DOCSLIB.ORG

Endocannabinoid System in Neurodegenerative Disorders

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Endocannabinoid System in Neurodegenerative Disorders JOURNAL OF NEUROCHEMISTRY | 2017 | 142 | 624–648 doi: 10.1111/jnc.14098 , , , *Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA †New York State Psychiatric Institute, New York City, New York, USA ‡Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York City, New York, USA §Department of Psychiatry, New York University Langone Medical Center, New York City, New York, USA Abstract enzymes that catabolize these compounds, has been shown Most neurodegenerative disorders (NDDs) are characterized to contribute to the development of NDDs in several animal by cognitive impairment and other neurological defects. The models and human studies. In this review, we discuss the definite cause of and pathways underlying the progression of functions of the endocannabinoid system in NDDs and these NDDs are not well-defined. Several mechanisms have converse the therapeutic efficacy of targeting the endo- been proposed to contribute to the development of NDDs. cannabinoid system to rescue NDDs. These mechanisms may proceed concurrently or succes- Keywords: Alzheimer’s disease, CB1 receptors, Huntington’s sively, and they differ among cell types at different develop- disease, Loss of neurons, motor and memory behavior, mental stages in distinct brain regions. The endocannabinoid Parkinson’s disease. system, which involves cannabinoid receptors type 1 (CB1R) J. Neurochem. (2017) 142, 624–648. and type 2 (CB2R), endogenous cannabinoids and the Cannabinoids are naturally occurring compounds found in the plant Cannabis sativa. Of over 500 different compounds Received April 6, 2017; revised manuscript received May 22, 2017; present in the plant, only approximately 85 are termed accepted June 2, 2017. cannabinoids (Brenneisen 2007). The most well-known Address for correspondence and reprint request to Dr Balapal S. among these compounds is delta-9-tetrahydrocannabinol Basavarajappa, Division of Analytical Psychopharmacology, Nathan (D9-THC) (Dewey 1986; Hollister 1986). D9-THC elicits Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, New York, NY 10962, USA. E-mail: basavaraj.balapal its psychoactive effects by binding to receptors on the cell @nki.rfmh.org membrane called cannabinoid receptors (CBRs) (Howlett Abbreviations used: 2-AG, 2-arachidonylglycerol; ABHD4, abhydro- et al. 1990). These receptors are present in both the central lase domain 4; AEA, arachidonylethanolamide (anandamide); AMPAR, nervous system (CNS) and the periphery and are classified as a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AMT, type 1 (CB1R) and type 2 (CB2R). Signaling downstream of AEA membrane transporter; BDNF, brain-derived neurotrophic factor; fi CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; these CBRs is signi cantly involved in a variety of standard DAGL, diacylglycerollipase; EC, endocannabinoid; FAAH, fatty acid functions as well as several pathophysiological functions of amide hydrolase; FAK, focal adhesion kinase; GABAA, gamma-amino the CNS. Signaling events of CB1R and CB2R are depicted butyric acid-A receptor; GDE1, glycerophosphodiesterase; GPCR, G in Figs 1 and 2 respectively. Discovery of the first endoge- protein coupled receptor; MAGL, monoacylglycerol lipase; MAPK, nous cannabinoid substance, anandamide (N-arachidonoyl mitogen-activated protein kinase; miRNAs, microRNAs; NAPE-PLD, N-acylphosphatidylethanolamine-specific phospholipase D; N-ArPE, ethanolamine, AEA) (Devane and Axelrod 1994), in the N-arachidonyl phosphatidylethanolamine; NAT, N-acyltransferase; NMDA, brain emphasized the importance of the cannabinoid receptor N-methyl-D-aspartate; PGH2, prostaglandin H2; PTPN22, phosphatase; and its endogenous ligands in the regulation of a wide variety VR1, vanilloid receptor type 1; D9-THC, delta-9-tetrahydrocannabinol. 