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1.
J Evid Based Integr Med ; 26: 2515690X211036875, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34384258

RESUMO

Worldwide, the turmoil of the SARS-CoV-2 (COVID-19) pandemic has generated a burst of research efforts in search of effective prevention and treatment modalities. Current recommendations on natural supplements arise from mostly anecdotal evidence in other viral infections and expert opinion, and many clinical trials are ongoing. Here the authors review the evidence and rationale for the use of natural supplements for prevention and treatment of COVID-19, including those with potential benefit and those with potential harms. Specifically, the authors review probiotics, dietary patterns, micronutrients, antioxidants, polyphenols, melatonin, and cannabinoids. Authors critically evaluated and summarized the biomedical literature published in peer-reviewed journals, preprint servers, and current guidelines recommended by expert scientific governing bodies. Ongoing and future trials registered on clinicaltrials.gov were also recorded, appraised, and considered in conjunction with the literature findings. In light of the controversial issues surrounding the manufacturing and marketing of natural supplements and limited scientific evidence available, the authors assessed the available data and present this review to equip clinicians with the necessary information regarding the evidence for and potential harms of usage to promote open discussions with patients who are considering dietary supplements to prevent and treat COVID-19.


Assuntos
Antioxidantes/uso terapêutico , COVID-19/tratamento farmacológico , Suplementos Nutricionais , Micronutrientes/uso terapêutico , Extratos Vegetais/uso terapêutico , Antioxidantes/farmacologia , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Humanos , Melatonina/farmacologia , Melatonina/uso terapêutico , Micronutrientes/farmacologia , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Probióticos/uso terapêutico , SARS-CoV-2
2.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445634

RESUMO

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called "hunger" hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.


Assuntos
Corpo Estriado/patologia , Dieta Hiperlipídica/efeitos adversos , Grelina/metabolismo , Neurônios/patologia , Obesidade/patologia , Receptor CB2 de Canabinoide/metabolismo , Receptores de Grelina/metabolismo , Animais , Canabinoides/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Feminino , Grelina/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Receptor CB2 de Canabinoide/genética , Receptores de Grelina/genética , Transdução de Sinais , Regulação para Cima
3.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361095

RESUMO

BACKGROUND: marijuana, the common name for cannabis sativa preparations, is one of the most consumed drug all over the world, both at therapeutical and recreational levels. With the legalization of medical uses of cannabis in many countries, and even its recreational use in most of these, the prevalence of marijuana use has markedly risen over the last decade. At the same time, there is also a higher prevalence in the health concerns related to cannabis use and abuse. Thus, it is mandatory for oral healthcare operators to know and deal with the consequences and effects of cannabis use on oral cavity health. This review will briefly summarize the components of cannabis and the endocannabinoid system, as well as the cellular and molecular mechanisms of biological cannabis action in human cells and biologic activities on tissues. We will also look into oropharyngeal tissue expression of cannabinoid receptors, together with a putative association of cannabis to several oral diseases. Therefore, this review will elaborate the basic biology and physiology of cannabinoids in human oral tissues with the aim of providing a better comprehension of the effects of its use and abuse on oral health, in order to include cannabinoid usage into dental patient health records as well as good medicinal practice. METHODS: the paper selection was performed by PubMed/Medline and EMBASE electronic databases, and reported according to the PRISMA guidelines. The scientific products were included for qualitative analysis. RESULTS: the paper search screened a total of 276 papers. After the initial screening and the eligibility assessment, a total of 32 articles were considered for the qualitative analysis. CONCLUSIONS: today, cannabis consumption has been correlated to a higher risk of gingival and periodontal disease, oral infection and cancer of the oral cavity, while the physico-chemical activity has not been completely clarified. Further investigations are necessary to evaluate a therapeutic efficacy of this class of drugs for the promising treatment of several different diseases of the salivary glands and oral diseases.


