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1
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Guo Y, Wei X, Pei J, Yang H, Zheng XL. Dissecting the role of cannabinoids in vascular health and disease. J Cell Physiol 2024; 239:e31373. [PMID: 38988064 DOI: 10.1002/jcp.31373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/04/2024] [Accepted: 06/27/2024] [Indexed: 07/12/2024]
Abstract
Cannabis, often recognized as the most widely used illegal psychoactive substance globally, has seen a shift in its legal status in several countries and regions for both recreational and medicinal uses. This change has brought to light new evidence linking cannabis consumption to various vascular conditions. Specifically, there is an association between cannabis use and atherosclerosis, along with conditions such as arteritis, reversible vasospasm, and incidents of aortic aneurysm or dissection. Recent research has started to reveal the mechanisms connecting cannabinoid compounds to atherosclerosis development. It is well known that the primary biological roles of cannabinoids operate through the activation of cannabinoid receptor types 1 and 2. Manipulation of the endocannabinoid system, either genetically or pharmacologically, is emerging as a promising approach to address metabolic dysfunctions related to obesity. Additionally, numerous studies have demonstrated the vasorelaxant properties and potential atheroprotective benefits of cannabinoids. In preclinical trials, cannabidiol is being explored as a treatment option for monocrotaline-induced pulmonary arterial hypertension. Although existing literature suggests a direct role of cannabinoids in the pathogenesis of atherosclerosis, the correlation between cannabinoids and other vascular diseases was only reported in some case series or observational studies, and its role and precise mechanisms remain unclear. Therefore, it is necessary to summarize and update previously published studies. This review article aims to summarize the latest clinical and experimental research findings on the relationship between cannabis use and vascular diseases. It also seeks to shed light on the potential mechanisms underlying these associations, offering a comprehensive view of current knowledge in this evolving field of study.
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Affiliation(s)
- Yanan Guo
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Xiaoyun Wei
- Department of Cardiology, The Fifth School of Clinical Medicine of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Junyu Pei
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Haibo Yang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Rakotoarivelo V, Mayer TZ, Simard M, Flamand N, Di Marzo V. The Impact of the CB 2 Cannabinoid Receptor in Inflammatory Diseases: An Update. Molecules 2024; 29:3381. [PMID: 39064959 PMCID: PMC11279428 DOI: 10.3390/molecules29143381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/10/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
The emergence of inflammatory diseases is a heavy burden on modern societies. Cannabis has been used for several millennia to treat inflammatory disorders such as rheumatism or gout. Since the characterization of cannabinoid receptors, CB1 and CB2, the potential of cannabinoid pharmacotherapy in inflammatory conditions has received great interest. Several studies have identified the importance of these receptors in immune cell migration and in the production of inflammatory mediators. As the presence of the CB2 receptor was documented to be more predominant in immune cells, several pharmacological agonists and antagonists have been designed to treat inflammation. To better define the potential of the CB2 receptor, three online databases, PubMed, Google Scholar and clinicaltrial.gov, were searched without language restriction. The full texts of articles presenting data on the endocannabinoid system, the CB2 receptor and its role in modulating inflammation in vitro, in animal models and in the context of clinical trials were reviewed. Finally, we discuss the clinical potential of the latest cannabinoid-based therapies in inflammatory diseases.
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Affiliation(s)
- Volatiana Rakotoarivelo
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
| | - Thomas Z. Mayer
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels, and Centre NUTRISS, École de Nutrition, Université Laval, Québec City, QC G1V 0V6, Canada
| | - Mélissa Simard
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
| | - Nicolas Flamand
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
| | - Vincenzo Di Marzo
- Centre de Recherche de l’Institut Universitaire De Cardiologie Et De Pneumologie de Québec, Département of Médecine, Université Laval, Québec City, QC G1V 4G5, Canada
- Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec City, QC G1V 0V6, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels, and Centre NUTRISS, École de Nutrition, Université Laval, Québec City, QC G1V 0V6, Canada
- Joint International Unit between the CNR of Italy and Université Laval on Chemical and Biomolecular Research on the Microbiome and Its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Québec City, QC G1V 0V6, Canada
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Jiao J, Hu B, Mou T, Li Q, Tian Y, Zhang N, Zhang Y, Yun M, Nan N, Tian J, Yu W, Mi H, Dong W, Song X. Translocator Protein 18 kDa Tracer 18F-FDPA PET/CTA Imaging for the Evaluation of Inflammation in Vulnerable Plaques. Mol Pharm 2024; 21:3623-3633. [PMID: 38819959 DOI: 10.1021/acs.molpharmaceut.4c00344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2024]
Abstract
Inflammation induced by activated macrophages within vulnerable atherosclerotic plaques (VAPs) constitutes a significant risk factor for plaque rupture. Translocator protein (TSPO) is highly expressed in activated macrophages. This study investigated the effectiveness of TSPO radiotracers, 18F-FDPA, in detecting VAPs and quantifying plaque inflammation in rabbits. 18 New Zealand rabbits were divided into 3 groups: sham group A, VAP model group B, and evolocumab treatment group C. 18F-FDPA PET/CTA imaging was performed at 12, 16, and 24 weeks in all groups. Optical coherence tomography (OCT) was performed on the abdominal aorta at 24 weeks. The VAP was defined through OCT images, and ex vivo aorta PET imaging was also performed at 24 weeks. The SUVmax and SUVmean of 18F-FDPA were measured on the target organ, and the target-to-background ratio (TBRmax) was calculated as SUVmax/SUVblood pool. The arterial sections of the isolated abdominal aorta were analyzed by HE staining, CD68 and TSPO immunofluorescence staining, and TSPO Western blot. The results showed that at 24 weeks, the plaque TBRmax of 18F-FDPA in group B was significantly higher than in groups A and C. Immunofluorescence staining of CD68 and TSPO, as well as Western blot, confirmed the increased expression of macrophages and TSPO in the corresponding regions of group B. HE staining revealed an increased presence of the lipid core, multiple foam cells, and inflammatory cell infiltration in the area with high 18F-FDPA uptake. This indicates a correlation between 18F-FDPA uptake, inflammation severity, and VAPs. The TSPO-targeted tracer 18F-FDPA shows specific uptake in macrophage-rich regions of atherosclerotic plaques, making it a valuable tool for assessing inflammation in VAPs.
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Affiliation(s)
- Jian Jiao
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Biao Hu
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Tiantian Mou
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Quan Li
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Yi Tian
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Nan Zhang
- Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Ying Zhang
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Mingkai Yun
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Nan Nan
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Jing Tian
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Wei Yu
- Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Hongzhi Mi
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Wei Dong
- Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Xiantao Song
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
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Bo Y, Zhao X, Li L. Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors. Clin Sci (Lond) 2024; 138:413-434. [PMID: 38505994 DOI: 10.1042/cs20231156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 02/23/2024] [Accepted: 03/12/2024] [Indexed: 03/21/2024]
Abstract
Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public health and drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in the regulation of heart health and disease, with mounting evidence linking CBRs with the pathogenesis and progression of drug-induced cardiotoxicity. This review aims to summarize fundamental characteristics of two well-documented CBRs (CB1R and CB2R) from aspects of molecular structure, signaling and their functions in cardiovascular physiology and pathophysiology. Moreover, we describe the roles of CB1R and CB2R in the occurrence of cardiotoxicity induced by common drugs such as antipsychotics, anti-cancer drugs, marijuana, and some emerging synthetic cannabinoids. We highlight the 'yin-yang' relationship between CB1R and CB2R in drug-induced cardiotoxicity and propose future perspectives for CBR-based translational medicine toward cardiotoxicity curation and clinical monitoring.
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Affiliation(s)
- Yiming Bo
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xin Zhao
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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More SA, Deore RS, Pawar HD, Sharma C, Nakhate KT, Rathod SS, Ojha S, Goyal SN. CB2 Cannabinoid Receptor as a Potential Target in Myocardial Infarction: Exploration of Molecular Pathogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:1683. [PMID: 38338960 PMCID: PMC10855244 DOI: 10.3390/ijms25031683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-β/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.
