. Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats. Brain Behav. Immun.,  2014, 41, 90-100.
 [http://dx.doi.org/10.1016/j.bbi.2014.04.007] [PMID:  24859041]

[133]
Du, R.H.; Tan, J.; Sun, X.Y.; Lu, M.; Ding, J.H.; Hu, G. Fluoxetine inhibits NLRP3 inflammasome activation: Implication in depression. Int. J. Neuropsychopharmacol.,  2016, 19(9), pyw037.
 [http://dx.doi.org/10.1093/ijnp/pyw037] [PMID:  27207922]

[134]
Arioz, B.I.; Tastan, B.; Tarakcioglu, E.; Tufekci, K.U.; Olcum, M.; Ersoy, N.; Bagriyanik, A.; Genc, K.; Genc, S. Melatonin attenuates LPS-induced acute depressive-like behaviors and microglial NLRP3 inflammasome activation through the SIRT1/Nrf2 pathway. Front. Immunol.,  2019, 10, 1511.
 [http://dx.doi.org/10.3389/fimmu.2019.01511] [PMID:  31327964]

[135]
Li, J.M.; Liu, L.L.; Su, W.J.; Wang, B.; Zhang, T.; Zhang, Y.; Jiang, C.L. Ketamine may exert antidepressant effects via suppressing NLRP3 inflammasome to upregulate AMPA receptors. Neuropharmacology,  2019, 146, 149-153.
 [http://dx.doi.org/10.1016/j.neuropharm.2018.11.022] [PMID:  30496753]

[136]
Yang, C.; Shen, J.; Hong, T.; Hu, T.T.; Li, Z.J.; Zhang, H.T.; Zhang, Y.J.; Zhou, Z.Q.; Yang, J.J. Effects of ketamine on lipopolysaccharide-induced depressive-like behavior and the expression of inflammatory cytokines in the rat prefrontal cortex. Mol. Med. Rep.,  2013, 8(3), 887-890.
 [http://dx.doi.org/10.3892/mmr.2013.1600] [PMID:  23900245]

[137]
Alcocer-Gómez, E.; Casas-Barquero, N.; Williams, M.R.; Romero-Guillena, S.L.; Cañadas-Lozano, D.; Bullón, P.; Sánchez-Alcazar, J.A.; Navarro-Pando, J.M.; Cordero, M.D. Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition in Major depressive disorder. Pharmacol. Res.,  2017, 121, 114-121.
 [http://dx.doi.org/10.1016/j.phrs.2017.04.028] [PMID:  28465217]

[138]
Zhang, Y.; Liu, L.; Liu, Y.Z.; Shen, X.L.; Wu, T.Y.; Zhang, T.; Wang, W.; Wang, Y.X.; Jiang, C.L. NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation. Int. J. Neuropsychopharmacol.,  2015, 18(8), pyv006.
 [http://dx.doi.org/10.1093/ijnp/pyv006] [PMID:  25603858]

[139]
Alcocer-Gómez, E.; Ulecia-Morón, C.; Marín-Aguilar, F.; Rybkina, T.; Casas-Barquero, N.; Ruiz-Cabello, J.; Ryffel, B.; Apetoh, L.; Ghiringhelli, F.; Bullón, P.; Sánchez-Alcazar, J.A.; Carrión, A.M.; Cordero, M.D. Stress-induced depressive behaviors require a functional NLRP3 inflammasome. Mol. Neurobiol.,  2016, 53(7), 4874-4882.
 [http://dx.doi.org/10.1007/s12035-015-9408-7] [PMID:  26362308]

[140]
Dong, Y.; Li, S.; Lu, Y.; Li, X.; Liao, Y.; Peng, Z.; Li, Y.; Hou, L.; Yuan, Z.; Cheng, J. Stress-induced NLRP3 inflammasome activation negatively regulates fear memory in mice. J. Neuroinflammation,  2020, 17(1), 205.
 [http://dx.doi.org/10.1186/s12974-020-01842-0] [PMID:  32635937]

[141]
Iwata, M.; Ota, K.T.; Li, X.Y.; Sakaue, F.; Li, N.; Dutheil, S.; Banasr, M.; Duric, V.; Yamanashi, T.; Kaneko, K.; Rasmussen, K.; Glasebrook, A.; Koester, A.; Song, D.; Jones, K.A.; Zorn, S.; Smagin, G.; Duman, R.S. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol. Psychiatry,  2016, 80(1), 12-22.
 [http://dx.doi.org/10.1016/j.biopsych.2015.11.026] [PMID:  26831917]

[142]
Bitencourt, R.M.; Takahashi, R.N.; Carlini, E.A. From an alternative medicine to a new treatment for refractory epilepsies: Can cannabidiol follow the same path to treat neuropsychiatric disorders? Front. Psychiatry,  2021, 12, 638032.
 [http://dx.doi.org/10.3389/fpsyt.2021.638032] [PMID:  33643100]

[143]
Campos, A.C.; Fogaça, M.V.; Scarante, F.F.; Joca, S.R.L.; Sales, A.J.; Gomes, F.V.; Sonego, A.B.; Rodrigues, N.S.; Galve-Roperh, I.; Guimarães, F.S. Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders. Front. Pharmacol.,  2017, 8, 269.
 [http://dx.doi.org/10.3389/fphar.2017.00269] [PMID:  28588483]

[144]
García-Gutiérrez, M.S.; Navarrete, F.; Gasparyan, A.; Austrich-Olivares, A.; Sala, F.; Manzanares, J. Cannabidiol: A potential new alternative for the treatment of anxiety, depression, and psychotic disorders. Biomolecules,  2020, 10(11), E1575.
 [http://dx.doi.org/10.3390/biom10111575] [PMID:  33228239]

[145]
Silote, G.P.; Sartim, A.; Sales, A.; Eskelund, A.; Guimarães, F.S.; Wegener, G.; Joca, S. Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms. J. Chem. Neuroanat.,  2019, 98, 104-116.
 [http://dx.doi.org/10.1016/j.jchemneu.2019.04.006] [PMID:  31039391]

[146]
Zuardi, A.W.; Cosme, R.A.; Graeff, F.G.; Guimarães, F.S. Effects of ipsapirone and cannabidiol on human experimental anxiety. J. Psychopharmacol.,  1993, 7(1)(Suppl.), 82-88.
 [http://dx.doi.org/10.1177/026988119300700112] [PMID:  22290374]

[147]
Zuardi, A.W.; Rodrigues, N.P.; Silva, A.L.; Bernardo, S.A.; Hallak, J.E.C.; Guimarães, F.S.; Crippa, J.A.S. Inverted U-Shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front. Pharmacol.,  2017, 8, 259.
 [http://dx.doi.org/10.3389/fphar.2017.00259] [PMID:  28553229]

[148]
Bergamaschi, M.M.; Queiroz, R.H.; Chagas, M.H.; de Oliveira, D.C.; De Martinis, B.S.; Kapczinski, F.; Quevedo, J.; Roesler, R.; Schröder, N.; Nardi, A.E.; Martín-Santos, R.; Hallak, J.E.; Zuardi, A.W.; Crippa, J.A. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology,  2011, 36(6), 1219-1226.
 [http://dx.doi.org/10.1038/npp.2011.6] [PMID:  21307846]