Assuntos
Canabinoides/farmacologia , Doenças da Boca/tratamento farmacológico , Saúde Bucal/normas , Transtornos Relacionados ao Uso de Substâncias/etiologia , Humanos , Transtornos Relacionados ao Uso de Substâncias/patologia
4.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3540-3550, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402276

RESUMO

Cannabinoid receptor type 2( CB2 R),a member of the G protein-coupled receptor( GPCR) superfamily,has a variety of biological activities,such as regulating pain response,resisting inflammation and fibrosis,and mediating bone metabolism. Some CB2 R regulators exhibit a good regulatory effect on bone metabolism. Cannabinoids in Cannabis sativa can cause psychoactive effects despite various pharmacological actions they exerted by targeting CB2 R. Therefore,it is of great significance to discover CB2 R regulators in non-Cannabis plants for finding new lead compounds without psychoactive effects and elucidating the action mechanism of plant drugs. The present study clarifies the discovery,structure,and physiological functions of CB2 R,especially its regulatory effects on bone metabolism,summarized CB2 R regulators extracted from non-Cannabis plants,and systematically analyzes the regulatory effects of CB2 R regulators on bone metabolism in animals,osteoblasts,and osteoclasts,to provide a scientific basis for the discovery of new CB2 R regulators and the development of anti-osteoporotic drugs.


Assuntos
Canabinoides , Cannabis , Animais , Canabinoides/farmacologia , Osteoblastos , Osteoclastos , Receptores de Canabinoides
5.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445666

RESUMO

Epilepsy is characterized by repeated spontaneous bursts of neuronal hyperactivity and high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients, and nearly 30% of individuals are refractory to treatment of antiseizure drugs. Therefore, there is an urgent need to develop new drugs to manage and control refractory epilepsy. Cannabinoid ligands, including selective cannabinoid receptor subtype (CB1 or CB2 receptor) ligands and non-selective cannabinoid (synthetic and endogenous) ligands, may serve as novel candidates for this need. Cannabinoid appears to regulate seizure activity in the brain through the activation of CB1 and CB2 cannabinoid receptors (CB1R and CB2R). An abundant series of cannabinoid analogues have been tested in various animal models, including the rat pilocarpine model of acquired epilepsy, a pentylenetetrazol model of myoclonic seizures in mice, and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. In this review, we summarize the relationship between brain CB2 receptors and seizures and emphasize the potential mechanisms of their therapeutic effects involving the influences of neurons, astrocytes, and microglia cells. The unique features of CB2Rs, such as lower expression levels under physiological conditions and high inducibility under epileptic conditions, make it an important target for future research on drug-resistant epilepsy.


Assuntos
Canabinoides/farmacologia , Epilepsia/tratamento farmacológico , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Epilepsia/metabolismo , Humanos , Ligantes , Microglia/metabolismo , Neurônios/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptores de Canabinoides/metabolismo , Convulsões/tratamento farmacológico , Convulsões/metabolismo
6.
Adv Clin Chem ; 103: 191-214, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229850

RESUMO

Synthetic drugs of abuse contain various psychoactive substances. These substances have recently emerged as novel drugs of abuse in public; thus, they are known as novel psychoactive substances (NPS). As these compounds are artificially synthesized in a laboratory, they are also called designer drugs. Synthetic cannabinoids and synthetic cathinones are the two primary classes of NPS or designer drugs. Synthetic cannabinoids, also known as "K2" or "Spice," are potent agonists of the cannabinoid receptors. Synthetic cathinones, known as "Bath salts," are beta-keto amphetamine derivatives. These compounds can cause severe intoxication, including overdose deaths. NPS are accessible locally and online. NPS are scheduled in the US and other countries, but the underground chemists keep modifying the chemical structure of these compounds to avoid legal regulation; thus, these compounds have been evolving rapidly. These drugs are not detectable by traditional drug screening, and thus, these substances are mainly abused by young individuals and others who wish to avoid drug detection. These compounds are analyzed primarily by mass spectrometry.