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Affiliation(s)
- Sagar A. More
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Rucha S. Deore
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Harshal D. Pawar
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Kartik T. Nakhate
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Sumit S. Rathod
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Sameer N. Goyal
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
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Wilson G, Yang L, Su X, Ding S, Li L, Yang Y, Wang X, Wang W, Sa Y, Zhang Y, Chen J, Ma X. Exploring the therapeutic potential of natural compounds modulating the endocannabinoid system in various diseases and disorders: review. Pharmacol Rep 2023; 75:1410-1444. [PMID: 37906390 DOI: 10.1007/s43440-023-00544-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/07/2023] [Accepted: 10/09/2023] [Indexed: 11/02/2023]
Abstract
Cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes involved in the biosynthesis and degradation of the endocannabinoids make up the endocannabinoid system (ECS). The components of the ECS are proven to modulate a vast bulk of various physiological and pathological processes due to their abundance throughout the human body. Such discoveries have attracted the researchers' attention and emerged as a potential therapeutical target for the treatment of various diseases. In the present article, we reviewed the discoveries of natural compounds, herbs, herbs formula, and their therapeutic properties in various diseases and disorders by modulating the ECS. We also summarize the molecular mechanisms through which these compounds elicit their properties by interacting with the ECS based on the existing findings. Our study provides the insight into the use of natural compounds that modulate ECS in various diseases and disorders, which in turn may facilitate future studies exploiting natural lead compounds as novel frameworks for designing more effective and safer therapeutics.
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Affiliation(s)
- Gidion Wilson
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Lingling Yang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Xiaojuan Su
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Shuqin Ding
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Liuyan Li
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Youyue Yang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Xiaoying Wang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Weibiao Wang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Yuping Sa
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Yue Zhang
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China
| | - Jianyu Chen
- Fujian University of Traditional Chinese Medicine, No. 1, Huatuo Road, Minhoushangjie, Fuzhou, 350122, China.
| | - Xueqin Ma
- Department of Pharmaceutical Analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
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Rorabaugh BR, Guindon J, Morgan DJ. Role of Cannabinoid Signaling in Cardiovascular Function and Ischemic Injury. J Pharmacol Exp Ther 2023; 387:265-276. [PMID: 37739804 PMCID: PMC10658922 DOI: 10.1124/jpet.123.001665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 08/14/2023] [Accepted: 09/01/2023] [Indexed: 09/24/2023] Open
Abstract
Cardiovascular disease represents a leading cause of death, morbidity, and societal economic burden. The prevalence of cannabis use has significantly increased due to legalization and an increased societal acceptance of cannabis. Therefore, it is critically important that we gain a greater understanding of the effects and risks of cannabinoid use on cardiovascular diseases as well as the potential for cannabinoid-directed drugs to be used as therapeutics for the treatment of cardiovascular disease. This review summarizes our current understanding of the role of cannabinoid receptors in the pathophysiology of atherosclerosis and myocardial ischemia and explores their use as therapeutic targets in the treatment of ischemic heart disease. Endocannabinoids are elevated in patients with atherosclerosis, and activation of cannabinoid type 1 receptors (CB1Rs) generally leads to an enhancement of plaque formation and atherosclerosis. In contrast, selective activation of cannabinoid type 2 receptors (CB2Rs) appears to exert protective effects against atherosclerosis. Endocannabinoid signaling is also activated by myocardial ischemia. CB2R signaling appears to protect the heart from ischemic injury, whereas the role of CB1R in ischemic injury is less clear. This narrative review serves to summarize current research on the role of cannabinoid signaling in cardiovascular function with the goal of identifying critical knowledge gaps and future studies to address those gaps in a way that facilitates the development of new treatments and better cardiovascular health. SIGNIFICANCE STATEMENT: Cardiovascular diseases, including atherosclerosis and myocardial infarction, are a leading cause of death. Cannabinoid drugs have well known acute effects on cardiovascular function, including tachycardia and orthostatic hypotension. The recent legalization of marijuana and cannabinoids for both medical and recreational use has dramatically increased their prevalence of use. This narrative review on the role of cannabinoid signaling in cardiovascular disease contributes to a better understanding of this topic by integrating current knowledge and identifying critical gaps.
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Affiliation(s)
- Boyd R Rorabaugh
- Department of Biomedical Sciences (D.J.M.) and Department of Pharmaceutical Sciences (B.R.R.), Marshall University, Huntington, West Virginia; and Department of Neuroscience and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas (J.G.)
| | - Josée Guindon
- Department of Biomedical Sciences (D.J.M.) and Department of Pharmaceutical Sciences (B.R.R.), Marshall University, Huntington, West Virginia; and Department of Neuroscience and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas (J.G.)
| | - Daniel J Morgan
- Department of Biomedical Sciences (D.J.M.) and Department of Pharmaceutical Sciences (B.R.R.), Marshall University, Huntington, West Virginia; and Department of Neuroscience and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas (J.G.)
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Horton KKA, Campanaro CK, Clifford C, Nethery DE, Strohl KP, Jacono FJ, Dick TE. Cannabinoid Receptor mRNA Expression in Central and Peripheral Tissues in a Rodent Model of Peritonitis. Cannabis Cannabinoid Res 2023; 8:510-526. [PMID: 35446129 PMCID: PMC10249742 DOI: 10.1089/can.2021.0085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Introduction: Our laboratory investigates changes in the respiratory pattern during systemic inflammation in various rodent models. The endogenous cannabinoid system (ECS) regulates cytokine production and mitigates inflammation. Inflammation not only affects cannabinoid (CB) 1 and CB2 receptor gene expression (Cnr1 and Cnr2), but also increases the predictability of the ventilatory pattern. Objectives: Our primary objective was to track ventilatory pattern variability and transcription of Cnr1 and Cnr2 mRNA, and of Il1b, Il6, and tumor necrosis factor-alpha (Tnfa) mRNAs at multiple time points in central and peripheral tissues during systemic inflammation induced by peritonitis. Methods: In male Sprague Dawley rats (n=24), we caused peritonitis by implanting a fibrin clot containing either 0 or 25×106 Escherichia coli intraperitoneally. We recorded breathing with whole-animal plethysmography at baseline and 1 h before euthanasia. We euthanized the rats at 3, 6, or 12 h after inoculation and harvested the pons, medulla, lung, and heart for gene expression analysis. Results: With peritonitis, Cnr1 mRNA more than Cnr2 mRNA was correlated to Il1b, Il6, and Tnfa mRNAs in medulla, pons, and lung and changed oppositely in the pons, medulla, and lung. These changes were associated with increased predictability of ventilatory pattern. Specifically, nonlinear complexity index correlated with increased Cnr1 mRNA in the pons and medulla, and coefficient of variation for cycle duration correlated with Cnr1 and Cnr2 mRNAs in the lung. Conclusion: The mRNAs for ECS receptors varied with time during the central and peripheral inflammatory response to peritonitis. These changes occurred in the brainstem, which contains the network that generates breathing pattern and thus, may participate in ventilatory pattern changes during systemic inflammation.
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Affiliation(s)
- Kofi-Kermit A. Horton
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Cara K. Campanaro
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Caitlyn Clifford
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - David E. Nethery
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Kingman P. Strohl
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA
| | - Frank J. Jacono
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA
| | - Thomas E. Dick
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA
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9
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Swiderski J, Sakkal S, Apostolopoulos V, Zulli A, Gadanec LK. Combination of Taurine and Black Pepper Extract as a Treatment for Cardiovascular and Coronary Artery Diseases. Nutrients 2023; 15:nu15112562. [PMID: 37299525 DOI: 10.3390/nu15112562] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 05/21/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
The shift in modern dietary regimens to "Western style" and sedentary lifestyles are believed to be partly responsible for the increase in the global burden of cardiovascular diseases. Natural products have been used throughout human history as treatments for a plethora of pathological conditions. Taurine and, more recently, black pepper have gained attention for their beneficial health effects while remaining non-toxic even when ingested in excess. Taurine, black pepper, and the major terpene constituents found in black pepper (i.e., β-caryophyllene; α-pinene; β-pinene; α-humulene; limonene; and sabinene) that are present in PhytoCann BP® have been shown to have cardioprotective effects based on anti-inflammatory, antioxidative, anti-hypertensive and anti-atherosclerotic mechanisms. This comprehensive review of the literature focuses on determining whether the combination of taurine and black pepper extract is an effective natural treatment for reducing cardiovascular diseases risk factors (i.e., hypertension and hyperhomocysteinemia) and for driving anti-inflammatory, antioxidative and anti-atherosclerotic mechanisms to combat coronary artery disease, heart failure, myocardial infarction, and atherosclerotic disease.
