Please use this link to access this publication: Abstract The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway can be used to identify novel drug candidates for the treatment of age-associated neurodegenerative diseases that act by preserving mitochondrial function. Previously, we identified cannabinol (CBN) as a potent neuroprotector. Here, we demonstrate that not only does CBN protect nerve cells from oxytosis/ferroptosis in a manner that is dependent on mitochondria and it does so independently of cannabinoid receptors. Specifically, CBN directly targets mitochondria and preserves key mitochondrial functions including redox regulation, calcium...

Please use this link to access this publication. Abstract Serum is required for the survival and growth of most animal cells. In serum-free medium, B lymphoblastoid cells and fibroblasts die after 2 days. We report that submicromolar concentrations of Δ9-tetrahydrocannabinol (THC), Δ8-THC, cannabinol, or cannabidiol, but not WIN 55,212-2, prevented serum-deprived cell death. Δ9-THC also synergized with platelet-derived growth factor in activating resting NIH 3T3 fibroblasts. The cannabinoids' growth supportive effect did not correlate with their ability to bind to known cannabinoid receptors and showed no stereoselectivity, suggesting a nonreceptor-mediated pathway. Direct measurement of oxidative stress revealed that cannabinoids prevented serum-deprived cell death by...

Abstract Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH3 cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K+ currents (IK(M)), with an IC50 of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of IK(M) was not reversed by naloxone, suggesting that it was not mediated...

Abstract Cannabidiol (CBD), the main non-psychoactive component of Cannabis sativa L., is widely used in therapy for the treatment of different diseases and as an adjuvant drug. Our aim was to assess the effects of CBD on proinflammatory cytokine production and cell proliferation in human peripheral blood mononuclear cells (PBMCs) and on CD4+ T lymphocyte differentiation, and, furthermore, to test CBD’s ability to affect the functional properties of regulatory T cells (Treg). Experiments were performed on isolated PBMCs and purified CD4+ T lymphocytes obtained from the buffy coats of healthy subjects. Cytokines produced by CD4+ T cells were evaluated by flow cytometry and intracellular cytokine staining...

Abstract   The cellular microenvironment plays a critical role in the maintenance of bone marrow-derived mesenchymal stem cells (BM-MSCs) and their subsequent cell lineage differentiation. Recent studies suggested that individuals with adipocyte-related metabolic disorders have altered function and adipogenic potential of adipose stem cell subpopulations, primarily BM-MSCs, increasing the risk of heart attack, stroke or diabetes. In this study, we explored the potential therapeutic effect of some of the most abundant non-euphoric compounds derived from the Cannabis sativa plant (or phytocannabinoids) including tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), by analysing their pharmacological activity on viability of endogenous BM-MSCs as well as their ability to alter BM-MSC proliferation and differentiation into mature...

Cannabinoids are broadly immunosuppressive, and anti-inflammatory properties have been reported for certain marijuana constituents and endogenously produced cannabinoids. The CB2 cannabinoid receptor is an established constituent of immune systemcells, and we have recently established that the CB1 cannabinoid receptor is expressed in mast cells. In the present study, we sought to define a role for CB1 in mast cells and to identify the signalling pathways that may mediate the suppressive effects of CB1 ligation on mast cell activation. Our results show that CB1 and CB2 mediate diametrically opposed effects on cAMP levels in mast cells. The observed long-term stimulation of cAMP levels by the...

The present study investigated the inhibitory effect of cannabidiol (CBD), a major constituent of marijuana, on the catalytic activity of cytochrome P450 2C19 (CYP2C19). (S)-Mephenytoin 4'-hydroxylase activities of human liver microsomes (HLMs) and recombinant CYP2C19 were inhibited by CBD in a concentration-dependent manner (IC₅₀ = 8.70 and 2.51 µM, respectively). Omeprazole 5-hydroxylase and 3-O-methylfluorescein O-demethylase activities in recombinant CYP2C19 were also strongly inhibited by CBD (IC₅₀ = 1.55 and 1.79 µM, respectively). Kinetic analysis for inhibition revealed that CBD showed a mixed-type inhibition against (S)-mephenytoin 4'-hydroxylation by recombinant CYP2C19. To clarify the structural requirements for CBD-mediated CYP2C19 inhibition, the effects of CBD-related compounds on...

Cannabinoids and the endocannabinoid system have attracted considerable interest for therapeutic applications. Nevertheless, the mechanism of action of one of the main nonpsychoactive phytocannabinoids, cannabidiol (CBD), remains elusive despite potentially beneficial properties as an anti-convulsant and neuroprotectant. Here, we characterize the mechanisms by which CBD regulates Ca 2 homeostasis and mediates neuroprotection in neuronal preparations. Imaging studies in hippocampal cultures using fura-2 AM suggested that CBD-mediated Ca 2 regulation is bidirectional, depending on the excitability of cells. Under physiological K /Ca 2 levels, CBD caused a subtle rise in [Ca 2]i , whereas CBD reduced [Ca 2]i and prevented Ca 2 oscillations under high-excitability...

The ATP-dependent drug efflux transporter P-glycoprotein (Pgp) plays a significant role in the absorption and disposition of many compounds. The purpose of this study was to investigate the possible interaction of P-gp with each of four major marijuana constituents: 9-tetrahydrocannabinol (THC), 11-nor-9-tetrahydrocannabinol-carboxylic acid (THC-COOH), cannabinol (CBN), and cannabidiol (CBD). The results of a P-gp ATPase activity screen showed that THC-COOH, CBN, THC, and CBD all stimulated P-gp ATPase activity with a Michaelis-Menten parameter (Vmax/Km) value of 1.3, 0.7, 0.1, and 0.05, respectively. Furthermore, CBD showed a concentration-dependent inhibitory effect on verapamil-stimulated ATPase activity with an IC50 value of 39.6 M, whereas all other tested...