624 © 2017 International Society for Neurochemistry, J. Neurochem. (2017) 142, 624--648 Mechanisms of NDs 625 of biological functions (Pertwee 1997). Later, 2-arachidonoyl (Ohno-Shosaku et al. 1998, 2000, 2001, 2002; Wilson and glycerol (2-AG) was identified as a second endogenous Nicoll 2001, 2002; Wilson et al. 2001). The discovery of cannabinoid (Sugiura et al. 2006). These two endogenous ECs such as AEA and 2-AG and the widespread localization cannabinoids are derivatives of arachidonic acid (Fig. 3) and of CB1Rs in the brain have stimulated considerable excite- are synthesized and metabolized by different pathways ment regarding the role of the EC system in Alzheimer’s (Fig. 4a and b). Both AEA and 2-AG act on the CBRs to disease (AD). AD is the most devastating neurodegenerative elicit their biological activities; therefore, they are termed disorder in humans, and the most common symptom of AD endocannabinoids (ECs). ECs are lipophilic in nature and are is difficulty in retaining and recalling recently learned synthesized on demand from membrane phospholipids, and information. Cognitive deficits of AD patients correlate with they can readily partition into and diffuse throughout cellular cerebral disturbances in sensitive brain areas, largely in the membranes without storage in vesicles. After their release frontal cortex and the hippocampal region, areas that are rich from the post-synaptic neuron, ECs bind to CB1Rs located in CB1Rs (Glass et al. 1997; Biegon and Kerman 2001). AD on the pre-synaptic membrane to inhibit neurotransmitter pathology is characterized by the accumulation of b-amyloid release (Ohno-Shosaku et al. 2001; Berghuis et al. 2007; (Ab), neurofibrillary tangles consisting of hypophosphory- Harkany et al. 2008). ECs are removed from the synaptic lated tau, the loss of particular subsets of neurons, and junction after CB1R activation by process of cellular neuroinflammation resulting from glial activation. Although transport followed by hydrolysis. Anandamide is hydrolyzed the existence of familial AD, which shows early onset, has in post-synaptic neurons by fatty acid amide hydrolase been characterized, this form only accounts for a small (FAAH), thus terminating its action (Varvel et al. 2006, proportion of cases (Hardy 1996a,b; Campion et al. 1999; 2007). After CB1R activation, 2-AG is hydrolyzed in pre- Hardy and Selkoe 2002). The real cause of sporadic AD is synaptic neurons by monoacylglycerol lipase (MAGL) [see unknown, but numerous risk factors have been identified, recent reviews (Basavarajappa 2015; Lu and Anderson including hypercholesterolemia, ischemic stroke, hyperten- 2017)] (Fig. 4a and b). This retrograde signaling provides a sion, the ApoE4 allele and diabetes (Grammas 2011; mechanism for inhibitory feedback to regulate neurotrans- Carnevale et al. 2016; Hamel et al. 2016). mitter release in the brain. This unique function of ECs has Limited numbers of studies have reported reduced densi- provided a strong rationale for investigating them as ties of CB1Rs in aged animals (Mailleux and Vanderhaeghen therapeutic targets for autoimmune disease, stroke and some 1992a; Romero et al. 1998). ECs were shown to decrease other severe neurodegenerative diseases, including Alzhei- significantly with age in the mouse hippocampus and frontal mer’s disease (AD), Huntington’s disease (HD) and Parkin- cortex (Maroof et al. 2014). An autoradiographic examina- son’s disease (PD). We have recently reviewed the functions tion of sections of normal post-mortem brain suggested a no of EC system in the normal brain (Basavarajappa 2015; Lu significant reduction in CB1R binding with age (Ahmad and Anderson 2017); therefore, the current study aims to et al. 2014). Several investigators have studied the changes present the new understanding of the role and involvement of associated with the EC system during the progression of AD the EC system in neurodegenerative disorders (Tables 1 disease. Correlation analyses based on post-mortem cortical and 2). brain tissues (Brodmann area 10) from a cohort of neu- ropathologically confirmed AD patients indicated lower EC system and AD CB1R levels than in age-matched controls (Solas et al. The distribution of CB1Rs in the rodent adult brain is highly 2013). These lower CB1R levels correlated with hypophagia heterogeneous, with the highest densities of receptors present but not with any AD molecular markers or cognitive status in the basal ganglia, including the substantia nigra pars (Solas et al. 2013). The levels of AEA were reduced in the reticulata (SNr) and the globus pallidus, in the hippocampus, hippocampus of a mouse genetic model of AD (transgenic particularly within the dentate gyrus, and in the molecular mice overexpressing amyloid precursor protein, APP) layer of the cerebellum. Low levels of CB1Rs are also found (TgAPP-2576) (Kofalvi et al. 2016). The ECs acting through in the brainstem (Howlett 2002). There is a similar distribu- transient receptor potential cation channel subfamily V tion of CB1Rs in humans (Glass et al. 1997; Biegon and member 1 (TRPV1) were suggested to play a significant Kerman 2001). The highest densities are found in limbic role in Ab-induced cognitive impairment in D3 receptor KO cortices, with much lower levels observed within primary mice (Micale et al. 2010). sensory and motor regions, pointing an important role in Cannabinoid receptor agonists such as AEA and noladin motivational (limbic) and cognitive (Association) informa- ether have been shown to provide protection against the Ab- tion processing. CB1Rs have been shown to be localized pre- peptide induced neurotoxicity in neurons differentiated