[149]
Masataka, N. Anxiolytic effects of repeated cannabidiol treatment in teenagers with social anxiety disorders. Front. Psychol.,  2019, 10, 2466.
 [http://dx.doi.org/10.3389/fpsyg.2019.02466] [PMID:  31787910]

[150]
Leweke, F.M.; Piomelli, D.; Pahlisch, F.; Muhl, D.; Gerth, C.W.; Hoyer, C.; Klosterkötter, J.; Hellmich, M.; Koethe, D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry,  2012, 2(3), e94.
 [http://dx.doi.org/10.1038/tp.2012.15] [PMID:  22832859]

[151]
McGuire, P.; Robson, P.; Cubala, W.J.; Vasile, D.; Morrison, P.D.; Barron, R.; Taylor, A.; Wright, S. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: A multicenter randomized controlled trial. Am. J. Psychiatry,  2018, 175(3), 225-231.
 [http://dx.doi.org/10.1176/appi.ajp.2017.17030325] [PMID:  29241357]

[152]
Hurd, Y.L.; Spriggs, S.; Alishayev, J.; Winkel, G.; Gurgov, K.; Kudrich, C.; Oprescu, A.M.; Salsitz, E. Cannabidiol for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: A double-blind randomized placebo-controlled trial. Am. J. Psychiatry,  2019, 176(11), 911-922.
 [http://dx.doi.org/10.1176/appi.ajp.2019.18101191] [PMID:  31109198]

[153]
Frank, M.G.; Weber, M.D.; Watkins, L.R.; Maier, S.F. Stress-induced neuroinflammatory priming: A liability factor in the etiology of psychiatric disorders. Neurobiol. Stress,  2015, 4, 62-70.
 [http://dx.doi.org/10.1016/j.ynstr.2015.12.004] [PMID:  27981190]

[154]
Campos, A.C.; Ortega, Z.; Palazuelos, J.; Fogaça, M.V.; Aguiar, D.C.; Díaz-Alonso, J.; Ortega-Gutiérrez, S.; Vázquez-Villa, H.; Moreira, F.A.; Guzmán, M.; Galve-Roperh, I.; Guimarães, F.S. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int. J. Neuropsychopharmacol.,  2013, 16(6), 1407-1419.
 [http://dx.doi.org/10.1017/S1461145712001502] [PMID:  23298518]

[155]
Fogaça, M.V.; Campos, A.C.; Coelho, L.D.; Duman, R.S.; Guimarães, F.S. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology,  2018, 135, 22-33.
 [http://dx.doi.org/10.1016/j.neuropharm.2018.03.001] [PMID:  29510186]

[156]
Resstel, L.B.; Tavares, R.F.; Lisboa, S.F.; Joca, S.R.; Corrêa, F.M.; Guimarães, F.S. 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(1), 181-188.
 [http://dx.doi.org/10.1111/j.1476-5381.2008.00046.x] [PMID:  19133999]

[157]
Campos, A.C.; Ferreira, F.R.; Guimarães, F.S. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors. J. Psychiatr. Res.,  2012, 46(11), 1501-1510.
 [http://dx.doi.org/10.1016/j.jpsychires.2012.08.012] [PMID:  22979992]

[158]
Ibeas Bih, C.; Chen, T.; Nunn, A.V.; Bazelot, M.; Dallas, M.; Whalley, B.J. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics,  2015, 12(4), 699-730.
 [http://dx.doi.org/10.1007/s13311-015-0377-3] [PMID:  26264914]

[159]
Campos, A.C.; Guimarães, F.S. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl.),  2008, 199(2), 223-230.
 [http://dx.doi.org/10.1007/s00213-008-1168-x] [PMID:  18446323]

[160]
Casarotto, P.C.; Gomes, F.V.; Resstel, L.B.; Guimarães, F.S. Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behav. Pharmacol.,  2010, 21(4), 353-358.
 [http://dx.doi.org/10.1097/FBP.0b013e32833b33c5] [PMID:  20695034]

[161]
Nardo, M.; Casarotto, P.C.; Gomes, F.V.; Guimarães, F.S. Cannabidiol reverses the mCPP-induced increase in marble-burying behavior. Fundam. Clin. Pharmacol.,  2014, 28(5), 544-550.
 [http://dx.doi.org/10.1111/fcp.12051] [PMID:  24118015]

[162]
Bitencourt, R.M.; Pamplona, F.A.; Takahashi, R.N. Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. Eur. Neuropsychopharmacol.,  2008, 18(12), 849-859.
 [http://dx.doi.org/10.1016/j.euroneuro.2008.07.001] [PMID:  18706790]

[163]
Stern, C.A.J.; da Silva, T.R.; Raymundi, A.M.; de Souza, C.P.; Hiroaki-Sato, V.A.; Kato, L.; Guimarães, F.S.; Andreatini, R.; Takahashi, R.N.; Bertoglio, L.J. Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB1 and CB2 receptors. Neuropharmacology,  2017, 125, 220-230.
 [http://dx.doi.org/10.1016/j.neuropharm.2017.07.024] [PMID:  28754373]

[164]
Silva, N.R.; Gomes, F.V.; Fonseca, M.D.; Mechoulam, R.; Breuer, A.; Cunha, T.M.; Guimaraes, F.S. Antinociceptive effects of HUF101, a fluorinated cannabidiol derivative. Prog Neuropsychopharmacol Biol Psychiatry.,  2017, 79(Pt B), 369-377.
 [http://dx.doi.org/10.1016/j.pnpbp.2017.07.012] [PMID: 28720466]

[165]
Bisogno, T.; Hanus, L.; De Petrocellis, L.; Tchilibon, S.; Ponde, D.E.; Brandi, I.; Moriello, A.S.; Davis, J.B.; Mechoulam, R.; Di Marzo, V. 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(4), 845-852.
 [http://dx.doi.org/10.1038/sj.bjp.0704327] [PMID:  11606325]

[166]
Sartim, A.G.; Guimarães, F.S.; Joca, S.R. Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors. Behav. Brain Res.,  2016, 303, 218-227.
 [http://dx.doi.org/10.1016/j.bbr.2016.01.033] [PMID:  26801828]

[167]
Hartmann, A.; Lisboa, S.F.; Sonego, A.B.; Coutinho, D.; Gomes, F.V.; Guimarães, F.S. Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2019, 94, 109637.
 [http://dx.doi.org/10.1016/j.pnpbp.2019.109637] [PMID:  31054943]

[168]
Martin, L.J.; Banister, S.D.; Bowen, M.T. Understanding the complex pharmacology of cannabidiol: Mounting evidence suggests a common binding site with cholesterol. Pharmacol. Res.,  2021, 166, 105508.
 [http://dx.doi.org/10.1016/j.phrs.2021.105508] [PMID:  33610721]

