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Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins

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Abstract

A selection of seven phytocannabinoids representative of the major structural types of classic cannabinoids and their corresponding cannabivarins was investigated for in vivo topical anti-inflammatory activity in the Croton oil mouse ear dermatitis assay. Differences in the terpenoid moiety were far more important for anti-inflammatory activity than those at the C-3 alkyl residue, suggesting the involvement not only of cannabinoid receptors, but also of other inflammatory end-points targeted by phytocannabinoids.

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... Besides eCBs and THC, other pCBs also deserve attention as potential topical anti-inflammatory agents. Indeed, in a croton oil-induced murine cutaneous inflammation model [188], topical administration of several pCBs (CBC, CBCV, CBD, CBDV, ∆ 8 -THCV, ∆ 8 -THC, ∆ 9 -THC; 0.1-1 µmol/cm 2 ) was found to exert significant anti-inflammatory effects as revealed by reduced ear swelling [189]. Moreover, in poly-(I:C)-stimulated HaCaT cells (100 µg/mL, 6 h), CBD (5-20 µM) elevated the levels of AEA and concentration-dependently inhibited poly-(I:C)-induced release of CCL8 (a.k.a. ...
... Cell culture, as well as KO-validated animal data [143,144,186,187,191,192] Topical CBC, CBCV, CBD, CBDV, ∆ 8 -THCV, ∆ 8 -THC, ∆ 9 -THC In vivo mouse data [189] TRPV3 blockade or desensitization Cell culture data [119,121] Echinacea purpurea-derived alkylamides Cell culture data and clinical trials [199] PEA Cell culture data, animal data and human clinical trials [200][201][202]205] CB 2 blockade (?) 1 Animal data [214] Excessive MC activity Hypothesis based on the available data [57,338] ...
... This is the reason why the brain-penetrating CB 1 inverse agonist rimonabant ("SR141716"; previously marketed as "Acomplia" and "Zimulti"), although a highly potent anorexigenic agent, had to be withdrawn from the market [421,422]. Thus, designing novel, peripherally acting CB 1 antagonists/inverse agonists [423][424][425], as well as appropriate topical formulations delivering phyto-or other cannabinoids directly to the desired skin compartments (but, ideally, not to systemic circulation and especially not to the central nervous system) will be a key goal of future dermatological drug development [189,426]. ...
Article
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The endocannabinoid system (ECS) has lately been proven to be an important, multifaceted homeostatic regulator, which influences a wide-variety of physiological processes all over the body. Its members, the endocannabinoids (eCBs; e.g., anandamide), the eCB-responsive receptors (e.g., CB1, CB2), as well as the complex enzyme and transporter apparatus involved in the metabolism of the ligands were shown to be expressed in several tissues, including the skin. Although the best studied functions over the ECS are related to the central nervous system and to immune processes, experimental efforts over the last two decades have unambiguously confirmed that cutaneous cannabinoid (“c[ut]annabinoid”) signaling is deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration, and its dysregulation was implicated to contribute to several highly prevalent diseases and disorders, e.g., atopic dermatitis, psoriasis, scleroderma, acne, hair growth and pigmentation disorders, keratin diseases, various tumors, and itch. The current review aims to give an overview of the available skin-relevant endo- and phytocannabinoid literature with a special emphasis on the putative translational potential, and to highlight promising future research directions as well as existing challenges.
... In vitro functional data show that CBC increases viability of adult neural progenitor cells and inhibited their differentiation into astroglia, suggesting that CBC may be a candidate for treating neuroinflammatory diseases [12]. In rodents, CBC has displayed anti-microbial, anti-inflammatory, analgesic, and anti-depressant-like activity [13][14][15][16][17][18][19][20][21]. ...
... However, the present investigation was prompted by the observation that CBC was present in the clinical batch, and the studied doses (6.6-26.4 mg CBC daily) were not a priori based on doses found to be effective in published preclinical studies [13][14][15][16][17][18][19][20][21]. Future research evaluating the therapeutic potential of CBC may wish to study higher doses, and may need to collect data on safety at such doses. ...
Article
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Purpose Cannabichromene (CBC) is a phytocannabinoid commonly found in cannabis, yet its acute post-dose pharmacokinetics (PK) have not been examined in humans. This is a secondary data analysis from a trial investigating Spectrum Yellow oil, an oral cannabis product used for medical purposes that contained 20 mg cannabidiol (CBD), 0.9 mg Δ⁹-tetrahydrocannabinol (THC), and 1.1 mg CBC, per 1 mL of oil. Methods Participants (N = 43) were randomized to one of 5 groups: 120 mg CBD, 5.4 mg THC, and 6.6 mg CBC daily; 240 mg CBD, 10.8 mg THC, and 13.2 mg CBC daily; 360 mg CBD, 16.2 mg THC, and 19.8 mg CBC daily; 480 mg CBD, 21.6 mg THC, and 26.4 mg CBC daily; or placebo. Study medication was administered every 12 h for 7 days. Plasma CBC concentrations were analyzed by a validated two-dimensional high-performance liquid chromatography–tandem mass spectrometry assay. Results After a single dose and after the final dose, the Cmax of CBC increased by 1.3–1.8-fold for each twofold increase in dose; the tmax range was 1.6–4.3 h. Based on the ratio of administered CBD, THC, and CBC to the plasma concentration, the dose of CBD was 18 times higher than the dose of CBC, yet the AUC0–t of CBD was only 6.6–9.8-fold higher than the AUC0–t of CBC; the dose of THC was similar to the dose of CBC, yet THC was quantifiable in fewer plasma samples than was CBC. Conclusions CBC may have preferential absorption over CBD and THC when administered together. Trial Registration: Australian New Zealand Clinical Trials Registry #ACTRN12619001450101, registered 18 October 2019.
... Few studies demonstrated the antiinflammatory activity of CBD in animal models of skin inflammation (Lodzki et al., 2003;Tubaro et al., 2010). However, the molecular mechanisms underlying the antiinflammatory effect observed in vivo as well as the modulation of genes involved in skin inflammatory processes or wound healing have not been reported so far. ...
... CBD shows antiinflammatory activity in animal models including mouse challenged with Croton oil (Tubaro et al., 2010); moreover, transdermal application of CBD prevents inflammation and oedema FIGURE 5 Effect of CSE and CBD on TNFα-induced gene expression of 84 genes involved in the inflammatory process, in HaCaT cells. The cells were treated with the stimulus (TNFα, 10 ng/ml) and the extract (25 μg/ml) or pure compound (4 μM) for 6 hr. ...
... • Afamelanotide [43][44][45][46][47][48][49] • Dersimelagon (MT-7117) [50] • KdPT a [51,[54][55][56][57] • WOL074-009, WOL074-019 and WOL074-029 a [58] MC1 and additional effector pathways [85,[87][88][89][90]100] • Asimadoline [58,97,99,100] • Difelikefalin (CR845) [95] • WOL071-007 [92,94] • Compounds 5a [104,105] and 8a [104] • Compounds 3a, 4b, 5a and 5b [103] • Naltrexone [72,73,76,77] • Nalmefene [78][79][80] • Nalbuphine [81][82][83] • HU-308 [109,113] • Δ 9 -THC [109,111,112] • CBD [118][119][120][121][122][123] • S-777469 [114][115][116] • URB597 [125][126][127] • JZL184 [126] • OL-935 [125] • WOL067-531 [128,130] • WOBE440 [127,128] • WOBE479 [127] • ARN077 [131] CB1, CB2, FAAH, AEAuptake inhibitors MAGL, NAAA [181][182][183][184] • Glycopyrrolate c [178][179][180] • Umeclidinium bromide [154] • Sofpironium bromide [186] • Vagantin® d [153] • Oxybutynin [134][135][136][137][138][139][140][141][142][143][144][145][146][147][148] • Oxybutynin/pilocarpin [149] • PHA-543613 and AR-R17779 [191] mAChR, nAChR Cholinergic system [58,215,216,[218][219][220] • Tropisetron [214,221] to cause cardiovascular adverse effects. [24] In an ex vivo model of human HFs, eprotirome promoted anagen and increased proliferation of matrix keratinocytes, suggesting that eprotirome could be a drug candidate for the treatment of hair loss disorders such as androgenetic alopecia. ...
... [120] It showed anti-inflammatory activity in croton oil-induced dermatitis model. [121] CBD reduced TNF-αinduced MMP-9 secretion from HaCaT cells whereas IL-8 and VEGF secretion were not affected. In addition, the TNF-α-induced NF-κBdriven transcription was dose dependently inhibited in HaCaT but not in human dermal fibroblasts. ...
