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1
Fonseca, B. M., G. Correia-da-Silva, M. Almada, M. A. Costa, and N. A. Teixeira. "The Endocannabinoid System in the Postimplantation Period: A Role during Decidualization and Placentation." International Journal of Endocrinology 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/510540.
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Although the detrimental effects of cannabis consumption during gestation are known for years, the vast majority of studies established a link between cannabis consumption and foetal development. The complex maternal-foetal interrelationships within the placental bed are essential for normal pregnancy, and decidua definitively contributes to the success of this process. Nevertheless, the molecular signalling network that coordinates strategies for successful decidualization and placentation are not well understood. The discovery of the endocannabinoid system highlighted new signalling mediators in various physiological processes, including reproduction. It is known that endocannabinoids present regulatory functions during blastocyst development, oviductal transport, and implantation. In addition, all the endocannabinoid machinery was found to be expressed in decidual and placental tissues. Additionally, endocannabinoid’s plasmatic levels were found to fluctuate during normal gestation and to induce decidual cell death and disturb normal placental development. Moreover, aberrant endocannabinoid signalling during the period of placental development has been associated with pregnancy disorders. It indicates the existence of a possible regulatory role for these molecules during decidualization and placentation processes, which are known to be particularly vulnerable. In this review, the influence of the endocannabinoid system in these critical processes is explored and discussed.
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Lee, Yunna, Jeongbin Jo, Hae Young Chung, Charalabos Pothoulakis, and Eunok Im. "Endocannabinoids in the gastrointestinal tract." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 4 (October 1, 2016): G655—G666. http://dx.doi.org/10.1152/ajpgi.00294.2015.
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The endocannabinoid system mainly consists of endogenously produced cannabinoids (endocannabinoids) and two G protein-coupled receptors (GPCRs), cannabinoid receptors 1 and 2 (CB1 and CB2). This system also includes enzymes responsible for the synthesis and degradation of endocannabinoids and molecules required for the uptake and transport of endocannabinoids. In addition, endocannabinoid-related lipid mediators and other putative endocannabinoid receptors, such as transient receptor potential channels and other GPCRs, have been identified. Accumulating evidence indicates that the endocannabinoid system is a key modulator of gastrointestinal physiology, influencing satiety, emesis, immune function, mucosal integrity, motility, secretion, and visceral sensation. In light of therapeutic benefits of herbal and synthetic cannabinoids, the vast potential of the endocannabinoid system for the treatment of gastrointestinal diseases has been demonstrated. This review focuses on the role of the endocannabinoid system in gut homeostasis and in the pathogenesis of intestinal disorders associated with intestinal motility, inflammation, and cancer. Finally, links between gut microorganisms and the endocannabinoid system are briefly discussed.
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Suchopár, Josef, Zdeněk Laštůvka, Simona Mašková, Miroslava Alblová, and Antonín Pařízek. "Endocannabinoids." Česká gynekologie 86, no. 6 (December 21, 2021): 414–20. http://dx.doi.org/10.48095/cccg2021414.
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Objective: Overview of current knowledge in the field of the endocannabinoid system with emphasis on the relationships between endocannabinoids and exocannabinoids. The endocannabinoid system consists of cannabinoid receptors 1 and 2, ligands of these receptors, especially two "classical" endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoyl-glycerol. Transport systems that ensure the entry of endocannabinoids into cells, where they are degraded by fatty acid amide hydrolase or monoacylglycerol lipase. The endocannabinoid system is a signaling pathway for the regulation of a number of physiological or pathological conditions. So far, it is one of the less explored ways of regulation, as evidenced by the recent explosive increase in the number of published works. Dysregulation of endocannabinoid systems is a possible cause of many diseases. It can occur both in the genetic polymorphism of its individual components, but also in therapy with certain drugs or natural substances, typically cannabinoids. Due to the wide overlap of the regulation of physiological functions by the endocannabinoid system, a considerable number of drugs are being developed, the aim of which is to correct the dysregulation of the endocannabinoid system. Conclusion: The endocannabinoid system is one of the most important regulatory systems with a very broad intervention in physiological and pathological conditions. The resulting specific regulations intersect the interplay of many enzymes involved in the production and degradation of endocannabinoids, transport systems involved in the entry of endocannabinoids into cells, cannabinoid receptors and exogenous cannabinoids, or natural substances acting at various sites in the endocannabinoid system. Knowledge in this area can contribute to improving health care and increasing the safety of its provision. Key words: endocannabinoids – anandamide – 2-arachidoyl glycerol – cannabinoid receptor – fatty acid binding proteins – fatty acid amide hydrolases – lipase for monoacylglycerols – cannabinoids
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Ayakannu, Thangesweran, Anthony H. Taylor, Timothy H. Marczylo, Jonathon M. Willets, and Justin C. Konje. "The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers." International Journal of Endocrinology 2013 (2013): 1–14. http://dx.doi.org/10.1155/2013/259676.