[169]
Dos-Santos-Pereira, M.; Guimarães, F.S.; Del-Bel, E.; Raisman-Vozari, R.; Michel, P.P. Cannabidiol prevents LPS-induced microglial inflammation by inhibiting ROS/NF-κB-dependent signaling and glucose consumption. Glia,  2020, 68(3), 561-573.
 [http://dx.doi.org/10.1002/glia.23738] [PMID:  31647138]

[170]
Gomes, F.V.; Llorente, R.; Del Bel, E.A.; Viveros, M.P.; López-Gallardo, M.; Guimarães, F.S. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr. Res.,  2015, 164(1-3), 155-163.
 [http://dx.doi.org/10.1016/j.schres.2015.01.015] [PMID:  25680767]

[171]
Scarante, F.F.; Ribeiro, M.A.; Almeida-Santos, A.F.; Guimarães, F.S.; Campos, A.C. Glial cells and their contribution to the mechanisms of action of cannabidiol in neuropsychiatric disorders. Front. Pharmacol.,  2021, 11, 618065.
 [http://dx.doi.org/10.3389/fphar.2020.618065] [PMID:  33613284]

[172]
Sonego, A.B.; Prado, D.S.; Vale, G.T.; Sepulveda-Diaz, J.E.; Cunha, T.M.; Tirapelli, C.R.; Del Bel, E.A.; Raisman-Vozari, R.; Guimarães, F.S. Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors. Brain Behav. Immun.,  2018, 74, 241-251.
 [http://dx.doi.org/10.1016/j.bbi.2018.09.014] [PMID:  30217539]

[173]
Russo, E.B.; Burnett, A.; Hall, B.; Parker, K.K. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem. Res.,  2005, 30(8), 1037-1043.
 [http://dx.doi.org/10.1007/s11064-005-6978-1] [PMID:  16258853]

[174]
Haddjeri, N.; Blier, P.; de Montigny, C. Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. J. Neurosci.,  1998, 18(23), 10150-10156.
 [http://dx.doi.org/10.1523/JNEUROSCI.18-23-10150.1998] [PMID:  9822768]

[175]
Zanelati, T.V.; Biojone, C.; Moreira, F.A.; Guimarães, F.S.; Joca, S.R. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br. J. Pharmacol.,  2010, 159(1), 122-128.
 [http://dx.doi.org/10.1111/j.1476-5381.2009.00521.x] [PMID:  20002102]

[176]
Cryan, J.F.; Valentino, R.J.; Lucki, I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci. Biobehav. Rev.,  2005, 29(4-5), 547-569.
 [http://dx.doi.org/10.1016/j.neubiorev.2005.03.008] [PMID:  15893822]

[177]
Sales, A.J.; Crestani, C.C.; Guimarães, F.S.; Joca, S.R.L. Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2018, 86, 255-261.
 [http://dx.doi.org/10.1016/j.pnpbp.2018.06.002] [PMID:  29885468]

[178]
Abame, M.A.; He, Y.; Wu, S.; Xie, Z.; Zhang, J.; Gong, X.; Wu, C.; Shen, J. Chronic administration of synthetic cannabidiol induces antidepressant effects involving modulation of serotonin and noradrenaline levels in the hippocampus. Neurosci. Lett.,  2021, 744, 135594.
 [http://dx.doi.org/10.1016/j.neulet.2020.135594] [PMID:  33388355]

[179]
Réus, G.Z.; Stringari, R.B.; Ribeiro, K.F.; Luft, T.; Abelaira, H.M.; Fries, G.R.; Aguiar, B.W.; Kapczinski, F.; Hallak, J.E.; Zuardi, A.W.; Crippa, J.A.; Quevedo, J. Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala. Acta Neuropsychiatr.,  2011, 23(5), 241-248.
 [http://dx.doi.org/10.1111/j.1601-5215.2011.00579.x] [PMID:  25379896]

[180]
Sales, A.J.; Fogaça, M.V.; Sartim, A.G.; Pereira, V.S.; Wegener, G.; Guimarães, F.S.; Joca, S.R.L. Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex. Mol. Neurobiol.,  2019, 56(2), 1070-1081.
 [http://dx.doi.org/10.1007/s12035-018-1143-4] [PMID:  29869197]

[181]
Xu, C.; Chang, T.; Du, Y.; Yu, C.; Tan, X.; Li, X. Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model. Environ. Toxicol. Pharmacol.,  2019, 70, 103202.
 [http://dx.doi.org/10.1016/j.etap.2019.103202] [PMID:  31173966]

[182]
Linge, R.; Jiménez-Sánchez, L.; Campa, L.; Pilar-Cuéllar, F.; Vidal, R.; Pazos, A.; Adell, A.; Díaz, Á. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology,  2016, 103, 16-26.
 [http://dx.doi.org/10.1016/j.neuropharm.2015.12.017] [PMID:  26711860]

[183]
Shoval, G.; Shbiro, L.; Hershkovitz, L.; Hazut, N.; Zalsman, G.; Mechoulam, R.; Weller, A. Prohedonic effect of cannabidiol in a rat model of depression. Neuropsychobiology,  2016, 73(2), 123-129.
 [http://dx.doi.org/10.1159/000443890] [PMID:  27010632]

[184]
Shbiro, L.; Hen-Shoval, D.; Hazut, N.; Rapps, K.; Dar, S.; Zalsman, G.; Mechoulam, R.; Weller, A.; Shoval, G. Effects of cannabidiol in males and females in two different rat models of depression. Physiol. Behav.,  2019, 201, 59-63.
 [http://dx.doi.org/10.1016/j.physbeh.2018.12.019] [PMID:  30571957]

[185]
Silote, G.P.; Gatto, M.C.; Eskelund, A.; Guimarães, F.S.; Wegener, G.; Joca, S.R.L. Strain-, sex-, and time-dependent antidepressant-like effects of cannabidiol. Pharmaceuticals (Basel),  2021, 14(12), 1269.
 [http://dx.doi.org/10.3390/ph14121269] [PMID:  34959670]

[186]
Adu-Nti, F.; Ghartey-Kwansah, G.; Aboagye, B. Sex differences in the antidepressant effects of ketamine in animal models of depression. Int J Depress Anxiety,  2019, 2(2), 13.