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Affiliation(s)
- Jordan Swiderski
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
| | - Samy Sakkal
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
- Immunology Program, Australian Institute for Musculoskeletal Science, Melbourne, VIC 3021, Australia
| | - Anthony Zulli
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
| | - Laura Kate Gadanec
- Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia
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10
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Dziemitko S, Harasim-Symbor E, Chabowski A. How do phytocannabinoids affect cardiovascular health? An update on the most common cardiovascular diseases. Ther Adv Chronic Dis 2023; 14:20406223221143239. [PMID: 36636553 PMCID: PMC9830002 DOI: 10.1177/20406223221143239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 11/17/2022] [Indexed: 01/09/2023] Open
Abstract
Cardiovascular disease (CVD) causes millions of deaths worldwide each year. Despite the great progress in therapies available for patients with CVD, some limitations, including drug complications, still exist. Hence, the endocannabinoid system (ECS) was proposed as a new avenue for CVDs treatment. The ECS components are widely distributed through the body, including the heart and blood vessels, thus the action of its endogenous and exogenous ligands, in particular, phytocannabinoids play a key role in various pathological states. The cardiovascular action of cannabinoids is complex as they affect vasculature and myocardium directly via specific receptors and exert indirect effects through the central and peripheral nervous system. The growing interest in phytocannabinoid studies, however, has extended the knowledge about their molecular targets as well as therapeutical properties; nonetheless, some areas of their actions are not yet fully recognized. Researchers have reported various cannabinoids, especially cannabidiol, as a promising approach to CVDs; hence, the purpose of this review is to summarize and update the cardiovascular actions of the most potent phytocannabinoids and the potential therapeutic role of ECS in CVDs, including ischemic reperfusion injury, arrhythmia, heart failure as well as hypertension.
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Affiliation(s)
- Sylwia Dziemitko
- Department of Physiology, Medical University of
Bialystok, Bialystok 15-222, Poland
| | - Ewa Harasim-Symbor
- Department of Physiology, Medical University of
Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of
Bialystok, Bialystok, Poland
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11
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Mensah E, Tabrizchi R, Daneshtalab N. Pharmacognosy and Effects of Cannabinoids in the Vascular System. ACS Pharmacol Transl Sci 2022; 5:1034-1049. [PMID: 36407955 PMCID: PMC9667477 DOI: 10.1021/acsptsci.2c00141] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Indexed: 11/29/2022]
Abstract
Understanding the pharmacodynamics of cannabinoids is an essential subject due to the recent increasing global acceptance of cannabis and its derivation for recreational and therapeutic purposes. Elucidating the interaction between cannabinoids and the vascular system is critical to exploring cannabinoids as a prospective therapeutic agent for treating vascular-associated clinical conditions. This review aims to examine the effect of cannabinoids on the vascular system and further discuss the fundamental pharmacological properties and mechanisms of action of cannabinoids in the vascular system. Data from literature revealed a substantial interaction between endocannabinoids, phytocannabinoids, and synthetic cannabinoids within the vasculature of both humans and animal models. However, the mechanisms and the ensuing functional response is blood vessels and species-dependent. The current understanding of classical cannabinoid receptor subtypes and the recently discovered atypical cannabinoid receptors and the development of new synthetic analogs have further enhanced the pharmacological characterization of the vascular cannabinoid receptors. Compelling evidence also suggest that cannabinoids represent a formidable therapeutic candidate for vascular-associated conditions. Nonetheless, explanations of the mechanisms underlining these processes are complex and paradoxical based on the heterogeneity of receptors and signaling pathways. Further insight from studies that uncover the mechanisms underlining the therapeutic effect of cannabinoids in the treatment of vascular-associated conditions is required to determine whether the known benefits of cannabinoids thus currently outweigh the known/unknown risks.
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Affiliation(s)
- Eric Mensah
- Faculty
of Medicine, Division of Biomedical Sciences, Memorial University of Newfoundland and Labrador, St. John’s, NL A1C 5S7, Canada
| | - Reza Tabrizchi
- Faculty
of Medicine, Division of Biomedical Sciences, Memorial University of Newfoundland and Labrador, St. John’s, NL A1C 5S7, Canada
| | - Noriko Daneshtalab
- School
of Pharmacy, Memorial University of Newfoundland
and Labrador, St. John’s, NL A1B 3V6, Canada
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12
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Parikh K, Patel M, Bansal T, Raco J, Gupta S, Jain R, Jain R. Cannabis and the heart: unchartered territory. Future Cardiol 2022; 18:883-890. [PMID: 36098056 DOI: 10.2217/fca-2022-0018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Cannabis is one of the most commonly used illicit drugs. It is a psychoactive drug with tetrahydrocannabinol being the main active ingredient. With increasing decriminalization and legalization of marijuana use in the USA, it is essential to study its long-term effects on cardiovascular diseases, a leading cause of death in the USA. Cannabis can trigger acute myocardial infarction in otherwise healthy young individuals, affect atherogenesis, arrhythmia, develop Takotsubo cardiomyopathy and cannabis arteritis. The only definitive treatment for these pathologies is complete abstinence. In this review we focus on discussing the long-term effects of tetrahydrocannabinol on cardiovascular pathologies, its pathophysiology and a brief discussion on its clinical features and definitive management.
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Affiliation(s)
- Kinna Parikh
- Department of Internal Medicine, GMERS Medical College, Gandhinagar, India
| | - Meet Patel
- Department of Internal Medicine, Tianjin Medical University, Tianjin, PR China
| | | | - Joseph Raco
- Department of Internal Medicine, Penn State Milton S Hershey Medical Center, Hershey, PA 17033, USA
| | - Sachin Gupta
- Assistant Professor, Department of Internal Medicine Penn State Milton S Hershey Medical Center, Hershey, PA 17033, USA
| | - Rahul Jain
- Assistant Professor, Department of Cardiology, School of Medicine University of Missouri, MO 65212, USA
| | - Rohit Jain
- Assistant Professor, Department of Internal Medicine Penn State Milton S Hershey Medical Center, Hershey, PA 17033, USA
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13
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El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
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Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
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14
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Lott J, Jutkiewicz EM, Puthenveedu MA. The Synthetic Cannabinoid WIN55,212-2 Can Disrupt the Golgi Apparatus Independent of Cannabinoid Receptor-1. Mol Pharmacol 2022; 101:371-380. [PMID: 35236771 PMCID: PMC9092469 DOI: 10.1124/molpharm.121.000377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 02/22/2022] [Indexed: 11/22/2022] Open
Abstract
The synthetic cannabinoid WIN55,212-2 (WIN) is widely used as a pharmacological tool to study the biologic activity of cannabinoid receptors. In contrast to many other cannabinoid agonists, however, WIN also causes broad effects outside of neurons, such as reducing inflammatory responses, causing cell cycle arrest, and reducing general protein expression. How exactly WIN causes these broad effects is not known. Here we show that WIN partially disrupts the Golgi apparatus at nanomolar concentrations and fully disperses the Golgi apparatus in neuronal and non-neuronal cells at micromolar concentrations. WIN55,212-3, the enantiomer of WIN; JWH-018, a related alkylindole; or 2-arachidonoylglycerol, an endocannabinoid, did not cause Golgi disruption, suggesting that the effect was specific to the chirality of WIN. WIN treatment also perturbed the microtubule network. Importantly, WIN disrupted the Golgi in primary cortical neurons derived from mice where cannabinoid receptor-1 (CB1) was genetically knocked out, indicating that the effects were independent of CB1 signaling. The Golgi dispersion could not be explained by WIN's action on peroxisome proliferator-activated receptors. Our results show that WIN can disrupt the Golgi apparatus independent of CB1 in cultured cells. These effects could contribute to the unique physiologic effects that WIN exhibits in neuronal behavior, as well as its role as an antiproliferative and anti-inflammatory agent. SIGNIFICANCE STATEMENT: The synthetic cannabinoid WIN55,212-2 (WIN), widely used to investigate the cannabinoid system, also shows unique broader effects at cellular and organismal levels compared to endogenous cannabinoids. Our study shows that WIN can disrupt the Golgi apparatus and the microtubule network in multiple cell types, independent of cannabinoid receptors. These results could explain how WIN reduces surface levels of proteins and contributes to the unique physiological effects observed with WIN.
