CBD may have anti-inflammatory properties through activation of PPARγ. In addition, CBD stimulates neurogenesis and may therefore counteract neurodegeneration at multiple levels (Esposito et al., 2011).
In cultured astrocytes, Aβ1-42 reduced cell viability and PPARγ expression and increased cellular inflammation and anti-oxidant capacity. Specific CB1 stimulation (with WIN55,212-2, a synthetic analog of THC) prevented all these effects and increased cellular viability (Aguirre-Rueda et al., 2015).
In a rat model of autism (Valproic Acid model), GPR55, PPARα and PPARγ were reduced in several brain regions involved in higher cognitive functions (frontal cortex and hippocampus) (Kerr et al., 2013)
Functional Gastro-Intestinal Disorders
Apart from CB1 and CB2, there is evidence for the involvement of PPARγ and TRPV1 in Crohn’s Disease (de Fontgalland et al., 2014; Schicho and Storr, 2014).
In the LPS mouse model of colitis, 10 mg/kg i.p. CBD decreased reactive gliosis, mast cell and macrophage recruitment, TNFα expression and intestinal apoptosis. In ulcerative colitis patient rectal biopsies also reduced reactive gliosis, at least partially through PPARγ (De Filippis et al., 2011)
Activation of PPAR-γ receptor showed behavioral recovery and microglial supression in a model of stroke (Yu et al., 2015). CBD mechanisms would involve the modulation of excitotoxicity, oxidative stress and inflammation through CB2, 5HT1A, Adenosine A2A and PPAR-γ receptors (Castillo et al., 2010; Hind et al., 2015; Pazos et al., 2012, 2013)
In cancer cell lines (A549 and H460) and human metastatic lung cancer cells CBD induced apoptosis via COX-2 and PPARγ. In A549-xenografted mice CBD caused tumor regression (Ramer et al., 2013).
Regarding treatment of MS with sativex, the effects of CBD were PPARγ-mediated whereas THC signaling was CB1/2 dependent (Feliú et al., 2015).
In human neuroblastoma cells, THC, but not CBD was found to be neuroprotective. Neuroprotection was mediated by PPARγ (Carroll et al., 2012)
CBD and CBG do not function through classical CB receptors and none of the phytocannabinoids depended on TRPV1 for their effect (in contrast to endocannabinoid function below), but PPARγ and GPR55 may be involved in the effect of cannainoids in Psoriasis (Wilkinson and Williamson, 2007).
Psychosis and Schizophrenia
PPAR-γ receptor has also been related to Schizophrenia (Costa et al., 2013; Liu et al., 2014).
Aguirre-Rueda, D., Guerra-Ojeda, S., Aldasoro, M., Iradi, A., Obrador, E., Mauricio, M.D., Vila, J.M., Marchio, P., and Valles, S.L. (2015). WIN 55,212-2, Agonist of cannabinoid Receptors, Prevents Amyloid β1-42 Effects on Astrocytes in Primary Culture. PloS One 10, e0122843.
Carroll, C.B., Zeissler, M.-L., Hanemann, C.O., and Zajicek, J.P. (2012). Δ9-tetrahydrocannabinol (Δ9-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease. Neuropathol. Appl. Neurobiol. 38, 535–547.
Castillo, A., Tolón, M.R., Fernández-Ruiz, J., Romero, J., and Martinez-Orgado, J. (2010). 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. 37, 434–440.
Costa, M., Squassina, A., Congiu, D., Chillotti, C., Niola, P., Galderisi, S., Pistis, M., and Del Zompo, M. (2013). Investigation of endocannabinoid system genes suggests association between peroxisome proliferator activator receptor-α gene (PPARA) and Schizophrenia. Eur. Neuropsychopharmacol. 23, 749–759.
De Filippis, D., Esposito, G., Cirillo, C., Cipriano, M., De Winter, B.Y., Scuderi, C., Sarnelli, G., Cuomo, R., Steardo, L., De Man, J.G., et al. (2011). Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PloS One 6, e28159.
De Fontgalland, D., Brookes, S.J., Gibbins, I., Sia, T.C., and Wattchow, D.A. (2014). The neurochemical changes in the innervation of human colonic mesenteric and submucosal blood vessels in ulcerative colitis and Crohn’s disease. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 26, 731–744.
Esposito, G., Scuderi, C., Valenza, M., Togna, G.I., Latina, V., De Filippis, D., Cipriano, M., Carratù, M.R., Iuvone, T., and Steardo, L. (2011). Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PloS One 6, e28668.
Feliú, A., Moreno-Martet, M., Mecha, M., Carrillo-Salinas, F.J., de Lago, E., Fernández-Ruiz, J., and Guaza, C. (2015). A sativex-like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.
Hind, W.H., England, T.J., and O’Sullivan, S.E. (2015). Cannabidiol protects an in vitro model of the blood brain barrier (BBB) from oxygen-glucose deprivation via PPARγ and 5-HT1a. Br. J. Pharmacol.
Kerr, D.M., Downey, L., Conboy, M., Finn, D.P., and Roche, M. (2013). Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav. Brain Res. 249, 124–132.
Liu, Y.-R., Hu, T.-M., Lan, T.-H., Chiu, H.-J., Chang, Y.-H., Chen, S.-F., Yu, Y.-H., Chen, C.-C., and Loh, E.-W. (2014). Association of the PPAR-γ Gene with Altered Glucose Levels and Psychosis Profile in Schizophrenia Patients Exposed to Antipsychotics. Psychiatry Investig. 11, 179–185.
Pazos, M.R., Cinquina, V., Gómez, A., Layunta, R., Santos, M., Fernández-Ruiz, J., and Martínez-Orgado, J. (2012). Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. Neuropharmacology 63, 776–783.
Pazos, M.R., Mohammed, N., Lafuente, H., Santos, M., Martínez-Pinilla, E., Moreno, E., Valdizan, E., Romero, J., Pazos, A., Franco, R., et al. (2013). Mechanisms of cannabidiol neuroprotection in hypoxic–ischemic newborn pigs: Role of 5HT1A and CB2 receptors. Neuropharmacology 71, 282–291.
Ramer, R., Heinemann, K., Merkord, J., Rohde, H., Salamon, A., Linnebacher, M., & Hinz, B. (2013). COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human Lung Cancer cells. Molecular cancer Therapeutics, 12(1), 69-82. https://doi.org/10.1158/1535-7163.MCT-12-0335
Schicho, R., and Storr, M. (2014). Cannabis finds its way into treatment of Crohn’s disease. Pharmacology 93, 1–3.
Wilkinson, J.D., and Williamson, E.M. (2007). cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of Psoriasis. J. Dermatol. Sci. 45, 87–92.
Yu, S.-J., Reiner, D., Shen, H., Wu, K.-J., Liu, Q.-R., and Wang, Y. (2015). Time-Dependent Protection of CB2 Receptor Agonist in stroke. PloS One 10, e0132487.