Article
The skin as a neuroendocrine organ and the role of neuroendocrine signaling in the development of disorders affecting the skin and its appendages has received increasing attention in the last years. Different neuroendocrine systems have been described in the barrier organ skin, including the thyroid system, the hypothalamic‐pituitary‐adrenal axis, the opioid, the endocannabinoid, the cholinergic, the secosteroidogenic and the serotonergic systems. All of these systems have been implicated in the development of skin diseases, which often have an inflammatory origin. These discoveries have led to an increase in the development of new drugs targeting components of neuroendocrine signaling pathways. Additionally, attempts have been made to repurpose already approved drugs targeting neuroendocrine signaling pathways in other organs for the treatment of skin diseases. Recently published results from preclinical and clinical studies look promising and may offer improved therapies to patients suffering from skin diseases in the near future. In this review, from a pharmaceutical point of view, we focus on recent progress in synthetic drug development of compounds targeting neuroendocrine signaling in the skin and its appendages to treat skin diseases such as atopic dermatitis, psoriasis, acne, alopecia areata and hyperhidrosis.
... To date, very little research has been performed on CBDV, with the majority of papers reporting chemical or botanical studies. Recent work, however, reported on its anti-inflammatory action (Tubaro et al. 2010) and its beneficial effects on bone formation and fracture healing by stimulating the recruitment of quiescent mesenchymal stem cells present in bone marrow (Scutt and Williamson. 2007). ...
Article
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Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ(9)-tetrahydrocannabivarin (Δ(9)-THCV) and cannabigerol (CBG). We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic-pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice. All phytocannabinoids readily penetrated the blood-brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ(9)-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive-compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile. These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.
... Although the levels of CBD seen in the plasma of patients receiving Sativex are below (73) the CBD doses (= lower micromolar range) that exerted the most robust effects in our studies, such doses could easily be achieved after topical CBD application, using appropriate vehicles already used in current standard acne management. Due to its high lipophilicity, CBD is expected to preferentially enter the skin via the transfollicular route and to accumulate in the sebaceous gland (74,75). Of great importance, such an accumulation has been documented already In order to identify additional downstream targets, genomewide microarray experiments were performed on 3 independent sets of control and CBD-treated (10 μM for 24 hours) sebocytes. ...
Article
The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.
... Dried plant material (inflorescences, 404 g) was powdered and then heated in a ventilated oven at 120°C for 4 hr to decarboxylate pre-cannabinoids to cannabinoids. The compounds show outstanding potency in in vivo assays of inhibition of inflammatory responses [32]. Etoll: Benzene eluents obtained from Inula racemosa significantly affected inflammation in hind paw of albino rats by I. racemosa as well as its active principle [33]. ...
Article
Full-text available
Terpenoids accounts for the major class of secondary metabolites produced by plants. It shows defense activity against environmental stress and help to heal injuries. Medicinal plants are rich in monoterpenoids, diterpenoids, sesquiterpenes, triterpenes, tetraterpenes, and ceramide. A number of therapeutic applications such as antibacterial, antimicrobial, antitumor, anti-inflammatory activity have been identified. Terpenoids are compounds similar to terpenes derived from 5-carbon monomer isoprene units. The review puts and detail insight on different class of compounds isolated from natural source from 2000 to 2016 showing anti-inflammatory potential of pharmacologically interesting agent and their mechanism of action.
... 'Carma' was selected from 'Carmagnola,' which expresses its own unique phytochemistry, such as cannabioxepane, a tetracyclic cannabinoid (Pagani et al. 2011). Many "minor" cannabinoids show potent antibacterial activity (Appendino et al. 2008b) and anti-inflammatory activity (Tubaro et al. 2010). 'Ermo' also obtained Plant Breeders Rights. ...
Chapter
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This chapter has two parts. The first part details five characters that contribute to phenotypic diversity in Cannabis. Cannabinoids can be assayed by quantity (dry weight percentage of cannabinoids in harvested material) or by quality (the THC/CBD ratio, or chemotype). Cannabinoid quality is largely genetic, possibly monogenic. We dissect the monogenic inheritance model (two alleles at a single gene locus). Essential oil is composed of volatile, aromatic terpenoids. Terpenoid content varies between different varieties. Hemp seed oil consists of polyunsaturated fatty acids, including omega-6 and omega-3 fatty acids, which are under genetic control. Protein has received less attention than oil, despite hemp’s value as a protein supplement. Bast fibers are phloem (sap-conducting) cells in stalks. The second part presents the current breeding status of phenotypes for various uses. Breeding for fiber production includes monoecious cultivars, dioecious cultivars, high percentage of primary fiber, fast-retting phenotypes, and unique morphological markers in low-THC plants. Selective cross-breeding for cannabinoids includes prevalent-THC, prevalent-CBD, and cannabinoid-free plants. Relatively few cultivars have been bred specifically for seed production.
... Algunos de estos extractos se han encontrado en la Caléndula officinalis, Aloe vera y Cannabis sativa en los cuales además se han encontrado propiedades antioxidantes, antiinflamatorias, acción de factores de crecimiento que podrían favorecer la recuperación de estos tejidos al ser empleados en una fase aguda de la lesión. Sin embargo, antes del uso de cualquiera de estos extractos vegetales con potencial terapéutico, se hace necesario realizar estudios previos que aseguren la inocuidad química de los mismos a fin de utilizarlos garantizando la protección de la salud humana y del medio ambiente; de ahí que a nivel internacional, la Organización para la Cooperación y el Desarrollo Económico, OECD, haya emitido una serie de Guías que se han establecido como métodos estándar a nivel internacional a nivel mundial para evaluar los efectos potenciales de las sustancias químicas, incluyendo productos industriales, pesticidas y productos de cuidado personal (20)(21)(22)(23)(24)(25). ...
Article
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Introducción: Aunque las quemaduras cáusticas representan un bajo porcentaje de las quemaduras, dadas las complicaciones que asocian, son un problema de salud pública que exige nuevas opciones terapéuticas como son el uso de productos derivados de plantas, entre ellos, Caléndula offinalis, Aloe vera y Cannabis sativa, cuyo uso está condicionado, inicialmente a pruebas como la evaluación de su efecto irritativo/corrosivo agudo en piel. Materiales y métodos: Estudio experimental en animales, aleatorizado. El material vegetal se obtuvo del Jardín Medicinal Jorge Piñeros Corpas; los aceites y extractos de las plantas se obtuvieron por métodos clásicos de extracción; la base de excipientes fue provista por el Laboratorio de Farmacología Vegetal (LABFARVE). Se emplearon 8 Ratas wistar macho alojadas bajo condiciones controladas y parámetros de ética y bienestar animal. La prueba de irritación/corrosión dérmica aguda se hizo siguiendo la norma OECD 404, tras previa anestesia de los animales y siguiendo los criterios de dolor y punto final. Resultados: De Caléndula officinalis se obtuvieron dos aceites esenciales y tres extractos; el gel de Aloe vera y un extracto de Cannabis sativa. Ninguno de los extractos generó escara, eritema o edema en los animales, siendo negativa la prueba de irritación/corrosión aguda en piel. Discusión: Los resultados obtenidos desde esta investigación básica en medicina traslacional, brindan evidencia que complementa la información reportada en la literatura acerca del uso tradicional y los estudios in vitro e in vivo de estas plantas para el manejo de diversas enfermedades. La ausencia de efecto irritativo o corrosivo en piel es coherente con el conocimiento del tipo de metabolitos secundarios activos que se han identificado en ellas con actividad antiinflamatoria, antioxidante, antimicrobiana y cicatrizante. Los resultados aseguran su inocuidad química al contemplarlas para investigar su potencial uso terapéutico en lesiones dérmicas, tipo quemaduras cáusticas, garantizando su seguridad .
... Algunos de estos extractos se han encontrado en la Caléndula officinalis, Aloe vera y Cannabis sativa en los cuales además se han encontrado propiedades antioxidantes, antiinflamatorias, acción de factores de crecimiento que podrían favorecer la recuperación de estos tejidos al ser empleados en una fase aguda de la lesión. Sin embargo, antes del uso de cualquiera de estos extractos vegetales con potencial terapéutico, se hace necesario realizar estudios previos que aseguren la inocuidad química de los mismos a fin de utilizarlos garantizando la protección de la salud humana y del medio ambiente; de ahí que a nivel internacional, la Organización para la Cooperación y el Desarrollo Económico, OECD, haya emitido una serie de Guías que se han establecido como métodos estándar a nivel internacional a nivel mundial para evaluar los efectos potenciales de las sustancias químicas, incluyendo productos industriales, pesticidas y productos de cuidado personal (20)(21)(22)(23)(24)(25). ...