Assuntos
Alcaloides/síntese química , Canabinoides/síntese química , Psicotrópicos/síntese química , Transtornos Relacionados ao Uso de Substâncias , Alcaloides/farmacologia , Canabinoides/farmacologia , Humanos , Drogas Ilícitas , Psicotrópicos/farmacologia , Medicamentos Sintéticos
7.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299009

RESUMO

As many jurisdictions consider relaxing cannabis legislation and usage is increasing in North America and other parts of the world, there is a need to explore the possible genetic differences underlying the subjective effects of cannabis. This pilot study investigated specific genetic variations within the cannabinoid receptor 1 (CNR1) gene for association with the subjective effects of smoked cannabis. Data were obtained from a double-blinded, placebo-controlled clinical trial studying the impact of cannabis intoxication on driving performance. Participants randomized to the active cannabis group who consented to secondary genetic analysis (n = 52) were genotyped at the CNR1 rs1049353 and rs2023239 polymorphic areas. Maximum value and area under the curve (AUC) analyses were performed on subjective measures data. Analysis of subjective effects by genotype uncovered a global trend towards greater subjective effects for rs1049353 T-allele- and rs2023239 C-allele-carrying subjects. However, significant differences attributed to allelic identity were only documented for a subset of subjective effects. Our findings suggest that rs1049353 and rs2023239 minor allele carriers experience augmented subjective effects during acute cannabis intoxication.


Assuntos
Afeto/efeitos dos fármacos , Canabinoides/farmacologia , Cannabis/química , Fumar Maconha/genética , Receptor CB1 de Canabinoide/genética , Adulto , Alelos , Área Sob a Curva , Canabinoides/administração & dosagem , Canabinoides/sangue , Feminino , Genótipo , Humanos , Masculino , Fumar Maconha/psicologia , Projetos Piloto , Polimorfismo de Nucleotídeo Único
8.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298921

RESUMO

Chronic inflammation is considered to be a silent killer because it is the underlying cause of a wide range of clinical disorders, from cardiovascular to neurological diseases, and from cancer to obesity. In addition, there are over 80 different types of debilitating autoimmune diseases for which there are no cure. Currently, the drugs that are available to suppress chronic inflammation are either ineffective or overtly suppress the inflammation, thereby causing increased susceptibility to infections and cancer. Thus, the development of a new class of drugs that can suppress chronic inflammation is imperative. Cannabinoids are a group of compounds produced in the body (endocannabinoids) or found in cannabis (phytocannabinoids) that act through cannabinoid receptors and various other receptors expressed widely in the brain and immune system. In the last decade, cannabinoids have been well established experimentally to mediate anti-inflammatory properties. Research has shown that they suppress inflammation through multiple pathways, including apoptosis and inducing immunosuppressive T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Interestingly, cannabinoids also mediate epigenetic alterations in genes that regulate inflammation. In the current review, we highlight how the epigenetic modulations caused by cannabinoids lead to the suppression of inflammation and help identify novel pathways that can be used to target autoimmune diseases.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/genética , Canabinoides/farmacologia , Epigênese Genética/genética , Inflamação/tratamento farmacológico , Inflamação/genética , Animais , Humanos , Sistema Imunitário/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos
9.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299069

RESUMO

The endocannabinoid system (ECS) is a crucial modulatory system in which interest has been increasing, particularly regarding the regulation of behavior and neuroplasticity. The adolescent-young adulthood phase of development comprises a critical period in the maturation of the nervous system and the ECS. Neurogenesis occurs in discrete regions of the adult brain, and this process is linked to the modulation of some behaviors. Since marijuana (cannabis) is the most consumed illegal drug globally and the highest consumption rate is observed during adolescence, it is of particular importance to understand the effects of ECS modulation in these early stages of adulthood. Thus, in this article, we sought to summarize recent evidence demonstrating the role of the ECS and exogenous cannabinoid consumption in the adolescent-young adulthood period; elucidate the effects of exogenous cannabinoid consumption on adult neurogenesis; and describe some essential and adaptive behaviors, such as stress, anxiety, learning, and memory. The data summarized in this work highlight the relevance of maintaining balance in the endocannabinoid modulatory system in the early and adult stages of life. Any ECS disturbance may induce significant modifications in the genesis of new neurons and may consequently modify behavioral outcomes.