[187]
Sartim, A.G.; Marques, J.; Silveira, K.M.; Gobira, P.H.; Guimarães, F.S.; Wegener, G.; Joca, S.R. Co-administration of cannabidiol and ketamine induces antidepressant-like effects devoid of hyperlocomotor side-effects. Neuropharmacology,  2021, 195, 108679.
 [http://dx.doi.org/10.1016/j.neuropharm.2021.108679] [PMID:  34157363]

[188]
Sartim, A.G.; Sales, A.J.; Guimarães, F.S.; Joca, S.R. Hippocampal mammalian target of rapamycin is implicated in stress-coping behavior induced by cannabidiol in the forced swim test. J. Psychopharmacol.,  2018, 32(8), 922-931.
 [http://dx.doi.org/10.1177/0269881118784877] [PMID:  29968502]

[189]
Schiavon, A.P.; Bonato, J.M.; Milani, H.; Guimarães, F.S.; Weffort de Oliveira, R.M. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice. Prog. Neuropsychopharmacol. Biol. Psychiatry,  2016, 64, 27-34.
 [http://dx.doi.org/10.1016/j.pnpbp.2015.06.017] [PMID:  26187374]

[190]
Kraus, C.; Castrén, E.; Kasper, S.; Lanzenberger, R. Serotonin and neuroplasticity - Links between molecular, functional and structural pathophysiology in depression. Neurosci. Biobehav. Rev.,  2017, 77, 317-326.
 [http://dx.doi.org/10.1016/j.neubiorev.2017.03.007] [PMID:  28342763]

[191]
Corroon, J.; Phillips, J.A. A cross-sectional study of cannabidiol users. Cannabis Cannabinoid Res.,  2018, 3(1), 152-161.
 [http://dx.doi.org/10.1089/can.2018.0006] [PMID:  30014038]

[192]
Pacheco, J.C.; Souza, J.D.S.; Hallak, J.E.C.; Osório, F.L.; Campos, A.C.; Guimarães, F.S.; Zuardi, A.W.; Crippa, J.A.S. Cannabidiol as a treatment for mental health outcomes among health care workers during the coronavirus disease pandemic. J. Clin. Psychopharmacol.,  2021, 41(3), 327-329.
 [http://dx.doi.org/10.1097/JCP.0000000000001405] [PMID:  33843818]

[193]
Bitencourt, R.M.; Takahashi, R.N. Cannabidiol as a therapeutic alternative for post-traumatic stress disorder: from bench research to confirmation in human trials. Front. Neurosci.,  2018, 12, 502.
 [http://dx.doi.org/10.3389/fnins.2018.00502] [PMID:  30087591]

[194]
Stein, J.Y.; Wilmot, D.V.; Solomon, Z. Does one size fit all? Nosological, clinical, and scientific implications of variations in PTSD Criterion A. J. Anxiety Disord.,  2016, 43, 106-117.
 [http://dx.doi.org/10.1016/j.janxdis.2016.07.001] [PMID:  27449856]

[195]
Shalev, A.; Liberzon, I.; Marmar, C. Post-traumatic stress disorder. N. Engl. J. Med.,  2017, 376(25), 2459-2469.
 [http://dx.doi.org/10.1056/NEJMra1612499] [PMID:  28636846]

[196]
Campos, A.C.; Fogaça, M.V.; Sonego, A.B.; Guimarães, F.S. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol. Res.,  2016, 112, 119-127.
 [http://dx.doi.org/10.1016/j.phrs.2016.01.033] [PMID:  26845349]

[197]
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed; Washington, DC, 2013. 

[198]
Blessing, E.M.; Steenkamp, M.M.; Manzanares, J.; Marmar, C.R. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics,  2015, 12(4), 825-836.
 [http://dx.doi.org/10.1007/s13311-015-0387-1] [PMID:  26341731]

[199]
Careaga, M.B.L.; Girardi, C.E.N.; Suchecki, D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. Neurosci. Biobehav. Rev.,  2016, 71, 48-57.
 [http://dx.doi.org/10.1016/j.neubiorev.2016.08.023] [PMID:  27590828]

[200]
Crippa, J.A.; Guimarães, F.S.; Campos, A.C.; Zuardi, A.W. Translational investigation of the therapeutic potential of cannabidiol (CBD): Toward a new age. Front. Immunol.,  2018, 9, 2009.
 [http://dx.doi.org/10.3389/fimmu.2018.02009] [PMID:  30298064]

[201]
Lee, J.L.C.; Bertoglio, L.J.; Guimarães, F.S.; Stevenson, C.W. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. Br. J. Pharmacol.,  2017, 174(19), 3242-3256.
 [http://dx.doi.org/10.1111/bph.13724] [PMID:  28268256]

[202]
Lisboa, S.F.; Vila-Verde, C.; Rosa, J.; Uliana, D.L.; Stern, C.A.J.; Bertoglio, L.J.; Resstel, L.B.; Guimaraes, F.S. Tempering aversive/traumatic memories with cannabinoids: a review of evidence from animal and human studies. Psychopharmacology (Berl.),  2019, 236(1), 201-226.
 [http://dx.doi.org/10.1007/s00213-018-5127-x] [PMID:  30604182]

[203]
Ross, D.A.; Arbuckle, M.R.; Travis, M.J.; Dwyer, J.B.; van Schalkwyk, G.I.; Ressler, K.J. An integrated neuroscience perspective on formulation and treatment planning for posttraumatic stress disorder: An educational review. JAMA Psychiatry,  2017, 74(4), 407-415.
 [http://dx.doi.org/10.1001/jamapsychiatry.2016.3325] [PMID:  28273291]

[204]
Bienvenu, T.C.M.; Dejean, C.; Jercog, D.; Aouizerate, B.; Lemoine, M.; Herry, C. The advent of fear conditioning as an animal model of post-traumatic stress disorder: Learning from the past to shape the future of PTSD research. Neuron,  2021, 109(15), 2380-2397.
 [http://dx.doi.org/10.1016/j.neuron.2021.05.017] [PMID:  34146470]

[205]
Hill, M.N.; Campolongo, P.; Yehuda, R.; Patel, S. Integrating endocannabinoid signaling and cannabinoids into the biology and treatment of posttraumatic stress disorder. Neuropsychopharmacology,  2018, 43(1), 80-102.
 [http://dx.doi.org/10.1038/npp.2017.162] [PMID:  28745306]

[206]
Levin, R.; Almeida, V.; Peres, F.F.; Calzavara, M.B.; da Silva, N.D.; Suiama, M.A.; Niigaki, S.T.; Zuardi, A.W.; Hallak, J.E.; Crippa, J.A.; Abílio, V.C. Antipsychotic profile of cannabidiol and rimonabant in an animal model of emotional context processing in schizophrenia. Curr. Pharm. Des.,  2012, 18(32), 4960-4965.
 [http://dx.doi.org/10.2174/138161212802884735] [PMID:  22716146]

[207]
Norris, C.; Loureiro, M.; Kramar, C.; Zunder, J.; Renard, J.; Rushlow, W.; Laviolette, S.R. Cannabidiol modulates fear memory formation through interactions with serotonergic transmission in the mesolimbic system. Neuropsychopharmacology,  2016, 41(12), 2839-2850.
 [http://dx.doi.org/10.1038/npp.2016.93] [PMID:  27296152]

[208]
Resstel, L.B.; Joca, S.R.; Moreira, F.A.; Corrêa, F.M.; Guimarães, F.S. Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav. Brain Res.,  2006, 172(2), 294-298.
 [http://dx.doi.org/10.1016/j.bbr.2006.05.016] [PMID:  16780966]

[209]
Gomes, F.V.; Reis, D.G.; Alves, F.H.; Corrêa, F.M.; Guimarães, F.S.; Resstel, L.B. Cannabidiol injected into the bed nucleus of the stria terminalis reduces the expression of contextual fear conditioning via 5-HT1A receptors. J. Psychopharmacol.,  2012, 26(1), 104-113.
 [http://dx.doi.org/10.1177/0269881110389095] [PMID:  21148020]