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Affiliation(s)
- Joshua Lott
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Emily M Jutkiewicz
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan
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15
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Fields JA, Swinton MK, Montilla-Perez P, Ricciardelli E, Telese F. The Cannabinoid Receptor Agonist, WIN-55212-2, Suppresses the Activation of Proinflammatory Genes Induced by Interleukin 1 Beta in Human Astrocytes. Cannabis Cannabinoid Res 2022; 7:78-92. [PMID: 33998879 PMCID: PMC8864424 DOI: 10.1089/can.2020.0128] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background: Alterations of astrocyte function play a crucial role in neuroinflammatory diseases due to either the loss of their neuroprotective role or the gain of their toxic inflammatory properties. Accumulating evidence highlights that cannabinoids and cannabinoid receptor agonists, such as WIN55,212-2 (WIN), reduce inflammation in cellular and animal models. Thus, the endocannabinoid system has become an attractive target to attenuate chronic inflammation in neurodegenerative diseases. However, the mechanism of action of WIN in astrocytes remains poorly understood. Objective: We studied the immunosuppressive property of WIN by examining gene expression patterns that were modulated by WIN in reactive astrocytes. Materials and Methods: Transcriptomic analysis by RNA-seq was carried out using primary human astrocyte cultures stimulated by the proinflammatory cytokine interleukin 1 beta (IL1β) in the presence or absence of WIN. Real-time quantitative polymerase chain reaction analysis was conducted on selected transcripts to characterize the dose-response effects of WIN, and to test the effect of selective antagonists of cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptors (PPAR). Results: Transcriptomic analysis showed that the IL1β-induced inflammatory response is robustly inhibited by WIN pretreatment. WIN treatment alone also induced substantial gene expression changes. Pathway analysis revealed that the anti-inflammatory properties of WIN were linked to the regulation of kinase pathways and gene targets of neuroprotective transcription factors, including PPAR and SMAD (mothers against decapentaplegic homolog). The inhibitory effect of WIN was dose-dependent, but it was not affected by selective antagonists of CB1 or PPAR. Conclusions: This study suggests that targeting the endocannabinoid system may be a promising strategy to disrupt inflammatory pathways in reactive astrocytes. The anti-inflammatory activity of WIN is independent of CB1, suggesting that alternative receptors mediate the effects of WIN. These results provide mechanistic insights into the anti-inflammatory activity of WIN and highlight that astrocytes are a potential therapeutic target to ameliorate neuroinflammation in the brain.
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Affiliation(s)
- Jerel Adam Fields
- Department of Psychiatry and University of California San Diego, La Jolla, California, USA
| | - Mary K. Swinton
- Department of Psychiatry and University of California San Diego, La Jolla, California, USA
| | | | - Eugenia Ricciardelli
- Institute of Genomic Medicine, University of California San Diego, La Jolla, California, USA
| | - Francesca Telese
- Department of Medicine, University of California San Diego, La Jolla, California, USA.,*Address correspondence to: Francesca Telese, PhD, Department of Medicine, University of California San Diego, La Jolla, CA 93093, USA,
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16
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Haspula D, Clark MA. Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. Int J Mol Sci 2020; 21:E7693. [PMID: 33080916 PMCID: PMC7590033 DOI: 10.3390/ijms21207693] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 12/16/2022] Open
Abstract
The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task. An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases. This review focusses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized.
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Affiliation(s)
- Dhanush Haspula
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA;
| | - Michelle A. Clark
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33314, USA
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17
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Kourounakis AP, Xanthopoulos D, Tzara A. Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules. Med Res Rev 2019; 40:709-752. [PMID: 31512284 DOI: 10.1002/med.21634] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/22/2019] [Accepted: 08/21/2019] [Indexed: 12/15/2022]
Abstract
Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active-site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug-like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.
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Affiliation(s)
- Angeliki P Kourounakis
- Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Xanthopoulos
- Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
| | - Ariadni Tzara
- Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
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18
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Manolis TA, Manolis AA, Manolis AS. Cannabis Associated "High" Cardiovascular Morbidity and Mortality: Marijuana Smoke Like Tobacco Smoke? A Déjà Vu/Déjà Vécu Story? Mini Rev Med Chem 2019; 19:870-879. [PMID: 30426899 DOI: 10.2174/1389557518666181114113947] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 05/21/2018] [Accepted: 05/22/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Cannabis use has increased over the past several years as some countries have legalized its use for the treatment of certain medical conditions and/or for recreational use. Thus, concerns have risen about potential adverse health effects. Increasing number of reports have associated cannabis use with serious cardiovascular (CV) complications. Furthermore, there appears to be a likeness in the harmful health effects, especially on the CV and respiratory systems, of cannabis smoking to those of tobacco smoking. OBJECTIVE To review the CV effects of cannabis use and compare them with those of tobacco use. METHODS Articles were reviewed that were published in English literature reporting on cannabis and cannabinoid pharmacology and their effects on the CV system and their consequences. Emphasis was also placed on articles reporting on cannabis use in adolescents, exposure to secondhand smoke, its effect on exercise and finally its inter-relationship and similarities with tobacco use. RESULTS With growing cannabis use, an increasing number of reports have emerged associating marijuana use with serious and life-threatening CV complications, including acute coronary syndromes, potentially lethal cardiac arrhythmias and ischemic strokes. There are certain similarities of the deleterious CV and respiratory effects of cannabis smoking with those of tobacco smoking. Despite the difference in the active ingredients (tetrahydrocannabinol vs. nicotine), each substance produces a plethora of chemicals when smoked and these are largely identical; furthermore, due to different modes of smoking, cannabis chemicals are retained in the body for a longer time. Of course, concomitant tobacco and cannabis smoking is a perplexing factor in isolating damages specifically pertaining to cannabis use, while the health risk is additive. Although the mechanisms producing CV harm may be somewhat different between these two substances, the outcome appears similar, or even worse, as the effects may emerge at a younger age. CONCLUSION There is an increasing concern that, apart from the mental health problem with cannabis smoking, societies may be facing another wave of a déjà vu/déjà vécu phenomenon similar to the tobacco smoking story.
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Affiliation(s)
| | | | - Antonis S Manolis
- Third Department of Cardiology, Athens University School of Medicine, Athens, Greece
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19
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18F-PBR06 PET/CT imaging for evaluating atherosclerotic plaques linked to macrophage infiltration. Nucl Med Commun 2019; 40:370-376. [PMID: 30875334 DOI: 10.1097/mnm.0000000000000978] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The present study explored the 18 kDa translocator protein radioligand [F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline (F-PBR06) targeting macrophages for PET imaging of atherosclerotic plaques and evaluating the vulnerability of atherosclerotic plaques toward rupture. MATERIALS AND METHODS F-PBR06 was synthesized using a Synthra RNplus module automatically. RAW264.7 cells were used for cell binding study with F-PBR06. In-vivo micro-PET/CT imaging for ApoE mice and C57 mice was performed 1 h after injection of F-PBR06. CD68 and F480 immunofluorescence stainings were performed in the aorta tissues. RESULTS In-vitro cell studies showed uptake of F-PBR06 to RAW264.7 cells. Micro-PET/CT imaging identified the atherosclerotic lesions in the aortic arch of ApoE mice successfully, whereas no signal was observed in C57 mice. The ratio of plaque-to-muscle in ApoE mice of 32 weeks was significantly higher than that in ApoE mice of 22 weeks, which was confirmed by CD68 immunofluorescence staining and F480 immunofluorescence staining. CONCLUSION TSPO radioligand F-PBR06 allows noninvasive PET/CT imaging of macrophage-abundant atherosclerotic plaques as well as positive correlation between PET imagings and ex-vivo immunofluorescence staining of plaques in mice with different ages, thereby representing a potential attractive tool for evaluating the vulnerability of atherosclerotic plaques towards rupture.
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20
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Espinosa-Riquer ZP, Ibarra-Sánchez A, Vibhushan S, Bratti M, Charles N, Blank U, Rodríguez-Manzo G, González-Espinosa C. TLR4 Receptor Induces 2-AG-Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells. THE JOURNAL OF IMMUNOLOGY 2019; 202:2360-2371. [PMID: 30814309 DOI: 10.4049/jimmunol.1800997] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 01/30/2019] [Indexed: 12/16/2022]
Abstract
Mast cells (MCs) contribute to the control of local inflammatory reactions and become hyporesponsive after prolonged TLR4 activation by bacterial LPS. The molecular mechanisms involved in endotoxin tolerance (ET) induction in MCs are not fully understood. In this study, we demonstrate that the endocannabinoid 2-arachidonoylglycerol (2-AG) and its receptor, cannabinoid receptor 2 (CB2), play a role in the establishment of ET in bone marrow-derived MCs from C57BL/6J mice. We found that CB2 antagonism prevented the development of ET and that bone marrow-derived MCs produce 2-AG in a TLR4-dependent fashion. Exogenous 2-AG induced ET similarly to LPS, blocking the phosphorylation of IKK and the p65 subunit of NF-κB and inducing the synthesis of molecular markers of ET. LPS caused CB2 receptor trafficking in Rab11-, Rab7-, and Lamp2-positive vesicles, indicating recycling and degradation of the receptor. 2-AG also prevented LPS-induced TNF secretion in vivo, in a MC-dependent model of endotoxemia, demonstrating that TLR4 engagement leads to 2-AG secretion, which contributes to the negative control of MCs activation. Our study uncovers a functional role for the endocannabinoid system in the inhibition of MC-dependent innate immune responses in vivo.
