Cannabinol inhibits oxytosis/ferroptosis by directly targeting mitochondria independently of cannabinoid receptors

Liang, Zhibin; Soriano-Castell, David; Kepchia, Devin; Duggan, Brendan M.; Currais, António; Schubert, David; Maher, Pamela

doi:10.1016/j.freeradbiomed.2022.01.001

Cited by 18 publications

(41 citation statements)

References 80 publications

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“…CBN has neuroprotective activity that is associated with its anti-oxidative actions, trophic support, and elimination of intraneuronal β-amyloid in neuronal cells [241]. CBN preserves mitochondrial functions, such as redox regulation, calcium uptake, mitochondrial membrane potential, and bioenergetics [242]. CBN promotes endogenous antioxidant defense mechanisms and triggers AMP-activated protein kinase (AMPK) signaling pathways [242].…”

Section: Cannabinol (Cbn)mentioning

confidence: 99%

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Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles

Sionov

Steinberg

2022

Biomedicines

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Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.

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Section: Cannabinol (Cbn)mentioning

confidence: 99%

“…CBN preserves mitochondrial functions, such as redox regulation, calcium uptake, mitochondrial membrane potential, and bioenergetics [242]. CBN promotes endogenous antioxidant defense mechanisms and triggers AMP-activated protein kinase (AMPK) signaling pathways [242].…”

Section: Cannabinol (Cbn)mentioning

confidence: 99%

Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles

Sionov

Steinberg

2022

Biomedicines

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“…Indeed, cannabinol was reported to inhibit ferroptosis in HT-22 cells with a potency of 1−2 μM. 47 Ferroptosis suppression by the dipeptide carnosine has led to the suggestion that acrolein�which is known to react with carnosine (among many other nucleophiles)�is a mediator of ferroptosis. 48 Previous reports have suggested that carnosine may modulate LPO via several distinct mechanisms including scavenging of aldehydic LPO products (such as acrolein), trapping of chain-carrying peroxyl radicals as an RTA, and/or chelation of divalent metals involved in the initiation of LPO.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…46 Cannabinol has been reported to inhibit ferroptosis by targeting mitochondria and restoring impaired function by an unspecified mechanism. 47 When cannabinol was assayed using FENIX-2, inhibitory activity was observed at 20 μM, suggesting that cannabinol is a modest RTA. To corroborate this observation, we carried out FENIX-1 assays between 2 and 20 μM and obtained k inh = 1.3 ± 0.7 × 10 3 M −1 s −1 for its reaction with lipidperoxyl radicals (see the Supporting Information), suggesting an expected anti-ferroptotic potency again in the low μM range.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

General Approach to Identify, Assess, and Characterize Inhibitors of Lipid Peroxidation and Associated Cell Death

et al. 2023

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Lipid peroxidation (LPO) is associated with a variety of pathologies and drives a form of regulated necrosis called ferroptosis. There is much interest in small-molecule inhibitors of LPO as potential leads for therapeutic development for neurodegeneration, stroke, and acute organ failure, but this has been hampered by the lack of a universal high-throughput assay that can identify and assess candidates. Herein, we describe the development and validation of such an approach. Phosphatidylcholine liposomes loaded with ∼10% phospholipid hydroperoxide and STY-BODIPY, a fluorescent signal carrier that co-autoxidizes with polyunsaturated phospholipids, are shown to autoxidize at convenient and constant rates when subjected to an optimized Fe 2+ -based initiation cocktail. The use of this initiation system enables the identification of each of the various classes of LPO inhibitors which have been shown to rescue from cell death in ferroptosis: radical-trapping antioxidants (RTAs), peroxidase mimics, and iron chelators. Furthermore, a limited dose−response profile of inhibitors enables the resolution of RTA and non-RTA inhibitors� thereby providing not only relative efficacy but mechanistic information in the same microplate-based experiment. Despite this versatility, the approach can still be used to estimate rate constants for the reaction of RTAs with chain-propagating peroxyl radicals, as demonstrated for a representative panel of RTAs. To illustrate the utility of this assay, we carried out a preliminary investigation of the 'off-target' activity of several ferroptosis suppressors that have been proposed to act independently of inhibition of LPO, including lipoxygenase inhibitors, cannabinoids, and necrostatins, the archetype inhibitors of necroptosis.

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“…Furthermore, CBN, CBG, CBC, and CBDV were found to not only block the accumulation of Aβ, but they also stimulated the degradation and removal of preformed Aβ aggregates. In addition, CBN, CBG, CBC, CBDV, and THCA prevented oxytosis, which in the case of CBN, was later confirmed to be via direct targeting of mitochondria and promotion of antioxidant defenses, indirectly of CB receptors (Liang et al, 2022). CBC has also been suggested to have pro-neurogenic benefits via suppression of reactive astrocytes (Shinjyo and Di Marzo, 2013), and THCA has demonstrated numerous PPARγ-dependent neuroprotective properties both in vitro and in vivo (Nadal et al, 2017).…”

Section: Effects Of Phytocannabinoids On Alzheimer's Diseasementioning

confidence: 91%

Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer’s disease

2022

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Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by declining cognition and behavioral impairment, and hallmarked by extracellular amyloid-β plaques, intracellular neurofibrillary tangles (NFT), oxidative stress, neuroinflammation, and neurodegeneration. There is currently no cure for AD and approved treatments do not halt or slow disease progression, highlighting the need for novel therapeutic strategies. Importantly, the endocannabinoid system (ECS) is affected in AD. Phytocannabinoids, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), interact with the ECS, have anti-inflammatory, antioxidant, and neuroprotective properties, can ameliorate amyloid-β and NFT-related pathologies, and promote neurogenesis. Thus, in recent years, purified CBD and THC have been evaluated for their therapeutic potential. CBD reversed and prevented the development of cognitive deficits in AD rodent models, and low-dose THC improved cognition in aging mice. Importantly, CBD, THC, and other phytochemicals present in Cannabis sativa interact with each other in a synergistic fashion (the “entourage effect”) and have greater therapeutic potential when administered together, rather than individually. Thus, treatment of AD using a multi-cannabinoid strategy (such as whole plant cannabis extracts or particular CBD:THC combinations) may be more efficacious compared to cannabinoid isolate treatment strategies. Here, we review the current evidence for the validity of using multi-cannabinoid formulations for AD therapy. We discuss that such treatment strategies appear valid for AD therapy but further investigations, particularly clinical studies, are required to determine optimal dose and ratio of cannabinoids for superior effectiveness and limiting potential side effects. Furthermore, it is pertinent that future in vivo and clinical investigations consider sex effects.

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Cannabinol inhibits oxytosis/ferroptosis by directly targeting mitochondria independently of cannabinoid receptors

Cited by 18 publications

References 80 publications

Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles

Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles

General Approach to Identify, Assess, and Characterize Inhibitors of Lipid Peroxidation and Associated Cell Death

Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer’s disease

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