Load more

Recommended publications
  • 615 Neuroscience-Cayman-Bertin
    Thomas G. Brock, Ph.D. Introduction to Neuroscience In our first Biology classes, we learned that lipids form the membranes around cells. For many students, interests quickly moved to the intracellular constituents ‘that really matter’, or to how cells or systems work in health and disease. If there was further thought about lipids, it might have been limited to more personal issues, like an expanding waistline. It was easy to forget about lipids in the complexities of, say, Alzheimer’s Disease, where tau protein is hyperphosphorylated by a host of kinases before forming neurofibrillary tangles and amyloid precursor protein is processed by assorted secretases, ultimately aggregating to form neurodegenerating plaques. What possible role could lipids have in all this? After all, lipids just form the membranes around cells. Fortunately, neuroscientists study complex systems. Whether working at the molecular, cellular, or organismal level, the research focus always returns to the intricately interconnected bigger picture. Perhaps surprisingly, lipids keep emerging as part of the bigger picture. At least, the smaller lipids do. Many of the smaller lipids, including the cannabinoids and eicosanoids, act as paracrine hormones, modulating cell functions in a receptor-mediated fashion. In this sense, they are rather like the peptide hormones in their diversity and actions. In the neurosystem, this means that these signaling lipids determine if synapses fire or not, when cells differentiate or die, and whether tissues remain healthy or become inflamed. Returning to the question posed above about lipids in Alzheimer’s, these mediators have roles at many levels in the course of the disease, as presented in an article on page 42 of this catalog.
    [Show full text]
  • Régulation De L'inflammation Par Les Lipides Bioactifs : Interactions Biosynthétiques Et Fonctionnelles Entre Les Endocannabinoïdes Et Les Éicosanoïdes
    Régulation de l'inflammation par les lipides bioactifs : interactions biosynthétiques et fonctionnelles entre les endocannabinoïdes et les éicosanoïdes Thèse Caroline Turcotte Doctorat en microbiologie-immunologie Philosophiæ doctor (Ph. D.) Québec, Canada © Caroline Turcotte, 2019 Régulation de l’inflammation par les lipides bioactifs : interactions biosynthétiques et fonctionnelles entre les endocannabinoïdes et les éicosanoïdes Thèse Caroline Turcotte Sous la direction de : Nicolas Flamand, directeur de recherche Marie-Renée Blanchet, codirectrice de recherche Résumé Les maladies inflammatoires chroniques sont un fardeau de santé important à travers le monde. Les traitements actuellement disponibles soulagent la douleur et l’inflammation, mais leurs effets secondaires rendent leur utilisation à long terme risquée. À la lumière de cette problématique, la communauté scientifique s’intéresse au potentiel d’anti-inflammatoires naturels comme les endocannabinoïdes. Les endocannabinoïdes sont des lipides endogènes qui activent les récepteurs cannabinoïdes (CB1 et CB2). Ils régulent ainsi divers processus physiologiques tels l’appétit, l’adipogénèse et la nociception. Les deux endocannabinoïdes les mieux caractérisés, le 2-AG et l’AEA, peuvent également moduler l’inflammation en activant le récepteur CB2 à la surface des cellules immunitaires. Les souris déficientes pour le récepteur CB2 présentent un phénotype inflammatoire exacerbé, suggérant que ce récepteur est anti-inflammatoire. Cependant, le rôle des endocannabinoïdes dans l’inflammation est beaucoup plus complexe puisqu’ils peuvent être métabolisés en une grande variété de médiateurs lipidiques de l’inflammation. Leur voie de dégradation principale est leur hydrolyse en acide arachidonique (AA), qui sert de précurseur à la biosynthèse d’éicosanoïdes pro-inflammatoires comme le leucotriène B4 et la prostaglandine E2. Ils peuvent également être métabolisés directement par certaines enzymes impliquées dans la synthèse d’éicosanoïdes, pour générer des médiateurs comme les prostaglandines-glycérol (PG-G).