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Affiliation(s)
- Zyanya P Espinosa-Riquer
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico
| | - Alfredo Ibarra-Sánchez
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico
| | - Shamila Vibhushan
- INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.,CNRS ERL8252, 75018 Paris, France; and.,Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France
| | - Manuela Bratti
- INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.,CNRS ERL8252, 75018 Paris, France; and.,Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France
| | - Nicolas Charles
- INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.,CNRS ERL8252, 75018 Paris, France; and.,Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France
| | - Ulrich Blank
- INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.,CNRS ERL8252, 75018 Paris, France; and.,Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France
| | - Gabriela Rodríguez-Manzo
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico;
| | - Claudia González-Espinosa
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico;
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21
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Gentili M, Ronchetti S, Ricci E, Di Paola R, Gugliandolo E, Cuzzocrea S, Bereshchenko O, Migliorati G, Riccardi C. Selective CB2 inverse agonist JTE907 drives T cell differentiation towards a Treg cell phenotype and ameliorates inflammation in a mouse model of inflammatory bowel disease. Pharmacol Res 2018; 141:21-31. [PMID: 30552973 DOI: 10.1016/j.phrs.2018.12.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 12/10/2018] [Accepted: 12/10/2018] [Indexed: 02/07/2023]
Abstract
Cannabinoids are known to possess anti-inflammatory and immunomodulatory properties, but the mechanisms involved are not fully understood. CB2 is the cannabinoid receptor that is expressed primarily on hematopoietic cells and mediates the immunoregulatory functions of cannabinoids. In order to study the effect of JTE907, a selective/inverse agonist of CB2 with anti-inflammatory properties, on the differentiation of T cell subtypes, we used an in vitro system of Th lineage-specific differentiation of naïve CD4+ T lymphocytes isolated from the mouse spleen. The results indicate that JTE907 was able to induce the differentiation of Th0 cells into the Treg cell phenotype, which was characterized by the expression of FoxP3, TGF-β and IL-10. P38 phosphorylation and STAT5A activation were found to mediate the signaling pathway triggered by JTE907 via the CB2 receptor in Th0 lymphocytes. In mice with DNBS-induced colitis, JTE907 treatment was able to induce an increase in the number of CD4+CD25+FoxP3+ cells in the lamina propria after 24 h of disease onset and reduce disease severity after 48 h. Further, longer JTE907 treatment resulted in less severe colitis even when administered orally, resulting in less body weight loss, reduction of the disease score, prevention of NF-κB activation, and reduction of the expression of adhesion molecules. Collectively, the results of this study indicate that specific signals delivered through the CB2 receptor can drive the immune response towards the Treg cell phenotype. Thus, ligands such as JTE907 may have use as potential therapeutic agents in autoimmune and inflammatory diseases.
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Affiliation(s)
- Marco Gentili
- Department of Medicine, Section of Pharmacology, University of Perugia, Italy
| | - Simona Ronchetti
- Department of Medicine, Section of Pharmacology, University of Perugia, Italy.
| | - Erika Ricci
- Department of Medicine, Section of Pharmacology, University of Perugia, Italy
| | - Rosanna Di Paola
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Italy
| | - Enrico Gugliandolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Italy
| | - Oxana Bereshchenko
- Department of Medicine, Section of Pharmacology, University of Perugia, Italy
| | | | - Carlo Riccardi
- Department of Medicine, Section of Pharmacology, University of Perugia, Italy
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Pacher P, Steffens S, Haskó G, Schindler TH, Kunos G. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 2018; 15:151-166. [PMID: 28905873 DOI: 10.1038/nrcardio.2017.130] [Citation(s) in RCA: 283] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ9-tetrahydrocannabinol (THC), is an agonist of both CB1R and CB2R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.
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Affiliation(s)
- Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, 5625 Fishers Lane, Bethesda, Maryland 20892, USA
| | - Sabine Steffens
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University and German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Pettenkoferstrasse 8a und 9b, Munich, D-80336, Germany
| | - György Haskó
- Department of Surgery, Rutgers New Jersey Medical School, 185 South Orange Avenue, Newark, New Jersey 07103, USA
| | - Thomas H Schindler
- Department of Radiology, Johns Hopkins University, 601 North Caroline Street, Baltimore, Maryland 21287, USA
| | - George Kunos
- Laboratory of Physiological Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, Bethesda, Maryland 20892, USA
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Fulmer ML, Thewke DP. The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2. Cardiovasc Hematol Disord Drug Targets 2018; 18:34-51. [PMID: 29412125 PMCID: PMC6020134 DOI: 10.2174/1871529x18666180206161457] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 01/01/2018] [Accepted: 01/01/2018] [Indexed: 12/24/2022]
Abstract
Decades of research has provided evidence for the role of the endocannabinoid system in human health and disease. This versatile system, consisting of two receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and metabolic enzymes has been implicated in a wide variety of disease states, ranging from neurological disorders to cancer. CB2 has gained much interest for its beneficial immunomodulatory role that can be obtained without eliciting psychotropic effects through CB1. Recent studies have shed light on a protective role of CB2 in cardiovascular disease, an ailment which currently takes more lives each year in Western countries than any other disease or injury. By use of CB2 knockout mice and CB2-selective ligands, knowledge of how CB2 signaling affects atherosclerosis and ischemia has been acquired, providing a major stepping stone between basic science and translational clinical research. Here, we summarize the current understanding of the endocannabinoid system in human pathologies and provide a review of the results from preclinical studies examining its function in cardiovascular disease, with a particular emphasis on possible CB2-targeted therapeutic interventions to alleviate atherosclerosis.
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Affiliation(s)
- Makenzie L. Fulmer
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Douglas P. Thewke
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
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Ho WSV, Kelly MEM. Cannabinoids in the Cardiovascular System. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2017; 80:329-366. [PMID: 28826540 DOI: 10.1016/bs.apha.2017.05.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation.
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Affiliation(s)
- Wing S V Ho
- Vascular Biology Research Centre, St George's University of London, London, United Kingdom.
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Abstract
Cannabis sativa has long been used for medicinal purposes. To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids. Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain. More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection. The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear. In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects. This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.
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Affiliation(s)
- Yan Lu
- a College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada.,b Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, 351 Taché Avenue, Winnipeg, MB R2H 2A6, Canada
| | - Hope D Anderson
- a College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada.,b Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, 351 Taché Avenue, Winnipeg, MB R2H 2A6, Canada.,c Department of Pharmacology and Therapeutics, Max Rady College of Medicine, University of Manitoba, 753 McDermot Avenue, Winnipeg, MB R3E 0T6, Canada
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Gertsch J. Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation? Br J Pharmacol 2017; 174:1464-1483. [PMID: 27891602 DOI: 10.1111/bph.13676] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 11/05/2016] [Accepted: 11/13/2016] [Indexed: 12/21/2022] Open
Abstract
The endocannabinoid system (ECS) is a major lipid signalling network that plays important pro-homeostatic (allostatic) roles not only in the nervous system but also in peripheral organs. There is increasing evidence that there is a dietary component in the modulation of the ECS. Cannabinoid receptors in hominids co-evolved with diet, and the ECS constitutes a feedback loop for food selection and energy metabolism. Here, it is postulated that the mismatch of ancient lipid genes of hunter-gatherers and pastoralists with the high-carbohydrate diet introduced by agriculture could be compensated for via dietary modulation of the ECS. In addition to the fatty acid precursors of endocannabinoids, the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed. Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid-type 2 (CB2 ) receptors may provide adaptive metabolic advantages and counteract inflammation. In contrast, chronic CB1 receptor activation in hedonic obese individuals may enhance pathophysiological processes related to hyperlipidaemia, diabetes, hepatorenal inflammation and cardiometabolic risk. Food able to modulate the CB1 /CB2 receptor activation ratio may thus play a role in the nutrition transition of Western high-calorie diets. In this review, the interplay between diet and the ECS is highlighted from an evolutionary perspective. The emerging potential of cannabimimetic food as a nutraceutical strategy is critically discussed. LINKED ARTICLES This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
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Affiliation(s)
- Jürg Gertsch
- Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland
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Turcotte C, Blanchet MR, Laviolette M, Flamand N. The CB 2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci 2016; 73:4449-4470. [PMID: 27402121 PMCID: PMC5075023 DOI: 10.1007/s00018-016-2300-4] [Citation(s) in RCA: 381] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/20/2016] [Accepted: 06/27/2016] [Indexed: 12/12/2022]
Abstract
The CB2 receptor is the peripheral receptor for cannabinoids. It is mainly expressed in immune tissues, highlighting the possibility that the endocannabinoid system has an immunomodulatory role. In this respect, the CB2 receptor was shown to modulate immune cell functions, both in cellulo and in animal models of inflammatory diseases. In this regard, numerous studies have reported that mice lacking the CB2 receptor have an exacerbated inflammatory phenotype. This suggests that therapeutic strategies aiming at modulating CB2 signaling could be promising for the treatment of various inflammatory conditions. Herein, we review the pharmacology of the CB2 receptor, its expression pattern, and the signaling pathways induced by its activation. We next examine the regulation of immune cell functions by the CB2 receptor and the evidence obtained from primary human cells, immortalized cell lines, and animal models of inflammation. Finally, we discuss the possible therapies targeting the CB2 receptor and the questions that remain to be addressed to determine whether this receptor could be a potential target to treat inflammatory disease.