Article
Full-text available
Resumen Introducción: Aunque las quemaduras cáusticas representan un bajo porcentaje de las quema-duras, dadas las complicaciones que asocian, son un problema de salud pública que exige nuevas opciones terapéuticas como son el uso de productos derivados de plantas, entre ellos, Calendula offinalis, Aloe vera y Cannabis sativa, cuyo uso está condicionado, inicialmente a pruebas como la evaluación de su efecto irritativo/corrosivo agudo en piel. Materiales y métodos: Estudio experimental en animales, aleatorizado. El material vegetal se obtuvo del Jardín Medicinal Jorge Piñeros Corpas; los aceites y extractos de las plantas se obtuvie-ron por métodos clásicos de extracción; la base de excipientes fue provista por el Laboratorio de Farmacología Vegetal (LABFARVE). Se emplearon 8 Ratas wistar macho alojadas bajo condicio-nes controladas y parámetros de ética y bienestar animal. La prueba de irritación/corrosión dérmica aguda se hizo siguiendo la norma OECD 404, tras previa anestesia de los animales y siguiendo los criterios de dolor y punto final. Resultados: De Calendula officinalis se obtuvieron dos aceites esenciales y tres extractos; el gel de Aloe vera y un extracto de Cannabis sativa. Ninguno de los extractos generó escara, eritema o edema en los animales, siendo negativa la prueba de irritación/corrosión aguda en piel. Discusión: Los resultados obtenidos desde esta investigación básica en medicina traslacional, brindan evidencia que complementa la información reportada en la literatura acerca del uso tradi-cional y los estudios in vitro e in vivo de estas plantas para el manejo de diversas enfermedades. La ausencia de efecto irritativo o corrosivo en piel es coherente con el conocimiento del tipo de metabolitos secundarios activos que se han identificado en ellas con actividad antiinflamato-ria, antioxidante, antimicrobiana y cicatrizante. Los resultados aseguran su inocuidad química al contemplarlas para investigar su potencial uso terapéutico en lesiones dérmicas, tipo quemaduras cáusticas, garantizando su seguridad. Palabras clave: Quemaduras químicas, Piel, Ratas wistar, Calendula officinalis, Aloe vera, Cannabis sativa, Cicatrización de heridas Evaluation of plant extracts in the management of caustic burns: Irritation / Acute dermal corrosion. Bogotá-2018. Abstract Introduction: Considering that caustic burns represent a low percentage of burns, given the complications they could associate, they are a public health problem that requires new therapeutic options such as the use of plant-derived products, including Calendula offinalis, Aloe vera and Cannabis sativa, whose use is conditioned, initially to tests such as the evaluation of its acute irri-tative / corrosive effect on skin.
... The topical anti-inflammatory activity of phytocannabinoids in a roton oil mouse ear dermatitis assay has been described by Tubaro et al. [92], while preclinical evaluations of the transdermal administration of CBD, via gel application, has been further tested on a rat complete Freund's adjuvant-induced monoarthritic knee joint model [93]. In this latter study, CBD was found to demonstrate therapeutic potential for the relief of arthritic pain-related behaviour and to exert an anti-inflammation effect without any evident high-brain-center psychoactive effects. ...
Article
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There is a growing body of evidence to suggest that cannabinoids are beneficial for a range of clinical conditions, including pain, inflammation, epilepsy, sleep disorders, the symptoms of multiple sclerosis, anorexia, schizophrenia and other conditions. The transformation of cannabinoids from herbal preparations into highly regulated prescription drugs is therefore progressing rapidly. The development of such drugs requires well-controlled clinical trials to be carried out in order to objectively establish therapeutic efficacy, dose ranges and safety. The low oral bioavailability of cannabinoids has led to feasible methods of administration, such as the transdermal route, intranasal administration and transmucosal adsorption, being proposed. The highly lipophilic nature of cannabinoids means that they are seen as suitable candidates for advanced nanosized drug delivery systems, which can be applied via a range of routes. Nanotechnology-based drug delivery strategies have flourished in several therapeutic fields in recent years and numerous drugs have reached the market. This review explores the most recent developments, from preclinical to advanced clinical trials, in the cannabinoid delivery field, and focuses particularly on pain and inflammation treatment. Likely future directions are also considered and reported.
... All cell lines were maintained in exponential growth in DMEM supplemented with 10 % heat-inactivated foetal calf serum plus 0.5 %v/v penicillin/streptomycin. Rosiglitazone and HU-331 were purchased from Cayman Chemical Company (Ann Arbor, MI, USA). Phytocannabinoids were isolated as described previously (Appendino et al. 2008;Tubaro et al. 2010). All other reagents were from Sigma-Aldrich (St. Louis, MO, USA) unless indicated. ...
... The oil, essential oils and resins of Cannabis sativa plants have been traditionally used as skin remedies, but there are also some experimental confirmations considering the skin treatment possibilities, indicating the influence of terpenophenolics on the inflammation-related signaling pathways, cytokine and chemokine genes expression, and the expression of growth factors and proteins associated with extracellular matrix rearrangement. The phytocannabinoids have been shown to inhibit inflammation in in vivo comparative studies of different moieties applied topically [84]. Cannabinoids have also influenced the proliferation and differentiation processes in human keratinocytes, which is crucial in psoriasis lesion formation [85]. ...
Article
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The incidence of inflammatory skin diseases is increasing, so the search for relevant therapeutics is of major concern. Plants are rich in phytochemicals which can alleviate many symptoms. In this review we concentrate on compounds found in the seeds of widely cultivated plants, regularly used for oil production. The oils from these plants are often used to alleviate the symptoms of inflammatory diseases through synergetic action of unsaturated fatty acids and other phytochemicals most commonly derived from the terpenoid pathway. The knowledge of the chemical composition of oil seeds and the understanding of the mechanisms of action of single components should allow for a more tailored approach to treatment for many diseases. In many cases these seeds could serve as an efficient material for the isolation of pure phytochemicals. Here we present the content of phytochemicals, assumed to be responsible for healing properties of plant oils, in widely cultivated oil seed plants and review the proposed mechanism of action for fatty acids, selected mono-, sesqui-, di- and triterpenes, carotenoids, tocopherol and polyphenols.
... The pCBs are lipophilic substances and hence, they are readily absorbed through the skin, where ECS plays a critical role in controlling epidermal differentiation and cutaneous inflammation [37,[42][43][44]. Unsurprisingly, some pCBs are promising drug candidates for the treatment of atopic dermatitis, psoriasis, scleroderma and acne, as well as keratin diseases, skin tumors and pruritus [17,29,32,36]. Furthermore, in recent years, the interest in rare pCBs has increased due to methodological advancements in the extraction/isolation, semi-synthesis or complete synthesis and microbial engineering (in E. coli, algae, yeast, etc.) of these compounds. ...
Article
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The decriminalization and legalization of cannabis has paved the way for investigations into the potential of the use of phytocannabinoids (pCBs) as natural therapeutics for the treatment of human diseases. This growing interest has recently focused on rare (less abundant) pCBs that are non-psychotropic compounds, such as cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). Notably, pCBs can act via the endocannabinoid system (ECS), which is involved in the regulation of key pathophysiological processes, and also in the skin. In this study, we used human keratinocytes (HaCaT cells) as an in vitro model that expresses all major ECS elements in order to systematically investigate the effects of CBG, CBC, THCV and CBGA. To this end, we analyzed the gene and protein expression of ECS components (receptors: CB1, CB2, GPR55, TRPV1 and PPARα/γ/δ; enzymes: NAPE-PLD, FAAH, DAGLα/β and MAGL) using qRT-PCR and Western blotting, along with assessments of their functionality using radioligand binding and activity assays. In addition, we quantified the content of endocannabinoid(-like) compounds (AEA, 2-AG, PEA, etc.) using UHPLC-MS/MS. Our results demonstrated that rare pCBs modulate the gene and protein expression of distinct ECS elements differently, as well as the content of endocannabinoid(-like) compounds. Notably, they all increased CB1/2 binding, TRPV1 channel stimulation and FAAH and MAGL catalytic activity. These unprecedented observations should be considered when exploring the therapeutic potential of cannabis extracts for the treatment of human skin diseases.
... The finding regarding frequency of topical use and migraine severity is particularly interesting, as no studies have examined the effects of topicals on migraine relief and the broader literature on topical cannabinoids and pain relief is limited. While topical cannabinoids have led to analgesia in animal models of inflammatory and neuropathic pain, [39][40][41] clinical evidence is scarce. Furthermore, as topical cannabinoids are hydrophilic, they are not easily absorbed into the bloodstream due to low skin penetration. ...
Article
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Objectives As the legal and cultural landscape surrounding cannabis use in the United States continues to evolve, more Americans are turning to cannabis to self-medicate a number of ailments, including migraines. The purpose of the present study was to examine patterns of cannabis use and its associated relief among migraineurs. Design Participants were N = 589 adult cannabis users living in states with full legal access. Using a cross-sectional design, participants completed an online survey assessing their cannabis use profiles, migraine experience, and self-reported relief from cannabis and non-cannabis treatments. Results 161 participants (27.3 %) reported experiencing migraines. 76.4 % of migraineurs (N = 123) endorsed using cannabis to treat their migraines. 69.9 % (N = 86) of migraineurs using cannabis for migraine relief also endorsed using non-cannabis products (e.g., over-the-counter pain medication, triptans) to treat their migraines. Although their subjective health was similar (p = .17), migraineurs who endorsed using cannabis to treat their migraines reported more severe migraines compared to those who did not (p = .02). Migraineurs reported significantly more migraine relief from cannabis compared to non-cannabis products, even after controlling for migraine severity (p = .03). The majority of migraineurs using cannabis to treat their migraines were not medical cardholders (65.0 %), suggesting that these individuals were self-medicating in lieu of physician guidance. Conclusions The present study provides insight into the prevalence of cannabis use for migraine relief in a sample of cannabis users, and suggests that these migraineurs experience a high level of migraine relief from cannabis. Future studies are needed to determine the cannabis forms, potencies, and dosages that are most effective at treating migraine pain.