    [Show full text]
  • Effects of Cannabinor, a Novel Selective Cannabinoid 2 Receptor Agonist, on Bladder Function in Normal Rats
    EURURO-3374; No. of Pages 8 EUROPEAN UROLOGY XXX (2010) XXX–XXX available at www.sciencedirect.com journal homepage: www.europeanurology.com Voiding Dysfunction Effects of Cannabinor, a Novel Selective Cannabinoid 2 Receptor Agonist, on Bladder Function in Normal Rats Christian Gratzke a,b,f, Tomi Streng c, Christian G. Stief b, Thomas R. Downs d, Iris Alroy e, Jan S. Rosenbaum d, Karl-Erik Andersson f,*, Petter Hedlund a,g a Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden b Department of Urology, Ludwig-Maximilians-University, Munich, Germany c Department of Pharmacology, Turku University, Finland d Women’s Health, Procter & Gamble Health Care, Cincinnati, OH, USA e Pharmos Limited, Rehovot, Israel f Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA g Urological Research Institute, San Raffaele University Hospital, Milan, Italy Article info Abstract Article history: Background: Cannabinoid (CB) receptors may be involved in the control of bladder Accepted February 19, 2010 function; the role of CB receptor subtypes in micturition has not been established. Published online ahead of Objectives: Our aim was to evaluate the effects of cannabinor, a novel CB2 receptor print on March 1, 2010 agonist, on rat bladder function. Design, setting, and participants: Sprague Dawley rats were used. Distribution of Keywords: CB2 receptors in sensory and cholinergic nerves of the detrusor was studied. Cannabinoid Selectivity of cannabinor for human and rat CB receptors was evaluated. Effects Urothelium of cannabinor on rat detrusor and micturition were investigated. Sensory Measurements: Immunohistochemistry, radioligand binding, tritium outflow Detrusor assays, organ bath studies of isolated bladder tissue, and cystometry in awake Cystometry rats were used.
    [Show full text]
  • Cannabinoid-Induced Hypotension and Bradycardia in Rats Is 1 Mediated by CB1-Like Cannabinoid Receptors
    0022-3565/97/2813-1030$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 281, No. 3 Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 281:1030–1037, 1997 Cannabinoid-Induced Hypotension and Bradycardia in Rats Is 1 Mediated by CB1-Like Cannabinoid Receptors KRISTY D. LAKE, DAVID R. COMPTON, KAROLY VARGA, BILLY R. MARTIN and GEORGE KUNOS Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia Accepted for publication February 19, 1997 ABSTRACT 9 Previous studies indicate that the CB1 cannabinoid receptor an- potency was (-)-11-OH-D -THC dimethylheptyl $ (-)-3-[2- tagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophe- hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]cy- nyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A), in- clohexan-1-ol . (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]- hibits the anandamide- and D9-tetrahydrocannabinol- (THC) 4-[3-hydroxy-propyl]cyclohexan-1-ol . THC . anandamide $ induced hypotension and bradycardia in anesthetized rats with a (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy- potency similar to that observed for SR141716A antagonism of propyl]cyclohexan-1-ol, which correlated well with CB1 receptor THC-induced neurobehavioral effects. To further test the role of affinity or analgesic potency (r 5 0.96-0.99). There was no hypo- CB1 receptors in the cardiovascular effects of cannabinoids, we tension or bradycardia after palmitoylethanolamine or (1)-11-OH- examined two additional criteria for receptor-specific interactions: D9-THC dimethylheptyl.