Assuntos
Encéfalo/efeitos dos fármacos , Canabinoides/farmacologia , Doenças Neurodegenerativas/fisiopatologia , Neurogênese , Comportamento Social , Estresse Psicológico , Adolescente , Adulto , Encéfalo/metabolismo , Humanos , Doenças Neurodegenerativas/induzido quimicamente , Receptores de Canabinoides/metabolismo , Adulto Jovem
10.
Neuroscience ; 468: 123-138, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34129911

RESUMO

Endocannabinoids are bioactive substances which participate in central motor control. The globus pallidus (GP) is a major nucleus in the basal ganglia circuit, which plays an important function in movement regulation. Both cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R) are expressed in the GP suggesting GP as a main action area of endocannabinoids. To investigate the direct electrophysiological and behavioral effects of cannabinoids in GP, in vivo single unit extracellular recordings and behavioral tests were performed in rats. Administration of WIN 55,212-2 exerted three neuronal response patterns from all sampled neurons of GP, including (1) increase of the firing rate; (2) decrease of the firing rate; (3) increase and then decrease of the firing rate. Selectively blocking CB1R by AM 251 decreased the firing rate and increased the firing rate. Selectively blocking CB2R by AM 630 did not change the firing rate significantly, which suggested that endocannabinoids modulated the spontaneous firing activity of pallidal neurons mainly via CB1R. Furthermore, co-application of AM 251, but not AM 630, blocked WIN 55,212-2-induced modulation of firing activity of pallidal neurons. Finally, both haloperidol-induced postural behavioral test and elevated body swing test (EBST) showed that unilateral microinjection of WIN 55,212-2 mainly induced contralateral-biased swing and deflection behaviors. Meanwhile, AM 251 produced opposite effect. The present in vivo study revealed that cannabinoids produced complicated electrophysiological and behavioral effects in the GP, which further demonstrated that the GP is a major functional region of endocannabinoid.


Assuntos
Canabinoides , Globo Pálido , Potenciais de Ação , Animais , Canabinoides/farmacologia , Fenômenos Eletrofisiológicos , Haloperidol , Neurônios , Ratos
11.
Molecules ; 26(9)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063214

RESUMO

Cannabis sativa L. is a source of over 150 active compounds known as phytocannabinoids that are receiving renewed interest due to their diverse pharmacologic activities. Indeed, phytocannabinoids mimic the endogenous bioactive endocannabinoids effects through activation of CB1 and CB2 receptors widely described in the central nervous system and peripheral tissues. All phytocannabinoids have been studied for their protective actions towards different biological mechanisms, including inflammation, immune response, oxidative stress that, altogether, result in an inhibitory activity against the carcinogenesis. The role of the endocannabinoid system is not yet completely clear in cancer, but several studies indicate that cannabinoid receptors and endogenous ligands are overexpressed in different tumor tissues. Recently, in vitro and in vivo evidence support the effectiveness of phytocannabinoids against various cancer types, in terms of proliferation, metastasis, and angiogenesis, actions partially due to their ability to regulate signaling pathways critical for cell growth and survival. The aim of this review was to report the current knowledge about the action of phytocannabinoids from Cannabis sativa L. against cancer initiation and progression with a specific regard to brain, breast, colorectal, and lung cancer as well as their possible use in the therapies. We will also report the known molecular mechanisms responsible for such positive effects. Finally, we will describe the actual therapeutic options for Cannabis sativa L. and the ongoing clinical trials.


Assuntos
Canabinoides/farmacologia , Cannabis/química , Neoplasias/patologia , Neoplasias/prevenção & controle , Sítio Alostérico , Animais , Antineoplásicos/farmacologia , Canabinoides/química , Sistema Nervoso Central/efeitos dos fármacos , Ensaios Clínicos como Assunto , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Endocanabinoides , Humanos , Sistema Imunitário , Inflamação , Estresse Oxidativo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Receptor CB1 de Canabinoide/química , Receptor CB2 de Canabinoide/química , Resultado do Tratamento
12.
Biomed Pharmacother ; 140: 111639, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34091179