... The antiinflammatory actions of synthetic cannabinoids and phytocannabinoids have been extensively reported (Burstein, 2015;Schonhofen et al., 2018), especially for CBD and its derivative molecules. Some findings also support an antiinflammatory property of CBDV (Tubaro et al., 2010;De Petrocellis et al., 2011;Amada et al., 2013;Pagano et al., 2019). On the other hand, chronic administration of this molecule induced an increase in GFAP expression in both control and VPA animals' PFC (Zamberletti et al., 2019b), reinforcing the necessity for further investigation about this topic. ...
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Schizophrenia and autism spectrum disorders (ASD) are psychiatric neurodevelopmental disorders that cause high levels of functional disabilities. Also, the currently available therapies for these disorders are limited. Therefore, the search for treatments that could be beneficial for the altered course of the neurodevelopment associated with these disorders is paramount. Preclinical and clinical evidence points to cannabidiol (CBD) as a promising strategy. In this review, we discuss clinical and preclinical studies on schizophrenia and ASD investigating the behavioral, molecular, and functional effects of chronic treatment with CBD (and with cannabidivarin for ASD) during neurodevelopment. In summary, the results point to CBD's beneficial potential for the progression of these disorders supporting further investigations to strengthen its use.
... Traces of THC-C 1 were detected by Vree et al. (1971), low proportions of CBD-C 3 by Turner et al. (1973). Tubaro et al. (2010) report on inbred plants with a mixture of THC-C 3 , CBD-C 3 and CBC-C 3 that together occupied up to 1/3 of the total cannabinoid fraction. Harvey (1976) found low concentrations of THC-C 4 , its degradant CBN-C 4 and CBD-C 4 in different samples. ...
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In order to complete a genetic model for the inheritance of chemotype in Cannabis, this paper explores the regulation of the propyl-/pentyl cannabinoid ratio. Plants almost pure in compounds with a C5 side chain are by far the most common, and such a chemotype can be considered a wild-type condition. Mutant progenitors with higher levels of the rarer cannabinoid THC-C3 (tetrahydrocannabivarin) were identified. Their propyl cannabinoid proportion in the total cannabinoid fraction (PC3) ranged from 14 to 69 %, which, through selective inbreeding, could be increased to highly specific lineage maxima. Inbred plants with maximised PC3 derived from the different progenitors, were then crossed with a pure C5 wild type and the PC3 distribution patterns of the F2s examined. Distinct patterns, compatible with oligogenic and polygenic segregation appeared. It was hypothesised that the PC3 regulating loci of the six source progenitors would be at least partially different, complementary, and additive in their phenotypical effect. So, high PC3 offspring from the different lineages were mutually crossed. Inbred lines derived from multi-cross hybrid combinations reached unprecedented PC3 levels of up to 96 % which supports the hypothesis. For the regulation of C3/C5 ratios, a model of a multiple locus A 1–A 2–…A n is proposed, with the pentyl- and propyl cannabinoid pathway being enhanced by alleles A pe1−n and A pr1−n, respectively.
... Similarly, Tubaro et al. [83] compared the topical effect of different cannabinoids (CBD, CBDV, CBC, CBCV, THC, THCV) against croton oil-induced ear edema in mice, in the dose range of 0.1-1 µmol/cm 2 . Δ 8 -THC, Δ 8 -THCV, and Δ 9 -THC were more effective (ID 50 = 0.46-0.55 ...
Article
The use of Cannabis sativa is currently recognized to ease certain types of chronic pain, reduce chemotherapy-induced nausea, and improve anxiety. Nevertheless, few studies highlighted the therapeutic potential of C. sativa extracts and related phytocannabinoids for a variety of widespread skin disorders including acne, atopic dermatitis, psoriasis, pruritus, and pain. This review summarized the current evidence on the effects of phytocannabinoids at the cutaneous level through the collection of in vitro, in vivo, and clinical studies published on PubMed, Scopus, Embase, and Web of Science until October 2020. Phytocannabinoids have demonstrated potential anti-inflammatory, antioxidant, anti-aging, and anti-acne properties by various mechanisms involving either CB1/2-dependent and independent pathways. Not only classical immune cells, but also several skin-specific actors, such as keratinocytes, fibroblasts, melanocytes, and sebocytes, may represent a target for phytocannabinoids. Cannabidiol, the most investigated compound, revealed photoprotective, antioxidant, and anti-inflammatory mechanisms at the cutaneous level, while the possible impact on cell differentiation, especially in the case of psoriasis, would require further investigation. Animal models and pilot clinical studies supported the application of cannabidiol in inflammatory-based skin diseases. Also, one of the most promising applications of non-psychotropic phytocannabinoids is the treatment of seborrheic disorders, especially acne. In conclusion, the incomplete knowledge of the role of the endocannabinoid system in skin disorders emerged as an important limit for pharmacological investigations. Moreover, the limited studies conducted on C. sativa extracts suggested a higher potency than single phytocannabinoids, thus stimulating new research on phytocannabinoid interaction.
... Special attention is paid in these studies to the bioactivity of plant and food components. The example of compounds that have recently been under the scrutiny of researchers are cannabinoids [1,2] the components of marijuana and hemp plants. Although Δ9-Tetrahydrocannabinol (Δ9-THC) is the most famous representative of this numerous compound group, recently much attention has been paid to another cannabinoid, namely cannabidiol (CBD), which -unlike Δ9-THC -does not show psychotropic effects. ...
Article
Positive effect of some cannabinoids in the treatment and prophylaxis of a wide variety of oxidation-associated diseases and growing popularity of supplements containing cannabinoids, mainly cannabinoid oils (e.g. CBD oil, CBG oil), in the self-medication of humans cause a growing interest in the antioxidant properties of these compounds, especially those not showing psychotropic effects. Herein, we report the antioxidant activity of cannabigerol (CBG), cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), cannabinol (CBN), cannabigerolic acid (CBGA), cannabinolic acid (CBDA) and Δ9-tetrahydrocannabinolic acid (Δ9-THCA) estimated by spectrophotometric methods: ABTS, DPPH, ORAC, beta-carotene CUPRAC and FRAP. The presented data prove that all the examined cannabinoids exhibit antioxidant activity manifested in their ability to scavenge free radicals, to prevent the oxidation process and to reduce metal ions. Although the intensity of these activities is not the same for the individual cannabinoids it is comparable for all of them with that of E vitamin. As results from the research, the significance of the two types of electron sources presenting in examined cannabinoids, phenolic groups and double bonds transferring electrons, depends on the type of electron-accepting species - radicals/metal ions.
... Apart from the mentioned oils recently, also oils containing acidic forms of these cannabinoids, cannabigerolic acid (CBGA) and cannabinolic acid (CBDA), which are precursors of CBG and CBD in the metabolic path of Cannabis sativa have become more and more common. They have gained popularity not only among people struggling with various health ailments, but also those who are looking for a neutral way to take care of their body and mind [1,2]. ...
Article
From the group of nearly 120 cannabinoids identified in the hemp sativa and marijuana, CBG, CBD, THC and their acidic forms CBGA, CBDA and THCA are the most frequently studied. All these cannabinoids exhibit antioxidant activity manifested in the ability to scavenge free radicals, to prevent the oxidation process and to reduce metal ions. The paper reports and discusses the antioxidant properties of binary mixtures of the mentioned cannabinoids as regards their ability to scavenge free radicals. The paper shows that, depending on cannabinoid type in their binary mixture and their amounts ratio, an additive, synergistic and antagonistic effect of their antioxidant activity is observed. Binary mixtures of the tested cannabinoids in the full range of their molar ratios were used in the experiments. The presented results seems to be essential in terms of more and more numerous reports showing greater pharmacological effectiveness of binary cannabinoid mixtures compared to that of their individual components.
... Cannabis use was demonstrated to be associated with a potentially beneficial decrease in systemic inflammation and immune activation such as IL-6 and TNFα in the context of antiretroviral-treated HIV infection 27 . Several studies illustrated the anti-inflammatory activity of CBD in cell lines and animal models of skin inflammation [28][29][30] . Sangiovanni et al. 29 showed that cannabis can inhibit the release of mediators of inflammation involved in wound healing via impairment of the NF-κB pathway and inhibiting the TNFα-induced NF-κB-driven transcription and inhibition of the release of IL-8 and MMP-9 in HDF and HaCaT cell lines. ...