    [Show full text]
  • In Vitro Immunopharmacological Profiling of Ginger (Zingiber Officinale Roscoe)
    Research Collection Doctoral Thesis In vitro immunopharmacological profiling of ginger (Zingiber officinale Roscoe) Author(s): Nievergelt, Andreas Publication Date: 2011 Permanent Link: https://doi.org/10.3929/ethz-a-006717482 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH Nr. 19591 In Vitro Immunopharmacological Profiling of Ginger (Zingiber officinale Roscoe) ABHANDLUNG zur Erlangung des Titels DOKTOR DER WISSENSCHAFTEN der ETH ZÜRICH vorgelegt von Andreas Nievergelt Eidg. Dipl. Apotheker, ETH Zürich geboren am 18.12.1978 von Schleitheim, SH Angenommen auf Antrag von Prof. Dr. Karl-Heinz Altmann, Referent Prof. Dr. Jürg Gertsch, Korreferent Prof. Dr. Michael Detmar, Korreferent 2011 Table of Contents Summary 6 Zusammenfassung 7 Acknowledgements 8 List of Abbreviations 9 1. Introduction 13 1.1 Ginger (Zingiber officinale) 13 1.1.1 Origin 14 1.1.2 Description 14 1.1.3 Chemical Constituents 15 1.1.4 Traditional and Modern Pharmaceutical Use of Ginger 17 1.1.5 Reported In Vitro Effects 20 1.2 Immune System and Inflammation 23 1.2.1 Innate and Adaptive Immunity 24 1.2.2 Cytokines in Inflammation 25 1.2.3 Pattern Recognition Receptors 29 1.2.4 Toll-Like Receptors 30 1.2.5 Serotonin 1A and 3 Receptors 32 1.2.6 Phospholipases A2 33 1.2.7 MAP Kinases 36 1.2.8 Fighting Inflammation, An Ongoing Task 36 1.2.9 Inflammation Assays Using Whole Blood 38 1.3 Arabinogalactan-Proteins 39 1.3.1 Origin and Biological Function of AGPs 40 1.3.2 Effects on Animals 41 1.3.3 The ‘Immunostimulation’ Theory 42 1/188 2.
    [Show full text]
  • N-Acyl-Dopamines: Novel Synthetic CB1 Cannabinoid-Receptor Ligands
    Biochem. J. (2000) 351, 817–824 (Printed in Great Britain) 817 N-acyl-dopamines: novel synthetic CB1 cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo Tiziana BISOGNO*, Dominique MELCK*, Mikhail Yu. BOBROV†, Natalia M. GRETSKAYA†, Vladimir V. BEZUGLOV†, Luciano DE PETROCELLIS‡ and Vincenzo DI MARZO*1 *Istituto per la Chimica di Molecole di Interesse Biologico, C.N.R., Via Toiano 6, 80072 Arco Felice, Napoli, Italy, †Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, R. A. S., 16/10 Miklukho-Maklaya Str., 117871 Moscow GSP7, Russia, and ‡Istituto di Cibernetica, C.N.R., Via Toiano 6, 80072 Arco Felice, Napoli, Italy We reported previously that synthetic amides of polyunsaturated selectivity for the anandamide transporter over FAAH. AA-DA fatty acids with bioactive amines can result in substances that (0.1–10 µM) did not displace D1 and D2 dopamine-receptor interact with proteins of the endogenous cannabinoid system high-affinity ligands from rat brain membranes, thus suggesting (ECS). Here we synthesized a series of N-acyl-dopamines that this compound has little affinity for these receptors. AA-DA (NADAs) and studied their effects on the anandamide membrane was more potent and efficacious than anandamide as a CB" transporter, the anandamide amidohydrolase (fatty acid amide agonist, as assessed by measuring the stimulatory effect on intra- hydrolase, FAAH) and the two cannabinoid receptor subtypes, cellular Ca#+ mobilization in undifferentiated N18TG2 neuro- CB" and CB#. NADAs competitively inhibited FAAH from blastoma cells. This effect of AA-DA was counteracted by the l µ N18TG2 cells (IC&! 19–100 M), as well as the binding of the CB" antagonist SR141716A.