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Affiliation(s)
- Caroline Turcotte
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de médecine, Université Laval, Quebec, QC, G1V 4G5, Canada
| | - Marie-Renée Blanchet
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de médecine, Université Laval, Quebec, QC, G1V 4G5, Canada
| | - Michel Laviolette
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de médecine, Université Laval, Quebec, QC, G1V 4G5, Canada
| | - Nicolas Flamand
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Département de médecine, Faculté de médecine, Université Laval, Quebec, QC, G1V 4G5, Canada.
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N-Oleoylethanolamine Reduces Inflammatory Cytokines and Adhesion Molecules in TNF-α-induced Human Umbilical Vein Endothelial Cells by Activating CB2 and PPAR-α. J Cardiovasc Pharmacol 2016; 68:280-291. [DOI: 10.1097/fjc.0000000000000413] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Javed H, Azimullah S, Haque ME, Ojha SK. Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson's Disease. Front Neurosci 2016; 10:321. [PMID: 27531971 PMCID: PMC4969295 DOI: 10.3389/fnins.2016.00321] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 06/27/2016] [Indexed: 01/12/2023] Open
Abstract
The cannabinoid type two receptors (CB2), an important component of the endocannabinoid system, have recently emerged as neuromodulators and therapeutic targets for neurodegenerative diseases including Parkinson's disease (PD). The downregulation of CB2 receptors has been reported in the brains of PD patients. Therefore, both the activation and the upregulation of the CB2 receptors are believed to protect against the neurodegenerative changes in PD. In the present study, we investigated the CB2 receptor-mediated neuroprotective effect of β-caryophyllene (BCP), a naturally occurring CB2 receptor agonist, in, a clinically relevant, rotenone (ROT)-induced animal model of PD. ROT (2.5 mg/kg BW) was injected intraperitoneally (i.p.) once daily for 4 weeks to induce PD in male Wistar rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers, following activation of glial cells (astrocytes and microglia). ROT also caused oxidative injury evidenced by the loss of antioxidant enzymes and increased nitrite levels, and induction of proinflammatory cytokines: IL-1β, IL-6 and TNF-α, as well as inflammatory mediators: NF-κB, COX-2, and iNOS. However, treatment with BCP attenuated induction of proinflammatory cytokines and inflammatory mediators in ROT-challenged rats. BCP supplementation also prevented depletion of glutathione concomitant to reduced lipid peroxidation and augmentation of antioxidant enzymes: SOD and catalase. The results were further supported by tyrosine hydroxylase immunohistochemistry, which illustrated the rescue of the DA neurons and fibers subsequent to reduced activation of glial cells. Interestingly, BCP supplementation demonstrated the potent therapeutic effects against ROT-induced neurodegeneration, which was evidenced by BCP-mediated CB2 receptor activation and the fact that, prior administration of the CB2 receptor antagonist AM630 diminished the beneficial effects of BCP. The present study suggests that BCP has the potential therapeutic efficacy to elicit significant neuroprotection by its anti-inflammatory and antioxidant activities mediated by activation of the CB2 receptors.
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Affiliation(s)
- Hayate Javed
- Departments of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University Al Ain, UAE
| | - Sheikh Azimullah
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University Al Ain, UAE
| | - M Emdadul Haque
- Departments of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University Al Ain, UAE
| | - Shreesh K Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University Al Ain, UAE
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Henry RJ, Kerr DM, Finn DP, Roche M. For whom the endocannabinoid tolls: Modulation of innate immune function and implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2016; 64:167-80. [PMID: 25794989 DOI: 10.1016/j.pnpbp.2015.03.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 03/03/2015] [Accepted: 03/03/2015] [Indexed: 12/21/2022]
Abstract
Toll-like receptors (TLRs) mediate the innate immune response to pathogens and are critical in the host defence, homeostasis and response to injury. However, uncontrolled and aberrant TLR activation can elicit potent effects on neurotransmission and neurodegenerative cascades and has been proposed to trigger the onset of certain neurodegenerative disorders and elicit detrimental effects on the progression and outcome of established disease. Over the past decade, there has been increasing evidence demonstrating that the endocannabinoid system can elicit potent modulatory effects on inflammatory processes, with clinical and preclinical evidence demonstrating beneficial effects on disease severity and symptoms in several inflammatory conditions. This review examines the evidence supporting a modulatory effect of endocannabinoids on TLR-mediated immune responses both peripherally and centrally, and the implications for psychiatric disorders such as depression and schizophrenia.
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Affiliation(s)
- Rebecca J Henry
- Physiology, School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland, Galway, Ireland
| | - Daniel M Kerr
- Physiology, School of Medicine, National University of Ireland, Galway, Ireland; Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland, Galway, Ireland
| | - David P Finn
- Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland, Galway, Ireland
| | - Michelle Roche
- Physiology, School of Medicine, National University of Ireland, Galway, Ireland; Galway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland, Galway, Ireland.
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31
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Vujic N, Schlager S, Eichmann TO, Madreiter-Sokolowski CT, Goeritzer M, Rainer S, Schauer S, Rosenberger A, Woelfler A, Doddapattar P, Zimmermann R, Hoefler G, Lass A, Graier WF, Radovic B, Kratky D. Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice. Atherosclerosis 2015; 244:9-21. [PMID: 26584135 PMCID: PMC4704137 DOI: 10.1016/j.atherosclerosis.2015.10.109] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 10/27/2015] [Accepted: 10/28/2015] [Indexed: 12/25/2022]
Abstract
Background and aims Monoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoglyceride (MG) to glycerol and fatty acid. MGL also hydrolyzes and thereby deactivates 2-arachidonoyl glycerol (2-AG), the most abundant endocannabinoid in the mammalian system. 2-AG acts as full agonist on cannabinoid receptor type 1 (CB1R) and CB2R, which are mainly expressed in brain and immune cells, respectively. Thus, we speculated that in the absence of MGL, increased 2-AG concentrations mediate CB2R signaling in immune cells to modulate inflammatory responses, thereby affecting the development of atherosclerosis. Methods and results We generated apolipoprotein E (ApoE)/MGL double-knockout (DKO) mice and challenged them with Western-type diet for 9 weeks. Despite systemically increased 2-AG concentrations in DKO mice, CB2R-mediated signaling remains fully functional, arguing against CB2R desensitization. We found increased plaque formation in both en face aortae (1.3-fold, p = 0.028) and aortic valve sections (1.5-fold, p = 0.0010) in DKO mice. Interestingly, DKO mice also presented reduced lipid (12%, p = 0.031) and macrophage content (18%, p = 0.061), elevated intraplaque smooth muscle staining (1.4-fold, p = 0.016) and thicker fibrous caps (1.8-fold, p = 0.0032), together with a higher ratio of collagen to necrotic core area (2.5-fold, p = 0.0003) and expanded collagen content (1.6-fold, p = 0.0007), which suggest formation of less vulnerable atherosclerotic plaques. Treatment with a CB2R inverse agonist prevents these effects in DKO mice, demonstrating that the observed plaque phenotype in DKO mice originates from CB2R activation. Conclusion Loss of MGL modulates endocannabinoid signaling in CB2R-expressing cells, which concomitantly affects the pathogenesis of atherosclerosis. We conclude that despite larger lesion size loss of MGL improves atherosclerotic plaque stability. Thus, pharmacological MGL inhibition may be a novel intervention to reduce plaque rupture.