[210]
Lemos, J.I.; Resstel, L.B.; Guimarães, F.S. Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav. Brain Res.,  2010, 207(1), 105-111.
 [http://dx.doi.org/10.1016/j.bbr.2009.09.045] [PMID:  19800921]

[211]
Assareh, N.; Gururajan, A.; Zhou, C.; Luo, J.L.; Kevin, R.C.; Arnold, J.C. Cannabidiol disrupts conditioned fear expression and cannabidiolic acid reduces trauma-induced anxiety-related behaviour in mice. Behav. Pharmacol.,  2020, 31(6), 591-596.
 [http://dx.doi.org/10.1097/FBP.0000000000000565] [PMID:  32483052]

[212]
Jurkus, R.; Day, H.L.; Guimarães, F.S.; Lee, J.L.; Bertoglio, L.J.; Stevenson, C.W. Cannabidiol regulation of learned fear: Implications for treating anxiety-related disorders. Front. Pharmacol.,  2016, 7, 454.
 [http://dx.doi.org/10.3389/fphar.2016.00454] [PMID:  27932983]

[213]
Song, C.; Stevenson, C.W.; Guimaraes, F.S.; Lee, J.L. Bidirectional effects of cannabidiol on contextual fear memory extinction. Front. Pharmacol.,  2016, 7, 493.
 [http://dx.doi.org/10.3389/fphar.2016.00493] [PMID:  28018227]

[214]
Do Monte, F.H.; Souza, R.R.; Bitencourt, R.M.; Kroon, J.A.; Takahashi, R.N. Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors. Behav. Brain Res.,  2013, 250, 23-27.
 [http://dx.doi.org/10.1016/j.bbr.2013.04.045] [PMID:  23643693]

[215]
Stern, C.A.; Gazarini, L.; Takahashi, R.N.; Guimarães, F.S.; Bertoglio, L.J. On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment. Neuropsychopharmacology,  2012, 37(9), 2132-2142.
 [http://dx.doi.org/10.1038/npp.2012.63] [PMID:  22549120]

[216]
Raymundi, A.M.; da Silva, T.R.; Zampronio, A.R.; Guimarães, F.S.; Bertoglio, L.J.; Stern, C.A.J. A time-dependent contribution of hippocampal CB1, CB2 and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation. Br. J. Pharmacol.,  2020, 177(4), 945-957.
 [http://dx.doi.org/10.1111/bph.14895] [PMID:  31648363]

[217]
Rossignoli, M.T.; Lopes-Aguiar, C.; Ruggiero, R.N.; Do Val da Silva, R.A.; Bueno-Junior, L.S.; Kandratavicius, L.; Peixoto-Santos, J.E.; Crippa, J.A.; Cecilio Hallak, J.E.; Zuardi, A.W.; Szawka, R.E.; Anselmo-Franci, J.; Leite, J.P.; Romcy-Pereira, R.N. Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits. Neuroscience,  2017, 350, 85-93.
 [http://dx.doi.org/10.1016/j.neuroscience.2017.03.019] [PMID:  28344069]

[218]
Bensinger, S.J.; Tontonoz, P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature,  2008, 454(7203), 470-477.
 [http://dx.doi.org/10.1038/nature07202] [PMID:  18650918]

[219]
Bernardo, A.; Minghetti, L. Regulation of glial cell functions by PPAR-gamma natural and synthetic agonists. PPAR Res.,  2008, 2008, 864140.
 [http://dx.doi.org/10.1155/2008/864140] [PMID:  18464925]

[220]
Moraes, L.A.; Piqueras, L.; Bishop-Bailey, D. Peroxisome proliferator-activated receptors and inflammation. Pharmacol. Ther.,  2006, 110(3), 371-385.
 [http://dx.doi.org/10.1016/j.pharmthera.2005.08.007] [PMID:  16168490]

[221]
Clark, S.M.; Soroka, J.A.; Song, C.; Li, X.; Tonelli, L.H. CD4(+) T cells confer anxiolytic and antidepressant-like effects, but enhance fear memory processes in Rag2(-/-) mice. Stress,  2016, 19(3), 303-311.
 [http://dx.doi.org/10.1080/10253890.2016.1191466] [PMID:  27295202]

[222]
Yu, Z.; Fukushima, H.; Ono, C.; Sakai, M.; Kasahara, Y.; Kikuchi, Y.; Gunawansa, N.; Takahashi, Y.; Matsuoka, H.; Kida, S.; Tomita, H. Microglial production of TNF-alpha is a key element of sustained fear memory. Brain Behav. Immun.,  2017, 59, 313-321.
 [http://dx.doi.org/10.1016/j.bbi.2016.08.011] [PMID:  27562421]

[223]
Young, M.B.; Howell, L.L.; Hopkins, L.; Moshfegh, C.; Yu, Z.; Clubb, L.; Seidenberg, J.; Park, J.; Swiercz, A.P.; Marvar, P.J. A peripheral immune response to remembering trauma contributes to the maintenance of fear memory in mice. Psychoneuroendocrinology,  2018, 94, 143-151.
 [http://dx.doi.org/10.1016/j.psyneuen.2018.05.012] [PMID:  29783162]

[224]
Hughes, B.; Herron, C.E. Cannabidiol reverses deficits in hippocampal LTP in a model of Alzheimer’s disease. Neurochem. Res.,  2019, 44(3), 703-713.
 [http://dx.doi.org/10.1007/s11064-018-2513-z] [PMID:  29574668]

[225]
Esposito, G.; Scuderi, C.; Valenza, M.; Togna, G.I.; Latina, V.; De Filippis, D.; Cipriano, M.; Carratù, M.R.; Iuvone, T.; Steardo, L. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One,  2011, 6(12), e28668.
 [http://dx.doi.org/10.1371/journal.pone.0028668] [PMID:  22163051]

[226]
Wen, J.; Ribeiro, R.; Tanaka, M.; Zhang, Y. Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis. Neuropharmacology,  2015, 99, 196-209.
 [http://dx.doi.org/10.1016/j.neuropharm.2015.07.010] [PMID:  26189763]

[227]
Turcotte, C.; Blanchet, M.R.; Laviolette, M.; Flamand, N. The CB2 receptor and its role as a regulator of inflammation. Cell. Mol. Life Sci.,  2016, 73(23), 4449-4470.
 [http://dx.doi.org/10.1007/s00018-016-2300-4] [PMID:  27402121]

[228]
Zoppi, S.; Madrigal, J.L.; Caso, J.R.; García-Gutiérrez, M.S.; Manzanares, J.; Leza, J.C.; García-Bueno, B. Regulatory role of the cannabinoid CB2 receptor in stress-induced neuroinflammation in mice. Br. J. Pharmacol.,  2014, 171(11), 2814-2826.
 [http://dx.doi.org/10.1111/bph.12607] [PMID:  24467609]