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ORIGINAL The effect of Cannabis sativa on memory, apoptotic genes and inflammatory cytokines in rat El efecto del Cannabis sativa sobre la memoria, los genes apoptóticos y las citoquinas inflamatorias en la rata Abstract Objectives: Cannabis sativa L. has important ingredients of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD is non-psychotropic, but THC is psychotropic responsible for making people feel "high". This study investigated changes in memory, apoptosis and inflammatory cytokines following C. sativa use in experimental rats. Methods: Forty-five Wistar rats were randomly divided to 3 equal groups of experimental receiving cannabis subcutaneously (2 mg/ kg in 0.6 mL volume) for 3 weeks, sham receiving ethanol identically (0.6 mL), and control receiving normal saline similarly (0.6 mL). The animals' spatial memory was assessed for 3 weeks using mean percentage of alternation and number of entries in a Y-maze to confirm cannabis effect on the brain. Real-time PCR was conducted for expression analysis of primer pairs for Bax and Bcl-2 genes in response to cannabis. Changes in inflammatory cytokines of IL-1, IL-6, IL-10, TNFα, INFγ, superoxidase dismutase (SOD) and malondialdehyde (MDA) were assessed following cannabis use. Results: Significant reduction in memory and expression of Bcl-2 genes and increase in expression of Bax and inflammatory cytokines of IL-1, IL-6, IL-10, TNFα, INFγ and SOD were noted following cannabis use. Conclusions: Based on our findings and reduction in memory and expression of Bcl-2 gene, and increase in expression of Bax gene and inflammatory cytokines following cannabis use, the paramount public health importance of cannabis use, when targeted for medical purposes should come into consideration. Resumen Objetivos: El Cannabis sativa L. tiene importantes ingredientes de delta-9-tetrahidrocannabinol (THC) y cannabidiol (CBD). El CBD no es psicotrópico, pero el THC es psicotrópico, responsable de hacer que las personas se sientan "colocadas". Este estudio investigó los cambios en la memoria, la apoptosis y las citoquinas inflamatorias tras el uso de C. sativa en ratas experimentales. Métodos: Cuarenta y cinco ratas Wistar fueron divididas aleatoriamente en 3 grupos iguales de experimentación que recibieron cannabis por vía subcutánea (2 mg/kg en 0,6 mL de volumen) durante 3 semanas, de simulación que recibieron etanol de forma idéntica (0,6 mL) y de control que recibieron solución salina normal de forma similar (0,6 mL). Se evaluó la memoria espacial de los animales durante 3 semanas utilizando el porcentaje medio de alternancia y el número de entradas en un laberinto en Y para confirmar el efecto del cannabis en el cerebro. Se realizó una PCR en tiempo real para el análisis de la expresión de los pares de cebadores para los genes Bax y Bcl-2 en respuesta al cannabis. Se evaluaron los cambios en las citoquinas inflamatorias de IL-1, IL-6, IL-10, TNFα, INFγ, superoxidasa dismutasa (SOD) y malondialdehído (MDA) tras el consumo de cannabis. Resultados: Se observó una reducción significativa de la memoria y la expresión de los genes Bcl-2 y un aumento de la expresión de Bax y de las citoquinas inflamatorias de IL-1, IL-6, IL-10, TNFα, INFγ y SOD tras el consumo de cannabis. Conclusiones: Basándonos en nuestros hallazgos y en la reducción de la memoria y la expresión del gen Bcl-2, y el aumento de la expresión del gen Bax y de las citoquinas inflamatorias tras el consumo de cannabis, debe tenerse en cuenta la importancia primordial del consumo de cannabis para la salud pública, cuando se destina a fines médicos. Palabras clave: Cannabis sativa, Memoria, Apoptosis, Inflamación. ID ID ID ID 97 2021/36 (4): 96-101 The effect of cannabis sativa on memory, apoptotic genes and inflammatory cytokines in rat
... # P < 0.001 versus control; *P < 0.05, and ***P < 0.001 versus LPS. mouse ear dermatitis assay (Tubaro et al., 2010). In the present study, we have demonstrated that CBC inhibits nitric oxide production in LPS-stimulated murine macrophages and ameliorates experimental colitis in mice. ...
Article
Background and purpose: The non-psychotropic cannabinoid cannabichromene is known to activate the transient receptor potential ankyrin-type1 (TRPA1) and to inhibit endocannabinoid inactivation, both of which are involved in inflammatory processes. We examined here the effects of this phytocannabinoid on peritoneal macrophages and its efficacy in an experimental model of colitis. Experimental approach: Murine peritoneal macrophages were activated in vitro by LPS. Nitrite levels were measured using a fluorescent assay; inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2) and cannabinoid (CB1 and CB2 ) receptors were analysed by RT-PCR (and/or Western blot analysis); colitis was induced by dinitrobenzene sulphonic acid (DNBS). Endocannabinoid (anandamide and 2-arachidonoylglycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry. Colonic inflammation was assessed by evaluating the myeloperoxidase activity as well as by histology and immunohistochemistry. Key results: LPS caused a significant production of nitrites, associated to up-regulation of anandamide, iNOS, COX-2, CB1 receptors and down-regulation of CB2 receptors mRNA expression. Cannabichromene significantly reduced LPS-stimulated nitrite levels, and its effect was mimicked by cannabinoid receptor and TRPA1 agonists (carvacrol and cinnamaldehyde) and enhanced by CB1 receptor antagonists. LPS-induced anandamide, iNOS, COX-2 and cannabinoid receptor changes were not significantly modified by cannabichromene, which, however, increased oleoylethanolamide levels. In vivo, cannabichromene ameliorated DNBS-induced colonic inflammation, as revealed by histology, immunohistochemistry and myeloperoxidase activity. Conclusion and implications: Cannabichromene exerts anti-inflammatory actions in activated macrophages - with tonic CB1 cannabinoid signalling being negatively coupled to this effect - and ameliorates experimental murine colitis.
... It inhibits diacylglycerol lipase in vitro and can therefore reduce the synthesis of its product, 2-AG (De Petrocellis et al. 2011). An antiinflammatory effect of 17 has been reported (Tubaro et al. 2010) and, as with THCV (16), a positive effect on bone formation and strength that could be used, for example, to accelerate fracture healing. The mechanism of this action is probably related to the stimulation of migration mesenchymal stem cells from the bone marrow to damaged bone tissue (Scutt and Williamson 2007). ...
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Cannabis spp. are some of the most controversial medicinal plants in the world. They contain great amounts of biologically active secondary metabolites, including the typical phenolic compounds called cannabinoids. Because of their low toxicity and complex biological activities, cannabinoids can be useful in the therapy of various diseases, but adverse psychological effects (of Δ9-THC in particular) raise concerns. This review summarizes the current knowledge of selected active C. indica compounds and their therapeutic potential. We summarize the main compounds contained in cannabis, the mechanisms of their effects, and their potential therapeutic applications. Further, we mention some of the clinical tests used to evaluate the efficacy of cannabinoids in therapy.
... Various minor cannabinoids including THCV, CBC, CBG and CBDV have shown promise in the treatment of skin disorders and are being investigated for the treatment of atopic dermatitis, psoriasis, scleroderma, acne hair growth and pigmentation disorders, keratin diseases, skin tumors, and pruritus (Tubaro, et al., 2010;Oláh, et al., 2016;Tóth, et al., 2019). It is postulated that these cannabinoids produce anti-acne effects by regulating homeostatic sebaceous lipogenesis and by exerting antiproliferative and anti-inflammatory actions. ...
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The medicinal use of Cannabis sativa L. can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids trans -Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ ⁹ -THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ ⁹ -THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT 1a receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.
... All cell lines were maintained in exponential growth in DMEM supplemented with 10 % heat-inactivated foetal calf serum plus 0.5 %v/v penicillin/streptomycin. Rosiglitazone and HU-331 were purchased from Cayman Chemical Company (Ann Arbor, MI, USA). Phytocannabinoids were isolated as described previously (Appendino et al. 2008; Tubaro et al. 2010 ). All other reagents were from Sigma- Aldrich (St. Louis, MO, USA) unless indicated. ...
Article
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Phytocannabinoids like ∆(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) show a beneficial effect on neuroinflammatory and neurodegenerative processes through cell membrane cannabinoid receptor (CBr)-dependent and -independent mechanisms. Natural and synthetic cannabinoids also target the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ), an attractive molecular target for the treatment of neuroinflammation. As part of a study on the SAR of phytocannabinoids, we have investigated the effect of the oxidation modification in the resorcinol moiety of cannabigerol (CBG) on CB(1), CB(2) and PPARγ binding affinities, identifying cannabigerol quinone (VCE-003) as a potent anti-inflammatory agent. VCE-003 protected neuronal cells from excitotoxicity, activated PPARγ transcriptional activity and inhibited the release of pro-inflammatory mediators in LPS-stimulated microglial cells. Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis (MS) was used to investigate the anti-inflammatory activity of this compound in vivo. Motor function performance was evaluated and the neuroinflammatory response and gene expression pattern in brain and spinal cord were studied by immunostaining and qRT-PCR. We found that VCE-003 ameliorated the symptoms associated to TMEV infection, decreased microglia reactivity and modulated the expression of genes involved in MS pathophysiology. These data lead us to consider VCE-003 to have high potential for drug development against MS and perhaps other neuroinflammatory diseases.