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Affiliation(s)
- Nemanja Vujic
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Stefanie Schlager
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Thomas O Eichmann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | | | - Madeleine Goeritzer
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Silvia Rainer
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Silvia Schauer
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Albert Woelfler
- Division of Hematology, Medical University of Graz, Graz, Austria
| | - Prakash Doddapattar
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Gerald Hoefler
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Wolfgang F Graier
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Branislav Radovic
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Dagmar Kratky
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
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Netherland-Van Dyke C, Rodgers W, Fulmer M, Lahr Z, Thewke D. Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice. ACTA ACUST UNITED AC 2015; 3:53-63. [PMID: 26413498 DOI: 10.12970/2311-052x.2015.03.02.2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE WIN55,212-2, a potent synthetic agonist of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), reduces atherosclerosis in apolipoprotein E (ApoE) null mice. Although pharmacologic evidence suggests the anti-atherosclerotic effects of WIN55,212-2 are mediated via CB2, this remains to be confirmed by genetic studies. Therefore, in this study, we investigated the effects of WIN55,212-2 on development of atherosclerosis in low-density lipoprotein receptor (Ldlr) null mice with and without homozygous deletion of the CB2 gene. METHODS After 6 weeks on an atherogenic diet, groups of CB2+/+ and CB2-/- Ldlr-null mice received a daily intraperitoneal injection of WIN55,212-2 or vehicle. After two weeks, plasma lipid levels and atherosclerosis in the aortic root were quantified. RESULTS Plasma cholesterol and triglyceride levels did not differ between CB2+/+ and CB2-/- mice and WIN55,212-2 had no effect on total cholesterol levels in either genotype. However, triglyceride levels in both CB2+/+ and CB2-/- mice were significantly lowered by WIN55,212-2. The size of aortic root lesions did not differ significantly between CB2+/+ and CB2-/- mice with or without WIN55,212-2 treatment. However, WIN55,212-2 treatment significantly lowered lesional macrophage accumulation in CB2+/+ mice, and lesional smooth muscle content in both CB2+/+ and CB2-/- mice. Lesional apoptosis was also greater in CB2+/+ mice compared to CB2-/-mice, and only reduced by WIN55,212-2 in CB2+/+ mice. Collagen content and elastin fiber fragmentation were unaffected by genotype or WIN55,212-2. CONCLUSIONS WIN55,212-2 treatment does not alter lesion size in Ldlr null-mice, but does modify lesion cellularity via CB2-dependent and CB2-independent mechanisms.
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Affiliation(s)
| | - Ward Rodgers
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Makenzie Fulmer
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Zachary Lahr
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Douglas Thewke
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
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Xia X, Li Y, Su Q, Huang Z, Shen Y, Li W, Yu C. Inhibitory effects of Mycoepoxydiene on macrophage foam cell formation and atherosclerosis in ApoE-deficient mice. Cell Biosci 2015; 5:23. [PMID: 26045945 PMCID: PMC4455339 DOI: 10.1186/s13578-015-0017-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 05/20/2015] [Indexed: 02/02/2023] Open
Abstract
Background Mycoepoxydiene (MED) is a polyketide that can be isolated from a marine fungus and is associated with various activities, including antitumor and anti-inflammatory functions. However, its effects on atherosclerosis remain unknown. Macrophage-derived foam cells play crucial roles in the initiation and progression of atherosclerotic plaques. In this study, we investigated the effects of MED on oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and activation, and on high fat diet (HFD)-induced atherosclerosis in ApoE-deficient (ApoE−/−) mice. Results Our findings show that MED could significantly inhibit ox-LDL-induced macrophage foam cell formation and suppress the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which is a receptor for ox-LDL. Additionally, MED could significantly inhibit the secretion of proinflammatory cytokines, such as tumor necrosis factor (TNF-α), interleukin (IL)-6, and IL-1β. Mechanistically, MED inhibited NF-κB activation by blocking IκB-α degradation and reducing NF-κB DNA binding activity. Moreover, MED dramatically reduced the occurrence of HFD-induced atherosclerotic lesions in ApoE−/− mice. Conclusions Our study shows that MED can inhibit macrophage foam cell formation and activation by inhibiting NF-κB activation, thereby protecting ApoE−/− mice from HFD-induced atherosclerosis. Our findings suggest that MED might be a potential lead compound for the development of antiatherosclerotic therapeutics. Electronic supplementary material The online version of this article (doi:10.1186/s13578-015-0017-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaochun Xia
- The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361005 China
| | - Yang Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang-An South Road, Xiamen, Fujian 360112 China
| | - Qiang Su
- Medical College, Xiamen University, Xiamen, China
| | - Zhengrong Huang
- The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361005 China
| | - Yuemao Shen
- School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012 China
| | - Weihua Li
- The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361005 China
| | - Chundong Yu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang-An South Road, Xiamen, Fujian 360112 China
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Turcotte C, Chouinard F, Lefebvre JS, Flamand N. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J Leukoc Biol 2015; 97:1049-70. [PMID: 25877930 DOI: 10.1189/jlb.3ru0115-021r] [Citation(s) in RCA: 171] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 02/28/2015] [Indexed: 12/26/2022] Open
Abstract
2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation. Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory. 2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids. In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions. This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.
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Affiliation(s)
- Caroline Turcotte
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - François Chouinard
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Julie S Lefebvre
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Nicolas Flamand
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Département de Médecine, Faculté de Médecine, Université Laval, Québec City, QC, Canada
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35
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Pathophysiology of Portal Hypertension. PANVASCULAR MEDICINE 2015. [PMCID: PMC7153457 DOI: 10.1007/978-3-642-37078-6_144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The bases of our current knowledge on the physiology of the hepatic portal system are largely owed to the work of three pioneering vascular researchers from the sixteenth and the seventeenth centuries: A. Vesalius, W. Harvey, and F. Glisson. Vesalius is referred to as the founder of modern human anatomy, and in his influential book, De humani corporis fabrica libri septem, he elaborated the first anatomical atlas of the hepatic portal venous system (Vesalius 2013). Sir William Harvey laid the foundations of modern cardiovascular research with his Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (Harvey 1931) in which he established the nature of blood circulation. Finally, F. Glisson characterized the gastrointestinal-hepatic vascular system (Child 1955). These physiological descriptions were later complemented with clinical observations. In the eighteenth and nineteenth centuries, Morgagni, Puckelt, Cruveilhier, and Osler were the first to make the connection between common hepatic complications – ascites, splenomegaly, and gastrointestinal bleeding – and obstruction of the portal system (Sandblom 1993). These were the foundations that allowed Gilbert, Villaret, and Thompson to establish an early definition of portal hypertension at the beginning of the twentieth century. In this period, Thompson performed the first direct measurement of portal pressure by laparotomy in some patients (Gilbert and Villaret 1906; Thompson et al. 1937). Considering all these milestones, and paraphrasing Sir Isaac Newton, if hepatologists have seen further, it is by standing on the shoulders of giants. Nowadays, our understanding of the pathogenesis of portal hypertension has largely improved thanks to the progress in preclinical and clinical research. However, this field is ever-changing and hepatologists are continually identifying novel pathological mechanisms and developing new therapeutic strategies for this clinical condition. Hence, the aim of this chapter is to summarize the current knowledge about this clinical condition.
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Abstract
Chemical atherogenesis is an emerging field that describes how environmental pollutants and endogenous toxins perturb critical pathways that regulate lipid metabolism and inflammation, thus injuring cells found within the vessel wall. Despite growing awareness of the role of environmental pollutants in the development of cardiovascular disease, the field of chemical atherogenesis can broadly include both exogenous and endogenous poisons and the study of molecular, biochemical, and cellular pathways that become dysregulated during atherosclerosis. This integrated approach is logical because exogenous and endogenous toxins often share the same mechanism of toxicity. Chemical atherogenesis is a truly integrative discipline because it incorporates concepts from several different fields, including biochemistry, chemical biology, pharmacology, and toxicology. This review will provide an overview of this emerging research area, focusing on cellular and animal models of disease.
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Abstract
In recent years, a growing interest has been dedicated to the study of the endocannabinoid system. The isolation of Cannabis sativa main psychotropic compound, Δ(9)-tetrahydrocannabinol (THC), has led to the discovery of an atypical neurotransmission system that modulates the release of other neurotransmitters and participates in many biological processes, including the cascade of inflammatory responses. In this context, cannabinoids have been studied for their possible therapeutic properties in neuroinflammatory diseases. In this review, historic and biochemical aspects of cannabinoids are discussed, as well as their function as modulators of inflammatory processes and therapeutic perspectives for neurodegenerative disorders, particularly, multiple sclerosis.