[229]
Zoppi, S.; Pérez Nievas, B.G.; Madrigal, J.L.; Manzanares, J.; Leza, J.C.; García-Bueno, B. Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation. Neuropsychopharmacology,  2011, 36(4), 805-818.
 [http://dx.doi.org/10.1038/npp.2010.214] [PMID:  21150911]

[230]
Pistis, M.; O’Sullivan, S.E. The role of nuclear hormone receptors in cannabinoid function. Adv. Pharmacol.,  2017, 80, 291-328.
 [http://dx.doi.org/10.1016/bs.apha.2017.03.008] [PMID:  28826538]

[231]
Fogaça, M.V.; Reis, F.M.; Campos, A.C.; Guimarães, F.S. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience. Eur. Neuropsychopharmacol.,  2014, 24(3), 410-419.
 [http://dx.doi.org/10.1016/j.euroneuro.2013.10.012] [PMID:  24321837]

[232]
Rock, E.M.; Bolognini, D.; Limebeer, C.L.; Cascio, M.G.; Anavi-Goffer, S.; Fletcher, P.J.; Mechoulam, R.; Pertwee, R.G.; Parker, L.A. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br. J. Pharmacol.,  2012, 165(8), 2620-2634.
 [http://dx.doi.org/10.1111/j.1476-5381.2011.01621.x] [PMID:  21827451]

[233]
Marinho, A.L.; Vila-Verde, C.; Fogaça, M.V.; Guimarães, F.S. Effects of intra-infralimbic prefrontal cortex injections of cannabidiol in the modulation of emotional behaviors in rats: contribution of 5HT₁A receptors and stressful experiences. Behav. Brain Res.,  2015, 286, 49-56.
 [http://dx.doi.org/10.1016/j.bbr.2015.02.023] [PMID:  25701682]

[234]
Lisboa, S.F.; Stecchini, M.F.; Corrêa, F.M.; Guimarães, F.S.; Resstel, L.B. Different role of the ventral medial prefrontal cortex on modulation of innate and associative learned fear. Neuroscience,  2010, 171(3), 760-768.
 [http://dx.doi.org/10.1016/j.neuroscience.2010.09.048] [PMID:  20883749]

[235]
Giustino, T.F.; Maren, S. The role of the medial prefrontal cortex in the conditioning and extinction of fear. Front. Behav. Neurosci.,  2015, 9, 298.
 [http://dx.doi.org/10.3389/fnbeh.2015.00298] [PMID:  26617500]

[236]
Sotres-Bayon, F.; Quirk, G.J. Prefrontal control of fear: more than just extinction. Curr. Opin. Neurobiol.,  2010, 20(2), 231-235.
 [http://dx.doi.org/10.1016/j.conb.2010.02.005] [PMID:  20303254]

[237]
Vidal-Gonzalez, I.; Vidal-Gonzalez, B.; Rauch, S.L.; Quirk, G.J. Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn. Mem.,  2006, 13(6), 728-733.
 [http://dx.doi.org/10.1101/lm.306106] [PMID:  17142302]

[238]
Szkudlarek, H.J. Desai, S.J.; Renard, J.; Pereira, B.; Norris, C.; Jobson, C.E.L.; Rajakumar, N.; Allman, B.L.; Laviolette, S.R. Δ-9-Tetrahydrocannabinol and Cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors. Neuropsychopharmacology,  2019, 44(4), 817-825.
 [http://dx.doi.org/10.1038/s41386-018-0282-7] [PMID:  30538288]

[239]
Rock, E.M.; Limebeer, C.L.; Petrie, G.N.; Williams, L.A.; Mechoulam, R.; Parker, L.A. Effect of prior foot shock stress and Δ9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats. Psychopharmacology (Berl.),  2017, 234(14), 2207-2217.
 [http://dx.doi.org/10.1007/s00213-017-4626-5] [PMID:  28424834]

[240]
Campos, A.C.; Moreira, F.A.; Gomes, F.V.; Del Bel, E.A.; Guimarães, F.S. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos. Trans. R. Soc. Lond. B Biol. Sci.,  2012, 367(1607), 3364-3378.
 [http://dx.doi.org/10.1098/rstb.2011.0389] [PMID:  23108553]

[241]
Shallcross, J.; Hámor, P.; Bechard, A.R.; Romano, M.; Knackstedt, L.; Schwendt, M. The divergent effects of CDPPB and cannabidiol on fear extinction and anxiety in a predator scent stress model of PTSD in rats. Front. Behav. Neurosci.,  2019, 13, 91.
 [http://dx.doi.org/10.3389/fnbeh.2019.00091] [PMID:  31133832]

[242]
Gasparyan, A.; Navarrete, F.; Manzanares, J. Cannabidiol and sertraline regulate behavioral and brain gene expression alterations in an animal model of PTSD. Front. Pharmacol.,  2021, 12, 694510.
 [http://dx.doi.org/10.3389/fphar.2021.694510] [PMID:  34262461]

[243]
Passos, I.C.; Vasconcelos-Moreno, M.P.; Costa, L.G.; Kunz, M.; Brietzke, E.; Quevedo, J.; Salum, G.; Magalhães, P.V.; Kapczinski, F.; Kauer-Sant’Anna, M. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry,  2015, 2(11), 1002-1012.
 [http://dx.doi.org/10.1016/S2215-0366(15)00309-0] [PMID:  26544749]

[244]
Yang, J.J.; Jiang, W. Immune biomarkers alterations in post-traumatic stress disorder: A systematic review and meta-analysis. J. Affect. Disord.,  2020, 268, 39-46.
 [http://dx.doi.org/10.1016/j.jad.2020.02.044] [PMID:  32158005]

[245]
Li, S.; Liao, Y.; Dong, Y.; Li, X.; Li, J.; Cheng, Y.; Cheng, J.; Yuan, Z. Microglial deletion and inhibition alleviate behavior of post-traumatic stress disorder in mice. J. Neuroinflammation,  2021, 18(1), 7.
 [http://dx.doi.org/10.1186/s12974-020-02069-9] [PMID:  33402212]

[246]
Yamanashi, T.; Iwata, M.; Shibushita, M.; Tsunetomi, K.; Nagata, M.; Kajitani, N.; Miura, A.; Matsuo, R.; Nishiguchi, T.; Kato, T.A.; Setoyama, D.; Shirayama, Y.; Watanabe, K.; Shinozaki, G.; Kaneko, K. Beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, attenuates anxiety-related behavior in a rodent post-traumatic stress disorder model. Sci. Rep.,  2020, 10(1), 21629.
 [http://dx.doi.org/10.1038/s41598-020-78410-2] [PMID:  33303808]

[247]
Nagarkatti, P.; Pandey, R.; Rieder, S.A.; Hegde, V.L.; Nagarkatti, M. Cannabinoids as novel anti-inflammatory drugs. Future Med. Chem.,  2009, 1(7), 1333-1349.
 [http://dx.doi.org/10.4155/fmc.09.93] [PMID:  20191092]

[248]
Nichols, J.M.; Kaplan, B.L.F. Immune responses regulated by cannabidiol. Cannabis Cannabinoid Res.,  2020, 5(1), 12-31.
 [http://dx.doi.org/10.1089/can.2018.0073] [PMID:  32322673]

