Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ<sup>9</sup>‐tetrahydrocannabinol in BV‐2 microglial cells

Juknat, Ana; Pietr, Maciej; Kozela, Ewa; Rimmerman, Neta; Levy, Rivka; Coppola, Giovanni; Geschwind, Daniel H.; Vogel, Zvi

doi:10.1111/j.1476-5381.2011.01461.x

Cited by 82 publications

(82 citation statements)

References 91 publications

(132 reference statements)

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“…CBD can also positively modulate COX via increased mRNA and protein expression of PPARγ and COX2, which also suggests that a COX2-generated increase in PGD 2 and 15d-PGJ 2 could underlie PPARγ activation in addition to any direct activation of PPARγ by CBD [18,54,93]. A possible mechanism for this is suggested by the observation that NRF2 can increase PPARγ expression as CBD can activate NRF2 [79,199,200].…”

Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 99%

“…However, the protective effect of CBD has also been associated with an upregulation of Cu,Zn superoxide dismutase mRNA, an antioxidant enzyme [220]. Indeed, CBD can activate the redox-sensing factor NRF2, which is key in detecting electrophilic xenobiotics [79,200,221]. Mazur et al [222] have suggested CBD is a good candidate for phase 1 metabolism, as it is very lipophilic, so would be oxidized and thus result in activation of phase II metabolism.…”

Section: Cbd Enzyme Targets In Neurodegenerationmentioning

confidence: 99%

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Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 99%

Section: Cbd Enzyme Targets In Neurodegenerationmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

View full text Add to dashboard Cite

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“…It shows efficacy against brain damage produced by different types of insults, and in a model of neonatal ischemia its neuroprotective effects are due to multiple receptor activation (126). During inflammatory conditions, CBD alters the expression of ϳ1,200 genes, many of which controlled by nuclear factors involved in the regulation of stress responses and inflammation (411). The anti-inflammatory effects of CBD were related also to the control of microglial cell migration (898), the subsequent production of pro-inflammatory mediators and the inhibitory control of NF-B signaling and inducible NO synthase (246).…”

Section: Neuroprotection and Neurodegenerative Diseasesmentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

366

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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“…However, other signalling pathways, such as vanilloid receptors (TRPV1) (Di Marzo et al, 2001), PPARs (O'Sullivan, 2007), reactive oxygen species (ROS) signalling and the intracellular Ca 2+ signalling (Siegmund et al, 2005;, have also been reported to be activated by AEA. Therefore, it is not known which signalling pathway(s) are affected by the increased activities of AEA in breast cancer cells.Recent study on comparative gene profiling of gene expression in BV-2 microglial cells treated with either nonpsychoactive cannabidiol (CBD) or with psychoactive cannabinoid D 9 -tetrahydrocannabinol (THC) showed differential transcriptional profiles by THC and CBD (Juknat et al, 2012). Specifically, THC and lower levels of CBP induced cellular stress response involving GCN2/e1F2a/p8/ATF-4/CHOP-TR1B3 pathway, which suggested that this effect could underlie its anti-inflammatory activity (Juknat et al, 2012).…”

mentioning

confidence: 99%

Inhibition of fatty acid amide hydrolase activates Nrf2 signalling and induces heme oxygenase 1 transcription in breast cancer cells

Wood

Whitten

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSE Endocannabinoids such as anandamide (AEA) are important lipid ligands regulating cell proliferation, differentiation and apoptosis. Their levels are regulated by hydrolase enzymes, the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Here, we investigated whether FAAH or AEA are involved in NF (erythroid-derived 2)-like 2 (Nrf2)/antioxidant responsive element (ARE) pathway. EXPERIMENTAL APPROACH The aim of this study was to analyse the effects of AEA or FAAH inhibition by the URB597 inhibitor or FAAH/siRNA on the activation of Nrf2-ARE signalling pathway and heme oxygenase-1 (HO-1) induction and transcription. KEY RESULTS Endogenous AEA was detected in the immortalized human mammary epithelial MCF-10A cells (0.034 ng per 10 6 cells) but not in MCF-7 or MDA-MB-231 breast cancer cells. Because breast tumour cells express FAAH abundantly, we examined the effects of FAAH on Nrf2/antioxidant pathway. We found that inhibition of FAAH by the URB597 inhibitor induced antioxidant HO-1 in breast cancer cells and MCF-10A cells. RNAi-mediated knockdown of FAAH or treatment with AEA-activated ARE-containing reporter induced HO-1 mRNA and protein expression, independent of the cannabinoid receptors, CB1, CB2 or TRPV1. Furthermore, URB597, AEA and siRNA-FAAH treatments induced the nuclear translocation of Nrf2, while siRNA-Nrf2 treatment and Keap1 expression blocked AEA, URB597 and si-FAAH from activation of ARE reporter and HO-1 induction. siRNA-HO-1 treatment decreased the viability of breast cancer cells and MCF-10A cells. CONCLUSIONS AND IMPLICATIONS These data uncovered a novel mechanism by which inhibition of FAAH or exposure to AEA induced HO-1 transcripts and implicating AEA and FAAH as direct modifiers in signalling mediated activation of Nrf2-HO-1 pathway, independent of cannabinoid receptors.

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Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ⁹‐tetrahydrocannabinol in BV‐2 microglial cells

Cited by 82 publications

References 91 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Inhibition of fatty acid amide hydrolase activates Nrf2 signalling and induces heme oxygenase 1 transcription in breast cancer cells

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Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9‐tetrahydrocannabinol in BV‐2 microglial cells

Cited by 82 publications

References 91 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Inhibition of fatty acid amide hydrolase activates Nrf2 signalling and induces heme oxygenase 1 transcription in breast cancer cells

Contact Info

Product

Resources

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Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ⁹‐tetrahydrocannabinol in BV‐2 microglial cells