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Affiliation(s)
- Viviane M Saito
- Laboratory of Immunopharmacology, Graduate Program in Neurosciences, UFMG, Belo Horizonte, Brazil
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38
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Tauber S, Paulsen K, Wolf S, Synwoldt P, Pahl A, Schneider-Stock R, Ullrich O. Regulation of MMP-9 by a WIN-binding site in the monocyte-macrophage system independent from cannabinoid receptors. PLoS One 2012; 7:e48272. [PMID: 23139770 PMCID: PMC3491062 DOI: 10.1371/journal.pone.0048272] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 09/21/2012] [Indexed: 11/21/2022] Open
Abstract
The cannabinoid system is known to be involved in the regulation of inflammatory processes. Therefore, drugs targeting cannabinoid receptors are considered as candidates for anti-inflammatory and tissue protective therapy. We demonstrated that the prototypical cannabinoid agonist R(+)WIN55,212-2 (WIN) reduced the secretion of matrix metalloproteinase-9 (MMP-9) in a murine model of cigarette-smoke induced lung inflammation. In experiments using primary cells and cell lines of the monocyte-macrophage-system we found that binding of the cannabinoid-receptor agonist WIN to a stereo-selective, specific binding site in cells of the monocyte-macrophage-system induced a significant down-regulation of MMP-9 secretion and disturbance of intracellular processing, which subsequently down-regulated MMP-9 mRNA expression via a ERK1/2-phosphorylation-dependent pathway. Surprisingly, the anti-inflammatory effect was independent from classical cannabinoid receptors. Our experiments supposed an involvement of TRPV1, but other yet unidentified sites are also possible. We conclude that cannabinoid-induced control of MMP-9 in the monocyte-macrophage system via a cannabinoid-receptor independent pathway represents a general option for tissue protection during inflammation, such as during lung inflammation and other diseases associated with inflammatory tissue damage.
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Affiliation(s)
- Svantje Tauber
- Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Institute of Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Katrin Paulsen
- Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Institute of Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Susanne Wolf
- Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | | | | | - Regine Schneider-Stock
- Institute of Pathology, Erlangen, Germany
- Institute of Pathology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Oliver Ullrich
- Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Institute of Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Department of Machine Design, Engineering Design and Product Development, Institute of Mechanical Engineering, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
- * E-mail:
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Steffens S, Pacher P. Targeting cannabinoid receptor CB(2) in cardiovascular disorders: promises and controversies. Br J Pharmacol 2012; 167:313-323. [PMID: 22612332 PMCID: PMC3481040 DOI: 10.1111/j.1476-5381.2012.02042.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Revised: 04/23/2012] [Accepted: 05/14/2012] [Indexed: 12/21/2022] Open
Abstract
Cardiovascular disease is the leading cause of death and disability worldwide, which can be largely attributed to atherosclerosis, a chronic inflammation of the arteries characterized by lesions containing immune and smooth muscle cells, lipids and extracellular matrix. In recent years, the lipid endocannabinoid system has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the cardiovascular system. The discovery that Δ-9-tetrahydrocannabinol (Δ9-THC), the main active constituent of marijuana, inhibited atherosclerotic plaque progression via a cannabinoid 2 (CB(2) ) receptor-dependent anti-inflammatory mechanism, and that certain natural and synthetic cannabinoid ligands could modulate the myocardial or cerebral ischaemia-reperfusion-induced tissue damage, have stimulated impetus for a growing number of studies investigating the implication of CB(2) receptors in atherosclerosis, restenosis, stroke, myocardial infarction and heart failure. The aim of this review is to update on recent findings and controversies on the role of CB(2) receptors in cardiovascular disease. Particular emphasis will be placed on novel insights in the potential cellular targets of CB(2) stimulation in cardiovascular system (e.g. endothelial and vascular smooth muscle cells, cardiomyocytes, infiltrating and/or resident monocytes/macrophages and leukocytes, etc.), their interplay and intracellular signalling mechanisms identified, as well as on experimental and clinical studies.
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Affiliation(s)
- Sabine Steffens
- Division of Cardiology, Department of Internal Medicine, University Hospital, Foundation for Medical ResearchesGeneva, Switzerland
| | - Pál Pacher
- Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health, NIAAABethesda, Maryland, USA
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Singla S, Sachdeva R, Mehta JL. Cannabinoids and atherosclerotic coronary heart disease. Clin Cardiol 2012; 35:329-35. [PMID: 22278660 PMCID: PMC6652534 DOI: 10.1002/clc.21962] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 12/13/2011] [Indexed: 12/31/2022] Open
Abstract
Marijuana is the most abused recreational drug in the United States. Cannabinoids, the active ingredients of marijuana, affect multiple organ systems in the human body. The pharmacologic effects of marijuana, based on stimulation of cannabinoid receptors CB1 and CB2, which are widely distributed in the cardiovascular system, have been well described. Activation of these receptors modulates the function of various cellular elements of the vessel wall, and may contribute to the pathogenesis of atherosclerosis. Clinically, there are reports linking marijuana smoking to the precipitation of angina and acute coronary syndromes. Recently, large published clinical trials with CB1 antagonist rimonabant did not show any significant benefit of this agent in preventing progression of atherosclerosis. In light of these findings and emerging data on multiple pathways linking cannabinoids to atherosclerosis, we discuss the literature on the role of cannabinoids in the pathophysiology of atherosclerosis. We also propose a marijuana paradox, which implies that inhalation of marijuana may be linked to precipitation of acute coronary syndromes, but modulation of the endocannabinoid system by a noninhalation route may have a salutary effect on the development of atherosclerosis.
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Affiliation(s)
- Sandeep Singla
- Department of Medicine, Division of Cardiology, University of Arkansas for Medical Sciences and VA Medical Center, Little Rock, AR, USA.
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Molica F, Matter CM, Burger F, Pelli G, Lenglet S, Zimmer A, Pacher P, Steffens S. Cannabinoid receptor CB2 protects against balloon-induced neointima formation. Am J Physiol Heart Circ Physiol 2012; 302:H1064-H1074. [PMID: 22227125 PMCID: PMC3774259 DOI: 10.1152/ajpheart.00444.2011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 01/04/2012] [Indexed: 12/12/2022]
Abstract
Cannabinoid receptor CB(2) activation inhibits inflammatory proliferation and migration of vascular smooth muscle cells in vitro. The potential in vivo relevance of these findings is unclear. We performed carotid balloon distension injury in hypercholesterolemic apolipoprotein E knockout (ApoE(-/-)) mice receiving daily intraperitoneal injection of the CB(2) agonist JWH133 (5 mg/kg) or vehicle, with the first injection given 30 min before injury. Alternatively, we subjected CB(2)(-/-) and wild-type (WT) mice to balloon injury. We determined CB(2) mRNA and protein expression in dilated arteries of ApoE(-/-) mice. Neointima formation was assessed histologically. We used bone marrow-derived murine CB(2)(-/-) and WT macrophages to study adhesion to plastic, fibronectin, or collagen, and migration was assayed by modified Boyden chamber. Aortic smooth muscle cells were isolated to determine in vitro proliferation rates. We found increased vascular CB(2) expression in ApoE(-/-) mice in response to balloon injury. Seven to twenty-one days after dilatation, injured vessels of JWH133-treated mice had less intimal nuclei numbers as well as intimal and medial areas, associated with less staining for proliferating cells, smooth muscle cells, and macrophages. Complete endothelial repair was observed after 14 days in both JWH133- and vehicle-treated mice. CB(2) deficiency resulted in increased intima formation compared with WT, whereas JWH133 did not affect intimal formation in CB(2)(-/-) mice. Apoptosis rates assessed by in situ terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining 1 h postballooning were significantly higher in the CB(2) knockouts. In vitro, bone marrow-derived CB(2)(-/-) macrophages showed enhanced adherence and migration compared with WT cells and elevated mRNA levels of adhesion molecules, chemokine receptors CCR1 and 5, and chemokine CCL2. Proliferation rates were significantly increased in CB(2)(-/-) smooth muscle cells compared with WT. In conclusion, pharmacological activation or genetic deletion of CB(2) receptors modulate neointima formation via protective effects in macrophages and smooth muscle cells.
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MESH Headings
- Angioplasty, Balloon/adverse effects
- Animals
- Apolipoproteins E/genetics
- Apolipoproteins E/physiology
- Apoptosis/drug effects
- Apoptosis/physiology
- Carotid Artery Injuries/drug therapy
- Carotid Artery Injuries/pathology
- Carotid Artery Injuries/physiopathology
- Cell Adhesion/drug effects
- Cell Adhesion/physiology
- Cell Movement/drug effects
- Cell Movement/physiology
- Cell Proliferation/drug effects
- Cholesterol, Dietary/metabolism
- Cholesterol, Dietary/pharmacology
- Macrophages/drug effects
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/physiology
- Neointima/drug therapy
- Neointima/pathology
- Neointima/physiopathology
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/biosynthesis
- Receptor, Cannabinoid, CB2/physiology
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Affiliation(s)
- Filippo Molica
- Division of Cardiology, Department of Internal Medicine, University Hospital, Geneva, Switzerland.
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