[249]
Zuardi, A.W. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev. Bras. Psiquiatr.,  2008, 30(3), 271-280.
 [http://dx.doi.org/10.1590/S1516-44462008000300015] [PMID:  18833429]

[250]
Barichello, T.; Ceretta, R.A.; Generoso, J.S.; Moreira, A.P.; Simões, L.R.; Comim, C.M.; Quevedo, J.; Vilela, M.C.; Zuardi, A.W.; Crippa, J.A.; Teixeira, A.L. Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis. Eur. J. Pharmacol.,  2012, 697(1-3), 158-164.
 [http://dx.doi.org/10.1016/j.ejphar.2012.09.053] [PMID:  23085269]

[251]
Borrelli, F.; Aviello, G.; Romano, B.; Orlando, P.; Capasso, R.; Maiello, F.; Guadagno, F.; Petrosino, S.; Capasso, F.; Di Marzo, V.; Izzo, A.A. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. J. Mol. Med. (Berl.),  2009, 87(11), 1111-1121.
 [http://dx.doi.org/10.1007/s00109-009-0512-x] [PMID:  19690824]

[252]
Campos, A.C.; Brant, F.; Miranda, A.S.; Machado, F.S.; Teixeira, A.L. Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria. Neuroscience,  2015, 289, 166-180.
 [http://dx.doi.org/10.1016/j.neuroscience.2014.12.051] [PMID:  25595981]

[253]
Esposito, G.; Scuderi, C.; Savani, C.; Steardo, L., Jr; De Filippis, D.; Cottone, P.; Iuvone, T.; Cuomo, V.; Steardo, L. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br. J. Pharmacol.,  2007, 151(8), 1272-1279.
 [http://dx.doi.org/10.1038/sj.bjp.0707337] [PMID:  17592514]

[254]
Mecha, M.; Feliú, A.; Iñigo, P.M.; Mestre, L.; Carrillo-Salinas, F.J.; 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.
 [http://dx.doi.org/10.1016/j.nbd.2013.06.016] [PMID:  23851307]

[255]
Vuolo, F.; Petronilho, F.; Sonai, B.; Ritter, C.; Hallak, J.E.; Zuardi, A.W.; Crippa, J.A.; Dal-Pizzol, F. Evaluation of serum cytokines levels and the role of cannabidiol treatment in animal model of asthma. Mediators Inflamm.,  2015, 2015, 538670.
 [http://dx.doi.org/10.1155/2015/538670] [PMID:  26101464]

[256]
Srivastava, M.D.; Srivastava, B.I.; Brouhard, B. Delta9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology,  1998, 40(3), 179-185.
 [http://dx.doi.org/10.1016/S0162-3109(98)00041-1] [PMID:  9858061]

[257]
Dos-Santos-Pereira, M.; da-Silva, C.A.; Guimarães, F.S.; Del-Bel, E. Co-administration of cannabidiol and capsazepine reduces L-DOPA-induced dyskinesia in mice: Possible mechanism of action. Neurobiol. Dis.,  2016, 94, 179-195.
 [http://dx.doi.org/10.1016/j.nbd.2016.06.013] [PMID:  27373843]

[258]
Hayakawa, K.; Mishima, K.; Nozako, M.; Ogata, A.; Hazekawa, M.; Liu, A.X.; Fujioka, M.; Abe, K.; Hasebe, N.; Egashira, N.; Iwasaki, K.; Fujiwara, M. Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology,  2007, 52(4), 1079-1087.
 [http://dx.doi.org/10.1016/j.neuropharm.2006.11.005] [PMID:  17320118]

[259]
Booz, G.W. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic. Biol. Med.,  2011, 51(5), 1054-1061.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2011.01.007] [PMID:  21238581]

[260]
Petrovici, A.R.; Simionescu, N.; Sandu, A.I.; Paraschiv, V.; Silion, M.; Pinteala, M. New insights on hemp oil enriched in cannabidiol: Decarboxylation, antioxidant properties and in vitro anticancer effect. Antioxidants,  2021, 10(5), 738.
 [http://dx.doi.org/10.3390/antiox10050738] [PMID:  34067035]

[261]
Liu, D.Z.; Hu, C.M.; Huang, C.H.; Wey, S.P.; Jan, T.R. Cannabidiol attenuates delayed-type hypersensitivity reactions via suppressing T-cell and macrophage reactivity. Acta Pharmacol. Sin.,  2010, 31(12), 1611-1617.
 [http://dx.doi.org/10.1038/aps.2010.155] [PMID:  21042286]

[262]
Kaplan, B.L.; Springs, A.E.; Kaminski, N.E. The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT). Biochem. Pharmacol.,  2008, 76(6), 726-737.
 [http://dx.doi.org/10.1016/j.bcp.2008.06.022] [PMID:  18656454]

[263]
Walter, L.; Franklin, A.; Witting, A.; Wade, C.; Xie, Y.; Kunos, G.; Mackie, K.; Stella, N. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. Neurosci.,  2003, 23(4), 1398-1405.
 [http://dx.doi.org/10.1523/JNEUROSCI.23-04-01398.2003] [PMID:  12598628]

[264]
Martín-Moreno, A.M.; Reigada, D.; Ramírez, B.G.; Mechoulam, R.; Innamorato, N.; Cuadrado, A.; de Ceballos, M.L. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: Relevance to Alzheimer’s disease. Mol. Pharmacol.,  2011, 79(6), 964-973.
 [http://dx.doi.org/10.1124/mol.111.071290] [PMID:  21350020]

[265]
Magen, I.; Avraham, Y.; Ackerman, Z.; Vorobiev, L.; Mechoulam, R.; Berry, E.M. Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation. Br. J. Pharmacol.,  2010, 159(4), 950-957.
 [http://dx.doi.org/10.1111/j.1476-5381.2009.00589.x] [PMID:  20128798]

[266]
Gurung, P.; Li, B.; Subbarao Malireddi, R.K.; Lamkanfi, M.; Geiger, T.L.; Kanneganti, T.D. Chronic TLR Stimulation controls NLRP3 inflammasome activation through IL-10 mediated regulation of NLRP3 expression and caspase-8 activation. Sci. Rep.,  2015, 5(1), 14488.
 [http://dx.doi.org/10.1038/srep14488] [PMID:  26412089]

[267]
Kozela, E.; Lev, N.; Kaushansky, N.; Eilam, R.; Rimmerman, N.; Levy, R.; Ben-Nun, A.; Juknat, A.; Vogel, Z. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br. J. Pharmacol.,  2011, 163(7), 1507-1519.
 [http://dx.doi.org/10.1111/j.1476-5381.2011.01379.x] [PMID:  21449980]

[268]
Juknat, A.; Gao, F.; Coppola, G.; Vogel, Z.; Kozela, E. miRNA expression profiles and molecular networks in resting and LPS-activated BV-2 microglia-Effect of cannabinoids. PLoS One,  2019, 14(2), e0212039.
 [http://dx.doi.org/10.1371/journal.pone.0212039] [PMID:  30742662]