... Early reports showed that CBC prolonged hexobarbital hypnosis in mice (Hatoum et al., 1981 ) exerted antiinflammatory effects and modest analgesic activity in rodents (Wirth et al., 1980; Turner and Elsohly, 1981; Davis and Hatoum, 1983), while showing no 'Cannabis like' activity in the Rheseus monkey (Mechoulam et al., 1970) and in human smoking experiments (Turner et al., 1980). In more recent years, it has been shown that CBC exerts antimicrobial (Appendino et al., 2008), anti-inflammatory (DeLong et al., 2010; Tubaro et al., 2010), analgesic (Maione et al., 2011) and antidepressant-like activity in rodents (El-Alfy et al., 2010). Pharmacodynamic studies have shown that CBC, like other plant natural products (Gertsch et al., 2010), is an inhibitor of endocannabinoid cellular reuptake (Ligresti et al., 2006) and a weak inhibitor of monoacylglycerol lipase (MAGL) (De Petrocellis et al., 2011), but is also a potent activator of transient receptor potential (TRP) ankyrin 1-type (TRPA1) channels (De Petrocellis et al., 2008;). ...
Article
Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states. Inflammation was induced in the mouse small intestine by croton oil. Endocannabinoid (anandamide and 2-arachidonoyl glycerol), palmitoylethanolamide and oleoylethanolamide levels were measured by liquid chromatography-mass spectrometry; TRPA1 and cannabinoid receptors were analysed by quantitative RT-PCR; upper gastrointestinal transit, colonic propulsion and whole gut transit were evaluated in vivo; contractility was evaluated in vitro by stimulating the isolated ileum, in an organ bath, with ACh or electrical field stimulation (EFS). Croton oil administration was associated with decreased levels of anandamide (but not 2-arachidonoyl glycerol) and palmitoylethanolamide, up-regulation of TRPA1 and CB₁ receptors and down-regulation of CB₂ receptors. Ex vivo CBC did not change endocannabinoid levels, but it altered the mRNA expression of TRPA1 and cannabinoid receptors. In vivo, CBC did not affect motility in control mice, but normalized croton oil-induced hypermotility. In vitro, CBC reduced preferentially EFS- versus ACh-induced contractions. Both in vitro and in vivo, the inhibitory effect of CBC was not modified by cannabinoid or TRPA1 receptor antagonists. CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.
... To stabilize the lipid membrane to water hydrolysis, lipophilic compounds were used, as they can intercalate into the phospholipid bilayer interface and displace water from the region [37][38][39]. For this reason, the authors used CBD to provide greater liposome stability as well as for its reported beneficial neuroprotective and anti-inflammatory activity [6,40,41]. In the present study, the authors demonstrated that these HNPs were effective in decreasing inflammation, as indicated by decreasing expression of the inflammatory cytokine IL-6 in cell cultures. ...
... This is expected to delay elimination of drugs metabolized by CYP3A4, thus increasing their blood concentration. Interactions between CBD and these drugs may contribute to clinical outcomes specific to the treatment for which they are indicated (9)(10)(11). Therefore, these drugs should be handled safely in recognition of both their beneficial and harmful effects (12). ...
Article
Objective: We aimed to examine the effects of cannabidiol (CBD)-containing hemp oil without delta-9-tetrahydrocannabinol (THC) as a supplemental treatment for canine atopic dermatitis (CAD), as well as its adverse effects, and effects on concurrent drug use in dogs. Animal: In this retrospective case series, 8 dogs with CAD were diagnosed by veterinary dermatologists certified by the Japanese Society of Veterinary Dermatology. Procedure: The medical records of dogs supplemented with CBD-containing hemp oil were evaluated with respect to signalment, physical examination, plasma C-reactive protein concentrations, pharmacologic management, the CAD Extent and Severity Index (4th iteration), and the Pruritus Visual Analog Scale. Results: Overall, CBD, used as a supplement in combination with other drugs, was well-tolerated over a wide dose range and decreased the occurrence of pruritus in dogs with CAD when ingested twice a day. Conclusion: This study provides the first report of supplementation with CBD without THC that was effective in controlling pruritic behavior in dogs with CAD. Clinical relevance: Further controlled studies are required to investigate the dose range, efficacy, and safety.
... In the Rhesus monkey [161] and in human smoking experiments [153] no 'Cannabis like' effects were described. In more recent years, studies showed that CBC exerts antimicrobial [127], anti-inflammatory [162,163], analgesic effects [164], cytotoxicity in cancer cell lines [121] and antidepressant-like activity in rodents [165,166]. Further reports have demonstrated that CBC, as other Cannabis-derived natural compounds [167], inhibits endocannabinoid cell re-uptake [121] and MAGL [149], but is also a potent activator of TRPV1 and ankyrin 1 -type (TRPA 1 ) channels [149,168]. ...
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Background: Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs. These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors. Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases. Methods: In this study, starting from the endocannabinoid mechanism of action in neuronal signaling, we highlight and discuss potential application and recent patents of cannabimimetic drugs in neurological disorders. Results: The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression. Conclusions: Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.
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Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with unclear etiology, namely ulcerative colitis and Crohn's disease. Various drug therapies including aminosalicylates and immunomodulators have been approved for use; they have shown to produce diverse side effects. To overcome these limitations of the current therapeutics for IBD, extensive research is underway to identify drugs that are effective and free of undesirable side effects. Recently, various naturally occurring phytochemicals that cover a wide range of chemical entities such as polyphenols, terpeniods, flavonoids, and alkaloids have received attention as alternative candidates for IBD therapy. These phytochemicals act by modulating the immune response, various transcription factors, or reduce cytokine secretion. This review summarizes the findings of recent studies on phytochemicals as therapeutic agents in the management of IBD. Copyright © 2015 John Wiley & Sons, Ltd.
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The cannabinoid 1(CB1 ) receptor inverse agonists/antagonists, rimonabant (SR141716, SR) and AM251, produce nausea and potentiate toxin-induced nausea by inverse agonism (rather than antagonism) of the CB1 receptor. Here, we evaluated two phytocannabinoids, cannabidivarin (CBDV) and Δ(9) -tetrahydrocannabivarin (THCV) for their ability to produce these behavioural effects characteristic of CB1 receptor inverse agonism in rats. In Experiment 1, we investigated the potential of THCV and CBDV to produce conditioned gaping (measure of nausea-induced behaviour), in the same manner as SR and AM251. In Experiment 2, we investigated the potential of THCV and CBDV to enhance conditioned gaping produced by a toxin, in the same manner as CB1 receptor inverse agonists. SR (10 and 20 mg kg(-1) ) and AM251 (10 mg kg(-1) ) produced conditioned gaping; however, THCV (10 or 20 mg kg(-1) ) and CBDV (10 or 200 mg kg(-1) ) did not. At a subthreshold dose for producing nausea, SR (2.5 mg kg(-1) ) enhanced LiCl-induced conditioned gaping, whereas Δ(9) -tetrahydrocannabinol (THC, 2.5 and 10 mg kg(-1) ), THCV (2.5 or 10 mg kg(-1) ) and CBDV (2.5 or 200 mg kg(-1) ) did not; in fact, THC (2.5 and 10 mg kg(-1) ), THCV (10 mg kg(-1) ) and CBDV (200 mg kg(-1) ) suppressed LiCl-induced conditioned gaping, suggesting anti-nausea potential. The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists. As well, these compounds may have therapeutic potential in reducing nausea.
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Objective. To investigate the therapeutic effect of CBD-ointment administered on severe skin chronic diseases and/or on their outcome scars. Methods. A spontaneous, anecdotal, retrospective study of 20 pa-tients with two most frequent skin disorders: psoriasis (n: 5 patients), atopic dermatitis (n: 5) and resulting outcome scars (n: 10). The sub-jects were instructed to administer topical CBD-enriched ointment to lesioned skin areas twice daily for three months treatment. Results. Based on skin evaluations (hydration, TEWL, elasticity), clinical questionnaires (SCORAD, ADI, PASI), and supported by photographic data and investigators’ clinical assessment, the results showed that topical treatment with CBD-enriched ointment signifi-cantly improved the skin parameters, the symptoms and also the PASI index score. No irritant or allergic reactions were documented during the period treatment. Conclusions. The topical administration of CBD ointment, without any THC, is a safe and effective non-invasive alternative for improve the quality of life in patients with some skin disorders, especially on inflammatory background.