RESUMO

The endocannabinoid system (ECS), a conserved physiological system emerged as a novel pharmacological target for its significant role and potential therapeutic benefits ranging from neurological diseases to cancer. Among both, CB1 and CB2R types, CB2R have received attention for its pharmacological effects as antioxidant, anti-inflammatory, immunomodulatory and antiapoptotic that can be achieved without causing psychotropic adverse effects through CB1R. The ligands activate CB2R are of endogenous, synthetic and plant origin. In recent years, ß-caryophyllene (BCP), a natural bicyclic sesquiterpene in cannabis as well as non-cannabis plants, has received attention due to its selective agonist property on CB2R. BCP has been well studied in a variety of pathological conditions mediating CB2R selective agonist property. The focus of the present manuscript is to represent the CB2R selective agonist mediated pharmacological mechanisms and therapeutic potential of BCP. The present narrative review summarizes insights into the CB2R-selective pharmacological properties and therapeutic potential of BCP such as cardioprotective, hepatoprotective, neuroprotective, nephroprotective, gastroprotective, chemopreventive, antioxidant, anti-inflammatory, and immunomodulator. The available evidences suggest that BCP, can be an important candidate of plant origin endowed with CB2R selective properties that may provide a pharmacological rationale for its pharmacotherapeutic application and pharmaceutical development like a drug. Additionally, given the wide availability in edible plants and dietary use, with safety, and no toxicity, BCP can be promoted as a nutraceutical and functional food for general health and well-being. Further, studies are needed to explore pharmacological and pharmaceutical opportunities for therapeutic and preventive applications of use of BCP in human diseases.


Assuntos
Canabinoides/farmacologia , Sesquiterpenos Policíclicos/farmacologia , Receptor CB2 de Canabinoide/metabolismo , Animais , Suplementos Nutricionais , Humanos , Plantas Comestíveis/química , Sesquiterpenos/farmacologia
13.
Fitoterapia ; 152: 104915, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33964342

RESUMO

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.


Assuntos
Antioxidantes/farmacologia , Canabinoides/farmacologia , Cannabis/química , Antioxidantes/isolamento & purificação , Benzoatos , Canabidiol , Canabinoides/isolamento & purificação , Canabinol/análogos & derivados , Estrutura Molecular
14.
Nat Rev Neurosci ; 22(7): 439-454, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34045693

RESUMO

Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis-related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis.


Assuntos
Canabinoides/farmacologia , Cannabis , Cognição/efeitos dos fármacos , Envelhecimento , Atenção/efeitos dos fármacos , Variação Biológica Individual , Biotransformação/genética , Encéfalo/efeitos dos fármacos , Canabinoides/administração & dosagem , Canabinoides/farmacocinética , Estado de Consciência/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/farmacocinética , Dronabinol/farmacologia , Tolerância a Medicamentos , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Fumar Maconha , Rede Nervosa/efeitos dos fármacos , Neurotransmissores/farmacologia , Personalidade , Desempenho Psicomotor/efeitos dos fármacos , Psicotrópicos/administração & dosagem , Psicotrópicos/farmacologia , Caracteres Sexuais , Fumaça
15.
Exp Clin Psychopharmacol ; 29(2): 137-146, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34043398

RESUMO

Cannabis and synthetic cannabinoids are abused in spite of possible adverse health consequences. The current study investigated the reinforcing effects of an ecologically relevant mode of administration (inhalation) of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, and three synthetic cannabinoids detected in synthetic cannabinoid products (JWH-018, JWH-073, and HU-210) in non-human primates (NHPs). Male and female (N = 4 each) rhesus macaques were trained to inhale warm air via a metal stem to receive a candy reinforcer, an alcohol aerosol vehicle was then paired with the candy. Dose-dependent responding for inhaled aerosols of THC (2.0-16.0 µg/kg/inhalation), JWH-018 (0.2-1.6 µg/kg/inhalation), JWH-073 (2.0-8.0 µg/kg/inhalation), and HU-210 (1.0-8.0 µg/kg/inhalation) was established using a fixed-ratio five schedule of reinforcement and compared to vehicle (alcohol) self-administration. Dose-dependent responding for inhaled heroin (25.0-100.0 µg/kg/inhalation), a known reinforcer in NHPs, was also established. Responding approximated vehicle levels for many drug doses tested, but at least half of the monkeys responded for ≥ one dose of each cannabinoid and heroin above vehicle, with the exception of THC. Drug deliveries calculated as percent vehicle followed a prototypical inverted-U shaped dose-response curve for cannabinoids and heroin except for THC and JWH-018 (in males). Grouped data according to sex demonstrated that peak percent of vehicle reinforcers earned for THC was greater in males than females, whereas peak percent of vehicle reinforcers earned for JWH-018, HU-210, and heroin were greater in females than males. These findings indicate minimal reinforcing effects of CB1 receptor agonists when self-administered by NHPs via aerosol inhalation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Dronabinol/análogos & derivados , Dronabinol/administração & dosagem , Indóis/administração & dosagem , Naftalenos/administração & dosagem , Animais , Canabinoides/farmacologia , Cannabis/química , Relação Dose-Resposta a Droga , Feminino , Heroína/administração & dosagem , Macaca mulatta , Masculino , Receptor CB1 de Canabinoide/agonistas , Reforço Psicológico , Autoadministração
16.
Mol Cell Biochem ; 476(9): 3285-3301, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33886060