[269]
Hampson, A.J.; Grimaldi, M.; Lolic, M.; Wink, D.; Rosenthal, R.; Axelrod, J. Neuroprotective antioxidants from marijuana. Ann. N. Y. Acad. Sci.,  2000, 899(1), 274-282.
 [http://dx.doi.org/10.1111/j.1749-6632.2000.tb06193.x] [PMID:  10863546]

[270]
Liu, C.; Li, H.; Xu, F.; Jiang, X.; Ma, H.; Seeram, N.P. Cannabidiol protects human skin Keratinocytes from hydrogen-peroxide-induced oxidative stress via modulation of the Caspase-1-IL-1β axis. J. Nat. Prod.,  2021, 84(5), 1563-1572.
 [http://dx.doi.org/10.1021/acs.jnatprod.1c00083] [PMID:  33955754]

[271]
Hao, F.; Feng, Y. Cannabidiol (CBD) enhanced the hippocampal immune response and autophagy of APP/PS1 Alzheimer’s mice uncovered by RNA-seq. Life Sci.,  2021, 264, 118624.
 [http://dx.doi.org/10.1016/j.lfs.2020.118624] [PMID:  33096116]

[272]
Yang, L.; Rozenfeld, R.; Wu, D.; Devi, L.A.; Zhang, Z.; Cederbaum, A. Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy. Free Radic. Biol. Med.,  2014, 68, 260-267.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2013.12.026] [PMID:  24398069]

[273]
Böckmann, S.; Hinz, B. Cannabidiol promotes endothelial cell survival by heme oxygenase-1-mediated autophagy. Cells,  2020, 9(7), E1703.
 [http://dx.doi.org/10.3390/cells9071703] [PMID:  32708634]

[274]
Gugliandolo, A.; Pollastro, F.; Bramanti, P.; Mazzon, E. Cannabidiol exerts protective effects in an in vitro model of Parkinson’s disease activating AKT/mTOR pathway. Fitoterapia,  2020, 143, 104553.
 [http://dx.doi.org/10.1016/j.fitote.2020.104553] [PMID:  32184097]

[275]
Shrivastava, A.; Kuzontkoski, P.M.; Groopman, J.E.; 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(7), 1161-1172.
 [http://dx.doi.org/10.1158/1535-7163.MCT-10-1100] [PMID:  21566064]

[276]
Vrechi, T.A.M.; Leão, A.H.F.F.; Morais, I.B.M.; Abílio, V.C.; Zuardi, A.W.; Hallak, J.E.C.; Crippa, J.A.; Bincoletto, C.; Ureshino, R.P.; Smaili, S.S.; Pereira, G.J.S. Cannabidiol induces autophagy via ERK1/2 activation in neural cells. Sci. Rep.,  2021, 11(1), 5434.
 [http://dx.doi.org/10.1038/s41598-021-84879-2] [PMID:  33686185]

[277]
Suryavanshi, S.V.; Kovalchuk, I.; Kovalchuk, O. Cannabinoids as key regulators of inflammasome signaling: A current perspective. Front. Immunol.,  2021, 11, 613613.
 [http://dx.doi.org/10.3389/fimmu.2020.613613] [PMID:  33584697]

[278]
Jiang, X.; Gu, Y.; Huang, Y.; Zhou, Y.; Pang, N.; Luo, J.; Tang, Z.; Zhang, Z.; Yang, L. CBD alleviates liver injuries in alcoholics with high-fat high-cholesterol diet through regulating NLRP3 inflammasome-pyroptosis pathway. Front. Pharmacol.,  2021, 12, 724747.
 [http://dx.doi.org/10.3389/fphar.2021.724747] [PMID:  34630100]

[279]
Huang, Y.; Wan, T.; Pang, N.; Zhou, Y.; Jiang, X.; Li, B.; Gu, Y.; Huang, Y.; Ye, X.; Lian, H.; Zhang, Z.; Yang, L. Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-κB and NLRP3 inflammasome pathway. J. Cell. Physiol.,  2019, 234(11), 21224-21234.
 [http://dx.doi.org/10.1002/jcp.28728] [PMID:  31032942]

[280]
Rimmerman, N.; Juknat, A.; Kozela, E.; Levy, R.; Bradshaw, H.B.; Vogel, Z. The non-psychoactive plant cannabinoid, cannabidiol affects cholesterol metabolism-related genes in microglial cells. Cell. Mol. Neurobiol.,  2011, 31(6), 921-930.
 [http://dx.doi.org/10.1007/s10571-011-9692-3] [PMID:  21533611]

[281]
Libro, R.; Scionti, D.; Diomede, F.; Marchisio, M.; Grassi, G.; Pollastro, F.; Piattelli, A.; Bramanti, P.; Mazzon, E.; Trubiani, O. Cannabidiol modulates the immunophenotype and inhibits the activation of the inflammasome in human gingival mesenchymal stem cells. Front. Physiol.,  2016, 7, 559.
 [http://dx.doi.org/10.3389/fphys.2016.00559] [PMID:  27932991]

[282]
Corpetti, C.; Del Re, A.; Seguella, L.; Palenca, I.; Rurgo, S.; De Conno, B.; Pesce, M.; Sarnelli, G.; Esposito, G. Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1 signaling suppression in Caco-2 cell line. Phytother. Res.,  2021, 35(12), 6893-6903.
 [http://dx.doi.org/10.1002/ptr.7302] [PMID:  34643000]

[283]
Liu, C.; Ma, H.; Slitt, A.L.; Seeram, N.P. Inhibitory effect of cannabidiol on the activation of NLRP3 inflammasome is associated with its modulation of the P2X7 receptor in human monocytes. J. Nat. Prod.,  2020, 83(6), 2025-2029.
 [http://dx.doi.org/10.1021/acs.jnatprod.0c00138] [PMID:  32374168]

[284]
Goodman, S.; Wadsworth, E.; Schauer, G.; Hammond, D. Use and perceptions of cannabidiol products in Canada and in the United States. Cannabis Cannabinoid Res.,  2020, 7(3), 355-364.
 [http://dx.doi.org/10.1089/can.2020.0093] [PMID:  33998872]

[285]
Moltke, J.; Hindocha, C. Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems. J Cannabis Res,  2021, 3(1), 5.
 [http://dx.doi.org/10.1186/s42238-021-00061-5] [PMID:  33602344]

[286]
Pavlovic, R.; Nenna, G.; Calvi, L.; Panseri, S.; Borgonovo, G.; Giupponi, L.; Cannazza, G.; Giorgi, A. Quality traits of “cannabidiol oils”: Cannabinoids content, terpene fingerprint and oxidation stability of european commercially available preparations. Molecules,  2018, 23(5), E1230.
 [http://dx.doi.org/10.3390/molecules23051230] [PMID:  29783790]
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DOI https://dx.doi.org/10.2174/1570159X20666220411101217	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190
Current Neuropharmacology

The NLRP3 Inflammasome in Stress Response: Another Target for the Promiscuous Cannabidiol

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