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Cannabis is an annual plant with a long history of use as food, feed, fiber, oil, medicine, and narcotics. Despite realizing its true value, it has not yet found its true place. Cannabis has had a long history with many ups and downs, and now it is our turn to promote it. Cannabis contains approximately 600 identified and many yet unidentified potentially useful compounds. Cannabinoids, phenolic compounds, terpenoids, and alkaloids are some of the secondary metabolites present in cannabis. However, among a plethora of unique chemical compounds found in this plant, the most important ones are phytocannabinoids (PCs). Over hundreds of 21-22-carbon compounds exclusively produce in cannabis glandular hairs through either polyketide and or deoxyxylulose phosphate/methylerythritol phosphate (DOXP/MEP) pathways. Trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are those that first come to mind while talking about cannabis. Nevertheless, despite the low concentration, cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabinodiol (CBND), and cannabinidiol (CBDL) may have potentially some medical effects. PCs and endocannabinoids (ECs) mediate their effects mainly through CB1 and CB2 receptors. Despite all concerns regarding cannabis, nobody can ignore the use of cannabinoids as promising tonic, analgesic, antipyretic, antiemetic, anti-inflammatory, anti-epileptic, anticancer agents, which are effective for pain relief, depression, anxiety, sleep disorders, nausea and vomiting, multiple sclerosis, cardiovascular disorders, and appetite stimulation. The scientific community and public society have now increasingly accepted cannabis specifically hemp as much more than a recreational drug. There are growing demands for cannabinoids, mainly CBD, with many diverse therapeutic and nutritional properties in veterinary or human medicine. The main objective of this review article is to historically summarize findings concerning cannabinoids, mainly THC and CBD, towards putting these valuable compounds into food, feed and health baskets and current and future trends in the consumption of products derived from cannabis.
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Though known as a medicinal herb for centuries, the recent legalization of cannabinoids across many states has ushered in a new era where cannabinoids have become a popular treatment option amongst clinicians and patients alike. Cannabinoids have demonstrated efficacy in wound healing, reducing inflammation, ameliorating pain, and have shown potential as an anti-tumor agent. As a result, cannabinoids have been rapidly woven into the fabric of modern medicine. However, the utility of cannabinoids in dermatologic surgery has not been explored to date. In this paper, we review the current literature to discuss the potential impact of cannabinoid use in dermatologic surgery.
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Pendahuluan. Salah satu faktor yang mempengaruhi tekanan darah adalah stres. Tingginya tingkat stres umumnya disebabkan karena faktor sosial ekonomi keluarga yang memiliki tekanan tersendiri, sehingga secara tidak langsung faktor sosial ekonomi juga dapat mempengaruhi kejadian hipertensi seseorang. Tujuan. menganalisis hubungan antara keadaan sosial ekonomi dan tingkat stres dengan kejadian hipertensi. Metode. Jenis penelitian ini deskriptif korelasional dengan rancangan cross sectional yang bertujuan untuk mengkaji hubungan antara keadaan sosial ekonomi dan tingkat stres dengan kejadian hipertensi. Penelitian ini menggunakan sampel sebanyak 93 responden dengan tehnik simple random sampling. Result. Hasil analisis data dengan uji korelasi rank spearman di dapatkan nilai (α: 0,000). Kesimpulan. Ada hubungan yang signifikan yang artinya ada hubungan antara sosial ekonomi dan stres dengan kejadian hipertensi di Wilayah Kerja Puskesmas Sawan II. Kata kunci : Sosial Ekonomi, Stres, Hipertensi
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Zinc has so many beneficial effects as a supplement, particularly for the treatment of diseases and prevention of the occurrence of several disorders through inflammatory reactions, especially in gastrointestinal cases. The present study was done to assess the Zn effect on Silent Information Regulator 1 (SIRT1) and Peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) gene expression among ulcerative colitis (UC) patients. Fifty patients with mild-to-moderate active UC were included and divided into two groups of treatment (25 patients received Zn (35 mg Zn gluconate/day for 40 days) and control (25 patients received placebo similar to the Zn capsules in shape and color for 40 days). The expression rates of SIRT1 and PGC-1α were examined in the patients using the Real-Time PCR. The mean age of included patients was 37.2±10.6 years. The male to female ratio was 23/27. Totally, the distribution of smoking and alcohol among patients were 55% and 31%, respectively. Pan UC (40%) and lift-sided (40%) had the higher distribution. The mean expression of the PGC1-α gene was increased amongst the UC patients treated with Zn supplement (P <0.05). The mean expression of the SIRT1 gene was increased amongst the UC patients treated with Zn supplement (P <0.05). However, in the control group, no any changes have been recorded for both genes. It seems that Zn caused significant decrease in the inflammatory response of the colon by significant increase in the expression of the SIRT1 and PGC1-α genes. Keywords: Ulcerative colitis, PGC1-α, SIRT1, Gene expression, Zinc supplement.
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The legalisation of cannabis in a growing number of jurisdictions has led to increasing interest in its potential therapeutic effects in a range of disorders, including cutaneous conditions. Cannabinoids have been used as natural medicines for centuries; however, their biological activity in the skin is a new area of study. Recent data suggest that cannabinoids are involved in neuro-immuno-endocrine modulation of skin functioning, yet their effect on the features of dermatologic conditions is unclear. This article sought to review the mechanisms by which cannabinoids regulate skin functioning through the lens of relevance to treatment of dermatologic diseases looking at the effects of cannabinoids on a range of cellular activities and dermatologic conditions both in vitro and in vivo. We identified studies demonstrating an inhibitory effect of cannabinoids on skin inflammation, proliferation, fibrosis, pain, and itch—biological mechanisms involved in the pathogenesis of many dermatologic conditions. Cannabinoids have the potential to expand the therapeutic repertoire of a wide spectrum of skin disorders. Given their widespread unregulated use by the general public, basic and clinical studies are required to elucidate the effectiveness and long-term effects of topical and systemic cannabinoids in cutaneous disorders.
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The therapeutic potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis, was explored in murine collagen-induced arthritis (CIA). CIA was elicited by immunizing DBA/1 mice with type II collagen (CII) in complete Freund's adjuvant. The CII used was either bovine or murine, resulting in classical acute CIA or in chronic relapsing CIA, respectively. CBD was administered after onset of clinical symptoms, and in both models of arthritis the treatment effectively blocked progression of arthritis. CBD was equally effective when administered i.p. or orally. The dose dependency showed a bell-shaped curve, with an optimal effect at 5 mg/kg per day i.p. or 25 mg/kg per day orally. Clinical improvement was associated with protection of the joints against severe damage. Ex vivo, draining lymph node cells from CBD-treated mice showed a diminished CII-specific proliferation and IFN-gamma production, as well as a decreased release of tumor necrosis factor by knee synovial cells. In vitro effects of CBD included a dose-dependent suppression of lymphocyte proliferation, both mitogen-stimulated and antigen-specific, and the blockade of the Zymosan-triggered reactive oxygen burst by peritoneal granulocytes. It also was found that CBD administration was capable of blocking the lipopolysaccharide-induced rise in serum tumor necrosis factor in C57/BL mice. Taken together, these data show that CBD, through its combined immunosuppressive and anti-inflammatory actions, has a potent anti-arthritic effect in CIA.
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Two new neutral cannabinoids, cannabichromevarin and cannabigerovarin, were isolated from the "Meao variant, "Thailand Cannabis and their structures were determined to be the homologues of cannabichromene and cannabigerol which have a propyl sidechain, respectively, on the basis of spectral and chemical evidences.
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Depending on the reaction conditions used, the physiologically active products obtained by Adams on isomerization of the inactive cannabidiol (Ia) with acids are shown to be either Δ1(6) tetrahydrocannabinol (II) or a mixture of II, Δ1 tetrahydrocannabinol (IIIa) and the two isomers of 1-ethoxy hexahydrocannabinol (VIIIa, VIIIb).
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The n-propyl homologue of Δ1-tetrahydrocannabinol (Δ1-THC) has been isolated from Cannabis sativa L. The structure of the compound was deduced by i.r., n.m.r., and mass spectroscopy, and was confirmed by synthesis. It has only one-fifth of the activity of Δ1-THC in the mouse catalepsy test, and although present in amounts comparable to Δ1-THC it probably makes only a small contribution to the effects produced by the consumption of crude cannabis.