RESUMO

Colorectal cancer (CRC) is between the top three occurring cancers worldwide. The anticancer effects of Cannabinoid receptor 2 (CB2) agonist (GW833972A) in the presence and absence of its inverse agonist (SR144528) on Human colorectal adenocarcinoma cells (HT-29) was investigated. Following cell viability assays on HT-29 and HFF cells, the molecular mechanism(s) of cytotoxicity and apoptotic pathways of cell death were analyzed. The anticancer effects of CB2 agonist were measured with tumor cell migration and colony-forming assays. Real-time PCR and Western blotting techniques were used to examine any alterations in the expression of apoptotic genes. A concentration and time-dependent cytotoxicity of CB2 agonist with IC50 value of 24.92 ± 6.99 µM was obtained. The rate of lipid peroxidation was elevated, while the TNF-α concentration was declined, significantly (p < 0.05). CB2 agonist (50 µM) reduced the colony-forming capability by 83% and tumor cell migration by 50%. Apoptotic effects of CB2 agonist were revealed with the increase of apoptotic cells in Acridine orange/Ethidium bromide staining, clear DNA fragmentation, pro-apoptotic genes and proteins upregulation (Caspase-3 and p53), and significant downregulation of anti-apoptotic Bcl-2. All assessments demonstrated that CB2 agonist-induced effects were reversed by CB2 inverse agonist. These data suggest that CB2 agonists at micro-molar concentrations might be considered in the CRC treatment, and their effectiveness attributes to the apoptosis induction via upregulation of caspase-3 and p53 and downregulation of Bcl-2.


Assuntos
Apoptose , Agonistas de Receptores de Canabinoides/farmacologia , Canabinoides/farmacologia , Neoplasias Colorretais/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Receptor CB2 de Canabinoide/agonistas , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Humanos , Células Tumorais Cultivadas
17.
Molecules ; 26(5)2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33800024

RESUMO

The endocannabinoid system (ECS) is involved in the modulation of several basic biological processes, having widespread roles in neurodevelopment, neuromodulation, immune response, energy homeostasis and reproduction. In the adult central nervous system (CNS) the ECS mainly modulates neurotransmitter release, however, a substantial body of evidence has revealed a central role in regulating neurogenesis in developing and adult CNS, also under pathological conditions. Due to the complexity of investigating ECS functions in neural progenitors in vivo, we tested the suitability of the ST14A striatal neural progenitor cell line as a simplified in vitro model to dissect the role and the mechanisms of ECS-regulated neurogenesis, as well as to perform ECS-targeted pharmacological approaches. We report that ST14A cells express various ECS components, supporting the presence of an active ECS. While CB1 and CB2 receptor blockade did not affect ST14A cell number, exogenous administration of the endocannabinoid 2-AG and the synthetic CB2 agonist JWH133 increased ST14A cell proliferation. Phospholipase C (PLC), but not PI3K pharmacological blockade negatively modulated CB2-induced ST14A cell proliferation, suggesting that a PLC pathway is involved in the steps downstream to CB2 activation. On the basis of our results, we propose ST14A neural progenitor cells as a useful in vitro model for studying ECS modulation of neurogenesis, also in prospective in vivo pharmacological studies.