    [Show full text]
  • Inhibition of Monoacylglycerol Lipase Reduces the Reinstatement Of
    International Journal of Neuropsychopharmacology (2019) 22(2): 165–172 doi:10.1093/ijnp/pyy086 Advance Access Publication: November 27, 2018 Regular Research Article regular research article Inhibition of Monoacylglycerol Lipase Reduces the Reinstatement of Methamphetamine-Seeking and Anxiety-Like Behaviors in Methamphetamine Self-Administered Rats Yoko Nawata, Taku Yamaguchi, Ryo Fukumori, Tsuneyuki Yamamoto Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, Nagasaki, Japan Correspondence: Tsuneyuki Yamamoto, PhD, Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, 2825–7 Huis Ten Bosch Sasebo, Nagasaki 859–3298, Japan ([email protected]). Abstract Background: Methamphetamine is a highly addictive psychostimulant with reinforcing properties. Our laboratory previously found that Δ8-tetrahydrocannabinol, an exogenous cannabinoid, suppressed the reinstatement of methamphetamine- seeking behavior. The purpose of this study was to determine whether the elevation of endocannabinoids modulates the reinstatement of methamphetamine-seeking behavior and emotional changes in methamphetamine self-administered rats. Methods: Rats were tested for the reinstatement of methamphetamine-seeking behavior following methamphetamine self- administration and extinction. The elevated plus-maze test was performed in methamphetamine self-administered rats during withdrawal. We investigated the effects of JZL184 and URB597, 2 inhibitors of endocannabinoid hydrolysis, on the reinstatement of methamphetamine-seeking and anxiety-like behaviors. Results: JZL184 (32 and 40 mg/kg, i.p.), an inhibitor of monoacylglycerol lipase, significantly attenuated both the cue- and stress-induced reinstatement of methamphetamine-seeking behavior. Furthermore, URB597 (3.2 and 10 mg/kg, i.p.), an inhibitor of fatty acid amide hydrolase, attenuated only cue-induced reinstatement. AM251, a cannabinoid CB1 receptor antagonist, antagonized the attenuation of cue-induced reinstatement by JZL184 but not URB597.
    [Show full text]
  • 2-Arachidonoylglycerol a Signaling Lipid with Manifold Actions in the Brain
    Progress in Lipid Research 71 (2018) 1–17 Contents lists available at ScienceDirect Progress in Lipid Research journal homepage: www.elsevier.com/locate/plipres Review 2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain T ⁎ Marc P. Baggelaara,1, Mauro Maccarroneb,c,2, Mario van der Stelta, ,2 a Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. b Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy c European Centre for Brain Research/IRCCS Santa Lucia Foundation, via del Fosso del Fiorano 65, 00143 Rome, Italy ABSTRACT 2-Arachidonoylglycerol (2-AG) is a signaling lipid in the central nervous system that is a key regulator of neurotransmitter release. 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. It is involved in a wide array of (patho)physiological functions, such as emotion, cognition, energy balance, pain sensation and neuroinflammation. In this review, we describe the biosynthetic and metabolic pathways of 2-AG and how chemical and genetic perturbation of these pathways has led to insight in the biological role of this signaling lipid. Finally, we discuss the potential therapeutic benefits of modulating 2-AG levels in the brain. 1. Introduction [24–26], locomotor activity [27,28], learning and memory [29,30], epileptogenesis [31], neuroprotection [32], pain sensation [33], mood 2-Arachidonoylglycerol (2-AG) is one of the most extensively stu- [34,35], stress and anxiety [36], addiction [37], and reward [38]. CB1 died monoacylglycerols. It acts as an important signal and as an in- receptor signaling is tightly regulated by biosynthetic and catabolic termediate in lipid metabolism [1,2].
