Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity

Nadal, Xavier; Río, Carmen del; Casano, S.; Palomares, Belén; Ferreiro‐Vera, Carlos; Navarrete, Carmen; Sánchez-Carnerero, Carolina; Cantarero, Irene; Bellido, M. Luz; Meyer, Stefan; Morello, Gaetano; Appendino, Giovanni; Muñóz, Eduardo

doi:10.1111/bph.14019

Cited by 94 publications

(64 citation statements)

References 56 publications

(62 reference statements)

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“…Δ 9 -THCA-A binds to the alternative site by interacting with Ser342 at the β-sheet (Ω-loop) through its carboxylate group. This may explain the observation that Δ 9 -THCA-A is at least 20-fold more potent than Δ 9 -THC to activate PPARγ (5). In addition, dietary long-and 310 medium-chain fatty acids, as well as small molecules, also bind to the same amino acid in the alternative site, highlighting the relevance of this site for a wide class of synthetic and natural compounds including acidic cannabinoids (40,41).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that Δ 9 -THCA-A is a PPARγ agonist at nanomolar concentrations (5). Herein, we have studied the selectivity of Δ 9 -THCA-A on different 150…”

Section: δ 9 -Thca-a Is a Selective And Non-adipogenic Pparγ Ligand Amentioning

confidence: 97%

“…Remarkably, the acidic precursor of Δ 9 -THC (Δ 9 -THCA-A) is not psychotropic, 85 and its binding to cannabinoid receptors is highly controversial and probably associated to contamination by its decarboxylation product (4). On the other hand, we recently showed that THCA-A, but not its decarboxylation product Δ 9 -THC, is a potent activator of the peroxisome proliferator-activated receptor-γ (PPARγ) endowed with remarkable neuroprotective activity (5). In agreement with these findings, the PPARγ activating properties of a Cannabis extract 90 with a high titer of Δ 9 -THC was greatly reduced by decarboxylation (5).…”

Section: Introduction 75mentioning

confidence: 99%

“…On the other hand, we recently showed that THCA-A, but not its decarboxylation product Δ 9 -THC, is a potent activator of the peroxisome proliferator-activated receptor-γ (PPARγ) endowed with remarkable neuroprotective activity (5). In agreement with these findings, the PPARγ activating properties of a Cannabis extract 90 with a high titer of Δ 9 -THC was greatly reduced by decarboxylation (5). Given the key metabolic roles of PPARγ, these findings provided a rationale to investigate the possibility that Δ 9 -THCA-A based therapies could be beneficial for the management of metabolic disorders.…”

Section: Introduction 75mentioning

confidence: 99%

“…Furthermore, liver injury, cancer, as well as an increased risk of heart failure have also been associated with the long-term use of glitazones (30). However, while the therapeutic potential of PPARγ ligand 135 agonist remains high, interest has substantially shifted towards partial ligands, preeminent examples of which are natural products such as armofrutins and acidic cannabinoids (5,31).…”

Section: Introduction 75mentioning

confidence: 99%

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Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity

Palomares

Ruíz-Pino

Garrido‐Rodríguez

et al. 2019

Preprint

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25Cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ 9 -tetrahydrocannabinol (Δ 9 -THC). Surprisingly, the biological profile of the non-narcotic native precursor of Δ 9 -THC (Δ 9 -THC acid A, Δ 9 -THCA-A) is still largely unexplored. We present evidence that Δ 9 -THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone 30 (RGZ) and with an enhanced osteoblastogenic activity in human mesenchymal stem cells.Docking and in vitro functional assays indicated that Δ 9 -THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain.Transcriptomic signatures at inguinal white adipose tissue (iWAT) from mice treated with Δ 9 -THCA-A confirmed its mode of action on PPARγ. Administration of Δ 9 -THCA-A in a mouse 35 model of high fat diet (HFD)-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ 9 -THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions 40 in HFD mice. Altogether, our data validate the potential of Δ 9 -THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation. These findings suggest that Δ 9 -THCA-A, and perhaps non-decarboxylated Cannabis sativa extracts, are worth considering for addition to our inventory of cannabis medicines. 45Key words: Medicinal cannabis, Δ 9 -THCA-A, PPARγ, obesity, metabolic syndrome, inflammation 50 3 SIGNIFICANCE STATEMENTThe medicinal use of Cannabis is gaining momentum, despite the adverse psychotropic effects of Δ 9 -THC, the decarboxylation product of its naturally occurring and nonpsychotropic precursor Δ 9 -THCA-A. We present evidence that Δ 9 -THCA-A is a partial ligand agonist of PPARγ with lower adipogenic activity compared to the full PPARγ agonist 55 rosiglitazone (RGZ). Moreover, chronic administration of Δ 9 -THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced body weight gain and fat mass, improved glucose intolerance and insulin resistance, and prevented liver steatosis and macrophage infiltration in fat tissues, additionally inducing white adipose tissue browning.Collectively, these observations qualify Δ 9 -THCA-A, a compound devoid of psychotropic 60 effects, as an efficacious pharmacological agent to manage metabolic syndrome and obesityassociated inflammation. 65Highlights -Δ 9 -THCA-A is a partial PPARγ ligand agonist with low adipogenic activity -Δ 9 -THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells.-Δ 9 -THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice 70 -Δ 9 -THCA-A impro...

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Section: Discussionmentioning

confidence: 99%

“…We have previously shown that Δ 9 -THCA-A is a PPARγ agonist at nanomolar concentrations (5). Herein, we have studied the selectivity of Δ 9 -THCA-A on different 150…”

Section: δ 9 -Thca-a Is a Selective And Non-adipogenic Pparγ Ligand Amentioning

confidence: 97%

Section: Introduction 75mentioning

confidence: 99%

Section: Introduction 75mentioning

confidence: 99%

Section: Introduction 75mentioning

confidence: 99%

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Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity

Palomares

Ruíz-Pino

Garrido‐Rodríguez

et al. 2019

Preprint

Self Cite

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A critical review of cannabis in medicine and dentistry: A look back and the path forward

Abidi

Alghamdi

Derefinko

2022

Clinical & Exp Dental Res

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Introduction: In the last two decades, our understanding of the therapeutic utility and medicinal properties of cannabis has greatly changed. This change has been accompanied by widespread cannabis use in various communities and different age groups, especially within the United States. With this increase, we should consider the potential effects of cannabis-hemp on general public health and how they could alter therapeutic outcomes. Material and Methods:The present investigation examined cannabis use for recreational and therapeutic use and a review of pertinent indexed literature was performed. The focused question evaluates "how cannabis or hemp products impact health parameters and do they provide potential therapeutic value in dentistry, and how do they interact with conventional medicines (drugs)." Indexed databases (PubMed/Medline, EMBASE) were searched without any time restrictions but language was restricted to English. Results:The review highlights dental concerns of cannabis usage, the need to understand the endocannabinoid system (ECS), cannabinoid receptor system, its endogenous ligands, pharmacology, metabolism, current oral health, and medical dilemma to ascertain the detrimental or beneficial effects of using cannabis-hemp products. The pharmacological effects of pure cannabidiol (CBD) have been studied extensively while cannabis extracts can vary significantly and lack empirical studies.Several metabolic pathways are affected by cannabis use and could pose a potential drug interaction. The chronic use of cannabis is associated with health issues, but the therapeutic potential is multifold since there is a regulatory role of ECS in many pathologies.

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Cannabis in Veterinary Medicine: Cannabinoid Therapies for Animals

Hartsel

Boyar

Pham³

et al. 2019

Nutraceuticals in Veterinary Medicine

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Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity

Abstract: Δ -THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.

Cited by 94 publications

References 56 publications

Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity

Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity

A critical review of cannabis in medicine and dentistry: A look back and the path forward

Cannabis in Veterinary Medicine: Cannabinoid Therapies for Animals

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