Microarray and Pathway Analysis Reveal Distinct Mechanisms Underlying Cannabinoid-Mediated Modulation of LPS-Induced Activation of BV-2 Microglial Cells

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

doi:10.1371/journal.pone.0061462

Cited by 102 publications

(103 citation statements)

References 76 publications

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“…It is also noteworthy that TRIB3 has been identified recently as a potent phytocannabinoid target gene (64)(65)(66). These results, together with our data presented here, strongly argue for the key participation of TRIB3 in mediating cellular effects of cannabinoids.…”

Section: Discussionsupporting

confidence: 83%

Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes

Oláh¹,

Tóth²,

Borbíró³

et al. 2014

J. Clin. Invest.

230

236

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Section: Discussionsupporting

confidence: 83%

Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes

Oláh¹,

Tóth²,

Borbíró³

et al. 2014

J. Clin. Invest.

230

236

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“…Oxidation of xenobiotics can potentially produce highly reactive intermediates and is why phase I and II metabolism is integrated with electrophilic sensors [e.g., the nuclear factor (erythroid-derived 2)-like 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway), which can upregulate cytoprotective genes and pathways [78]. In this regard, CBD can activate NRF2 [79].…”

Section: Other Enzymes Involved In Xenobiotic Metabolismmentioning

confidence: 99%

“…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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“…In a recent report, cannabidiol was found to up-regulate the transcription of Nrf-2 in BV-2 microglial cells [53]. Cannabidiol also increased the subsequent downstream enzymes including heme oxygenase-1, glutathione S-transferase, glutathione S-transferase peroxidase, NAD (P)H:quinone oxidoreductase and glutamatecysteine ligase, which play central role in providing defense against cytotoxic and electrophile induced oxidative stress [54].…”

Section: Cannabinoids In Parkinson's Diseasementioning

confidence: 95%