Assuntos
Moduladores de Receptores de Canabinoides/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/fisiologia , Receptores de Canabinoides/metabolismo , Animais , Canabinoides/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Corpo Estriado/citologia , Estrenos/farmacologia , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Pirrolidinonas/farmacologia , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/genética , Receptores de Canabinoides/genética , Fosfolipases Tipo C/antagonistas & inibidores
18.
Phytomedicine ; 88: 153533, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33812759

RESUMO

INTRODUCTION: The increased incidence of Glioblastoma Multiforme, the most aggressive and most common primary brain tumour, is evident worldwide. Survival rates are reaching only 15 months due to its high recurrence and resistance to current combination therapies including oncotomy, radiotherapy and chemotherapy. Light has been shed in the recent years on the anticancer properties of cannabinoids from Cannabis sativa. OBJECTIVE: To determine whether cannabinoids alone or in combination with radiotherapy and/or chemotherapy inhibit tumour progression, induce cancer cell death, inhibit metastasis and invasiveness and the mechanisms that underlie these actions. METHOD: PubMed and Web of Science were used for a systemic search to find studies on the anticancer effects of natural cannabinoids on glioma cancer cells in vitro and/or in vivo. RESULTS: A total of 302 papers were identified, of which 14 studies were found to fit the inclusion criteria. 5 studies were conducted in vitro, 2 in vivo and 7 were both in vivo and in vitro. 3 studies examined the efficacy of CBD, THC and TMZ, 1 study examined CBD and radiation, 2 studies examined efficacy of THC only and 3 studies examined the efficacy of CBD only. 1 study examined the efficacy of CBD, THC and radiotherapy, 2 studies examined the combination of CBD and THC and 2 more studies examined the efficacy of CBD and TMZ. CONCLUSION: The evidence in this systematic review leads to the conclusion that cannabinoids possess anticancer potencies against glioma cells, however this effect varies with the combinations and dosages used. Studies so far were conducted on cells in culture and on mice as well as a small number of studies that were conducted on humans. Hence in order to have more accurate results, higher quality studies mainly including human clinical trials with larger sample sizes are necessitated urgently for GBM treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Canabinoides/farmacologia , Glioblastoma/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Canabidiol/farmacologia , Canabinoides/administração & dosagem , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Camundongos
19.
J Med Chem ; 64(10): 6937-6948, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33887904

RESUMO

The activation of cannabinoid CB1 receptors (CB1R) by Δ9-tetrahydrocannabinol (THC), the main component of Cannabis sativa, induces analgesia. CB1R activation, however, also causes cognitive impairment via the serotonin 5HT2A receptor (5HT2AR), a component of a CB1R-5HT2AR heteromer, posing a serious drawback for cannabinoid therapeutic use. We have shown that peptides reproducing CB1R transmembrane (TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP), can alter the structure of the CB1R-5HT2AR heteromer and avert THC cognitive impairment while preserving analgesia. Here, we report the optimization of these prototypes into drug-like leads by (i) shortening the TM5, TM6, and CPP sequences, without losing the ability to disturb the CB1R-5HT2AR heteromer, and (ii) extensive sequence remodeling to achieve protease resistance and blood-brain barrier penetration. Our efforts have culminated in the identification of an ideal candidate for cannabis-based pain management, an orally active 16-residue peptide preserving THC-induced analgesia.


Assuntos
Analgésicos/química , Cannabis/química , Peptídeos/química , Administração Oral , Sequência de Aminoácidos , Analgésicos/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Canabinoides/química , Canabinoides/farmacologia , Cannabis/metabolismo , Dimerização , Camundongos , Camundongos Endogâmicos ICR , Simulação de Dinâmica Molecular , Dor/tratamento farmacológico , Dor/patologia , Peptídeos/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo
20.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916164

RESUMO

Cannabinoids are a family of heterogeneous compounds that mostly interact with receptors eliciting several physiological effects both in the central and peripheral nervous systems and in peripheral organs. They exert anticancer action by modulating signaling pathways involved in cancer progression; furthermore, the effects induced by their use depend on both the type of tumor and their action on the components of the endocannabinoid system. This review will explore the mechanism of action of the cannabinoids in signaling pathways involved in cancer proliferation, neovascularisation, migration, invasion, metastasis, and tumor angiogenesis.


Assuntos
Canabinoides/farmacologia , Endocanabinoides/metabolismo , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Canabinoides/uso terapêutico , Progressão da Doença , Humanos , Ligantes , Neoplasias/metabolismo
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