    [Show full text]
  • Role of the Endocannabinoid System and Medical Cannabis
    Brigham Young University BYU ScholarsArchive Student Works 2016-12-19 Role of the Endocannabinoid System and Medical Cannabis Sabrina Jarvis Brigham Young University, [email protected] Sean Rasmussen Brigham Young University, [email protected] Blaine Winters Brigham Young University - Provo Follow this and additional works at: https://scholarsarchive.byu.edu/studentpub Part of the Nursing Commons The College of Nursing showcases some of our best evidence based scholarly papers from graduate students in the Family Nurse Practitioner Program. The papers address relevant clinical problems for advance practice nurses and are based on the best evidence available. Using a systematic approach students critically analyze and synthesize the research studies to determine the strength of the evidence regarding the clinical problem. Based on the findings, recommendations are made for clinical practice. The papers are published in professional journals and presented at professional meetings. BYU ScholarsArchive Citation Jarvis, Sabrina; Rasmussen, Sean; and Winters, Blaine, "Role of the Endocannabinoid System and Medical Cannabis" (2016). Student Works. 192. https://scholarsarchive.byu.edu/studentpub/192 This Master's Project is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Student Works by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. Role of the Endocannabinoid System and Medical Cannabis Sean I. Rasmussen An evidence based scholarly paper submitted to the faculty of Brigham Young University in partial fulfillment of the requirements for the degree of Masters of Science Sabrina Jarvis, Chair Blaine Winters College of Nursing Brigham Young University Copyright © 2016 Sean I.
    [Show full text]
  • Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’S Disease
    Molecular Neurobiology https://doi.org/10.1007/s12035-019-1637-8 Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’s Disease David Schubert1 & Devin Kepchia1 & Zhibin Liang1 & Richard Dargusch1 & Joshua Goldberg & Pamela Maher1 Received: 30 January 2019 /Accepted: 6 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Finding a therapy for Alzheimer’s disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates. Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain. This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuropro- tective effects that were greater than additive. Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support.
    [Show full text]
  • The Expanded Endocannabinoid System/Endocannabinoidome As a Potential Target for Treating Diabetes Mellitus
    Current Diabetes Reports (2019) 19:117 https://doi.org/10.1007/s11892-019-1248-9 OBESITY (KM GADDE, SECTION EDITOR) The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus Alain Veilleux1,2,3 & Vincenzo Di Marzo1,2,3,4,5 & Cristoforo Silvestri3,4,5 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease. Recent Findings As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. Summary The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D. Keywords Endocannabinoidome . Bioactive lipids . Peripheral tissues . Glucose . Insulin Introduction: The Endocannabinoid System cannabis-derived natural product, Δ9-tetrahydrocannabinol and its Subsequent Expansion (THC), responsible for most of the psychotropic, euphoric to the “Endocannabinoidome” and appetite-stimulating actions (via CB1 receptors) and immune-modulatory effects (via CB2 receptors) of marijuana, The discovery of two G protein-coupled receptors, the canna- opened the way to the identification of the endocannabinoids binoid receptor type-1 (CB1) and − 2 (CB2) [1, 2], for the (eCBs).
    [Show full text]
  • Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model
    Glaucoma Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model Sally Miller,1 Emma Leishman,1 Sherry Shujung Hu,2 Alhasan Elghouche,1 Laura Daily,1 Natalia Murataeva,1 Heather Bradshaw,1 and Alex Straiker1 1Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States 2Department of Psychology, National Cheng Kung University, Tainan, Taiwan Correspondence: Alex Straiker, De- PURPOSE. Cannabinoids, such as D9-THC, act through an endogenous signaling system in the partment of Psychological and Brain vertebrate eye that reduces IOP via CB1 receptors. Endogenous cannabinoid (eCB) ligand, 2- Sciences, Indiana University, Bloom- arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol ington, IN 47405, USA; lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic [email protected]. potential of harnessing eCBs to lower IOP. Submitted: February 16, 2016 Accepted: May 16, 2016 METHODS. We tested the effect of topical application of 2-AG and MAGL blockers in normotensive mice and examined changes in eCB-related lipid species in the eyes and spinal Citation: Miller S, Leishman E, Hu SS, cord of MAGL knockout (MAGLÀ/À) mice using high performance liquid chromatography/ et al. Harnessing the endocannabinoid tandem mass spectrometry (HPLC/MS/MS). We also examined the protein distribution of 2-arachidonoylglycerol to lower intra- ocular pressure in a murine model. MAGL in the mouse anterior chamber. Invest Ophthalmol Vis Sci. RESULTS. 2-Arachidonoyl glycerol reliably lowered IOP in a CB1- and concentration-dependent 2016;57:3287–3296. DOI:10.1167/ manner. Monoacylglycerol lipase is expressed prominently in nonpigmented ciliary iovs.16-19356 epithelium.
    [Show full text]