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The phytocannabinoid, Delta(9)-tetrahydrocannabivarin (THCV), can block cannabinoid CB(1) receptors. This investigation explored its ability to activate CB(2) receptors, there being evidence that combined CB(2) activation/CB(1) blockade would ameliorate certain disorders. We tested the ability of THCV to activate CB(2) receptors by determining whether: (i) it inhibited forskolin-stimulated cyclic AMP production by Chinese hamster ovary (CHO) cells transfected with human CB(2) (hCB(2)) receptors; (ii) it stimulated [(35)S]GTPgammaS binding to hCB(2) CHO cell and mouse spleen membranes; (iii) it attenuated signs of inflammation/hyperalgesia induced in mouse hind paws by intraplantar injection of carrageenan or formalin; and (iv) any such anti-inflammatory or anti-hyperalgesic effects were blocked by a CB(1) or CB(2) receptor antagonist. THCV inhibited cyclic AMP production by hCB(2) CHO cells (EC(50)= 38 nM), but not by hCB(1) or untransfected CHO cells or by hCB(2) CHO cells pre-incubated with pertussis toxin (100 ng.mL(-1)) and stimulated [(35)S]GTPgammaS binding to hCB(2) CHO and mouse spleen membranes. THCV (0.3 or 1 mg.kg(-1) i.p.) decreased carrageenan-induced oedema in a manner that seemed to be CB(2) receptor-mediated and suppressed carrageenan-induced hyperalgesia. THCV (i.p.) also decreased pain behaviour in phase 2 of the formalin test at 1 mg.kg(-1), and in both phases of this test at 5 mg.kg(-1); these effects of THCV appeared to be CB(1) and CB(2) receptor mediated. THCV can activate CB(2) receptors in vitro and decrease signs of inflammation and inflammatory pain in mice partly via CB(1) and/or CB(2) receptor activation.
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Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
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Two extracts of Cannabis sativa herb, one being cannabinoid-free (ethanol) and the other containing the cannabinoids (petroleum), were shown to inhibit PBQ-induced writhing in mouse when given orally and also to antagonize tetradecanoylphorbol acetate (TPA)-induced erythema of mouse skin when applied topically. With the exception of cannabinol (CBN) and delta 1-tetrahydrocannabinol (delta 1-THC), the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 micrograms/kg. delta 1-THC only became maximally effective in doses of 10 mg/kg. This higher dose corresponded to that which induced catalepsy and is indicative of a central action. CNB demonstrated little activity and even at doses in excess of 10 mg/kg could only produce a 40% inhibition of PBQ-induced writhing. Cannabinoid (CBD) was the most effective of the cannabinoids at doses of 100 micrograms/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. The fact that delta 1-THC and CBN were the least effective in this test suggests a structural relationship between analgesic activity and antiinflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta 1-THC.
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measurement the ear plugs were homogenized in physiological saline containing 0.1% of hexadecyltrimethylammonium bromide. The post 15,000 g supernatants of the homogenates (which contained more than 95% of the PA) were used for the assay [5]. PA units are expressed as nmoles of tetraguaiacol/min at 25~ Results and discussion
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Δ9 Tetrahydrocannabinol (THC) is an orally effective anti edema and analgesic agent. In the carrageenan edema test the potency of THC is 20 times that of aspirin and nearly twice that of hydrocortisone. The anti edema activity of THC, at least in the carrageenan edema assay, appears to be mediated by stimulation of the pituitary adrenal axis, since this activity was markedly attenuated in both adrenalectomized and hypophysectomized rats. However, the compound is devoid of corticosteroid like activity since it did not prolong the survival time of adrenalectomized rats nor did it favorably influence the rate of change of body weight in these animals. Furthermore, THC is an effective inhibitor of developing adjuvant induced arthritis and suppresses further development of the established disease. The analgesic activity for THC is substantially greater than that for aspirin. The compound has no antipyretic activity at a dose producing profound anti edema effects.
Article
Cannabichromene (CBC) is one of four major cannabinoids in Cannabis sativa L. and is the second most abundant cannabinoid in drug-type cannabis. Cannabichromene and some of its homologs, analogs, and isomers were evaluated for antiinflammatory, antibacterial, and antifungal activity. Antiinflammatory activity was evaluated by the carrageenan-induced rat paw edema and the erythrocyte membrane stabilization method. In both tests, CBC was superior to phenylbutazone. Antibacterial activity of CBC and its isomers and homologs was evaluated using gram-positive, gram-negative, and acid-fast bacteria. Antifungal activity was evaluated using yeast-like and filamentous fungi and a dermatophyte. Antibacterial activity was strong, and the antifungal activity was mild to moderate.
Article
It was not known if Cannabichromene (CBC), which is a major constituent of drug types of , has anti-inflammatory properties as do other cannabinoids. CBC was tested using the rat paw edema test and using the erythrocyte membrane stabilization assay. CBC was as effective as phenylbutazone (PBZ) at equivalent doses. Since CBC is less toxic than PBZ, larger doses may be given to produce a greater therapeutic effect.
Article
Cannabidiol, the major non-psychoactive component of marijuana, has various pharmacological actions of clinical interest. It is reportedly effective as an anti-inflammatory and anti-arthritic in murine collagen-induced arthritis. The present study examined the anti-inflammatory and anti-hyperalgesic effects of cannabidiol, administered orally (5–40 mg/kg) once a day for 3 days after the onset of acute inflammation induced by intraplantar injection of 0.1 ml carrageenan (1% w/v in saline) in the rat. At the end of the treatment prostaglandin E2 (PGE2) was assayed in the plasma, and cyclooxygenase (COX) activity, production of nitric oxide (NO; nitrite/nitrate content), and of other oxygen-derived free radicals (malondialdehyde) in inflamed paw tissues. All these markers were significantly increased following carrageenan. Thermal hyperalgesia, induced by carrageenan and assessed by the plantar test, lasted 7 h. Cannabidiol had a time- and dose-dependent anti-hyperalgesic effect after a single injection. Edema following carrageenan peaked at 3 h and lasted 72 h; a single dose of cannabidiol reduced edema in a dose-dependent fashion and subsequent daily doses caused further time- and dose-related reductions. There were decreases in PGE2 plasma levels, tissue COX activity, production of oxygen-derived free radicals, and NO after three doses of cannabidiol. The effect on NO seemed to depend on a lower expression of the endothelial isoform of NO synthase. In conclusion, oral cannabidiol has a beneficial action on two symptoms of established inflammation: edema and hyperalgesia.
Article
The cannabis plant (Cannabis sativa L.) and products thereof (such as marijuana, hashish and hash oil) have a long history of use both as a medicinal agent and intoxicant. Over the last few years there have been an active debate regarding the medicinal aspects of cannabis. Currently cannabis products are classified as Schedule I drugs under the Drug Enforcement Administration (DEA) Controlled Substances act, which means that the drug is only available for human use as an investigational drug. In addition to the social aspects of the use of the drug and its abuse potential, the issue of approving it as a medicine is further complicated by the complexity of the chemical make up of the plant. This manuscript discusses the chemical constituents of the plant with particular emphasis on the cannabinoids as the class of compounds responsible for the drug's psychological properties.
Article
To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (eDelta(9)-THCV) is a CB(1) receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB(1) antagonists in vivo. O-4394 and O-4395 were compared with eDelta(9)-THCV as displacers of [(3)H]-CP55940 from specific CB(1) binding sites on mouse brain membranes and as antagonists of CP55940 in [(35)S]GTPgammaS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated. O-4394 and O-4395 exhibited similar potencies to eDelta(9)-THCV as displacers of [(3)H]-CP55940 (K (i)=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [(35)S]GTPgammaS binding assay (apparent K (B)=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K (B)=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg(-1) O-4394 and O-4395 attenuated Delta(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta(9)-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg(-1) (i.v.) and antinociception at doses above 10 mg kg(-1) (i.v.). O-4395 also induced hypothermia at 3 mg kg(-1) (i.v.) and above. O-4394 and O-4395 exhibit similar in vitro potencies to eDelta(9)-THCV as CB(1) receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.
Article
Over the past 50 years, a considerable research in medicinal chemistry has been carried out around the natural constituents of Cannabis sativa L. Following the identification of Delta9-tetrahydrocannabinol (Delta9-THC) in 1964, critical chemical modifications, e.g., variation of the side chain at C3 and the opening of the tricyclic scaffold, have led to the characterization of potent and cannabinoid receptor subtype-selective ligands. Those ligands that demonstrate high affinity for the cannabinoid receptors and good biological efficacy are still used as powerful pharmacological tools. This review summarizes past as well as recent developments in the structure-activity relationships of phytocannabinoids.
Article
Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. Cannabinoids have been shown to modulate a variety of immune cell functions and have therapeutic implications on central nervous system (CNS) inflammation, chronic inflammatory conditions such as arthritis, and may be therapeutically useful in treating autoimmune conditions such as multiple sclerosis. Many of these drug effects occur through cannabinoid receptor signalling mechanisms and the modulation of cytokines and other gene products. Further, endocannabinoids have been found to have many physiological and patho-physiological functions, including mood alteration and analgesia, control of energy balance, gut motility, motor and co-ordination activities, as well as alleviation of neurological, psychiatric and eating disorders. Plants offer a wide range of chemical diversity and have been a growing domain in the search for effective cannabinoid ligands. Cannabis sativa L. with the known plant cannabinoid, Delta(9-)tetrahydrocannabinol (THC) and Echinacea species with the cannabinoid (CB) receptor-binding lipophilic alkamides are the best known herbal cannabimimetics. This review focuses on the state of the art in CB ligands from plants, as well their possible therapeutic and immunomodulatory effects.
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