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The “endocannabinoid system (ECS)” comprises the endocannabinoids, the enzymes that regulate their synthesis and degradation, the prototypical cannabinoid receptors (CB1 and CB2), some noncannabinoid receptors, and an, as yet, uncharacterised transport system. Recent evidence suggests that both cannabinoid receptors are present in sex steroid hormone-dependent cancer tissues and potentially play an important role in those malignancies. Sex steroid hormones regulate the endocannabinoid system and the endocannabinoids prevent tumour development through putative protective mechanisms that prevent cell growth and migration, suggesting an important role for endocannabinoids in the regulation of sex hormone-dependent tumours and metastasis. Here, the role of the endocannabinoid system in sex steroid hormone-dependent cancers is described and the potential for novel therapies assessed.
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Keereetaweep, Jantana, and Kent D. Chapman. "Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification." Neural Plasticity 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/2426398.
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The endocannabinoidsN-arachidonoylethanolamide (or anandamide, AEA) and 2-arachidonoylglycerol (2-AG) belong to the larger groups ofN-acylethanolamines (NAEs) and monoacylglycerol (MAG) lipid classes, respectively. They are biologically active lipid molecules that activate G-protein-coupled cannabinoid receptors found in various organisms. After AEA and 2-AG were discovered in the 1990s, they have been extensively documented to have a broad range of physiological functions. Along with AEA, several NAEs, for example,N-palmitoylethanolamine (PEA),N-stearoylethanolamine (SEA), andN-oleoylethanolamine (OEA) are also present in tissues, usually at much larger concentrations than AEA. Any perturbation that involves the endocannabinoid pathway may subsequently alter basal level or metabolism of these lipid mediators. Further, the altered levels of these molecules often reflect pathological conditions associated with tissue damage. Robust and sensitive methodologies to analyze these lipid mediators are essential to understanding how they act as endocannabinoids. The recent advances in mass spectrometry allow researchers to develop lipidomics approaches and several methodologies have been proposed to quantify endocannabinoids in various biological systems.
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Chan, Hsiu-Wen, Natalie C. McKirdy, Hassendrini N. Peiris, Gregory E. Rice, and Murray D. Mitchell. "The role of endocannabinoids in pregnancy." REPRODUCTION 146, no. 3 (September 2013): R101—R109. http://dx.doi.org/10.1530/rep-12-0508.
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Endocannabinoids are a family of lipid signalling molecules. As with prostaglandins (PGs), endocannabinoids are derived from polyunsaturated fatty acids and affect cell function via receptor-mediated mechanisms. They also bind to PG receptors, although at a lower affinity. The endocannabinoid network is regulated in pregnancy from embryo development to labour onset. Even small changes in endocannabinoid exposure can retard embryo development and affect implantation success. There is now compelling evidence that aberrant expression of factors involved in the endocannabinoid pathway in the placenta and circulating lymphocytes results in spontaneous miscarriage and poor pregnancy outcomes. It is likely that competition between endocannabinoids, PGs and other similar lipids ultimately determines how phospholipid/fatty acid substrates are metabolised and, thus, the balance between the uterotonic and tocolytic activities. We, therefore, hypothesise that endocannabinoid profiles may be used as a biomarker to predict and/or identify spontaneous labour onset.
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Friend, Lindsey, Ryan Williamson, Collin Merrill, Scott Newton, Michael Christensen, Jake Petersen, Bridget Wu, Isaac Ostlund, and Jeffrey Edwards. "Hippocampal Stratum Oriens Somatostatin-Positive Cells Undergo CB1-Dependent Long-Term Potentiation and Express Endocannabinoid Biosynthetic Enzymes." Molecules 24, no. 7 (April 3, 2019): 1306. http://dx.doi.org/10.3390/molecules24071306.
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The hippocampus is thought to encode information by altering synaptic strength via synaptic plasticity. Some forms of synaptic plasticity are induced by lipid-based endocannabinoid signaling molecules that act on cannabinoid receptors (CB1). Endocannabinoids modulate synaptic plasticity of hippocampal pyramidal cells and stratum radiatum interneurons; however, the role of endocannabinoids in mediating synaptic plasticity of stratum oriens interneurons is unclear. These feedback inhibitory interneurons exhibit presynaptic long-term potentiation (LTP), but the exact mechanism is not entirely understood. We examined whether oriens interneurons produce endocannabinoids, and whether endocannabinoids are involved in presynaptic LTP. Using patch-clamp electrodes to extract single cells, we analyzed the expression of endocannabinoid biosynthetic enzyme mRNA by reverse transcription and then real-time PCR (RT-PCR). The cellular expression of calcium-binding proteins and neuropeptides were used to identify interneuron subtype. RT-PCR results demonstrate that stratum oriens interneurons express mRNA for both endocannabinoid biosynthetic enzymes and the type I metabotropic glutamate receptors (mGluRs), necessary for endocannabinoid production. Immunohistochemical staining further confirmed the presence of diacylglycerol lipase alpha, an endocannabinoid-synthesizing enzyme, in oriens interneurons. To test the role of endocannabinoids in synaptic plasticity, we performed whole-cell experiments using high-frequency stimulation to induce long-term potentiation in somatostatin-positive cells. This plasticity was blocked by AM-251, demonstrating CB1-dependence. In addition, in the presence of a fatty acid amide hydrolase inhibitor (URB597; 1 µM) and MAG lipase inhibitor (JZL184; 1 µM) that increase endogenous anandamide and 2-arachidonyl glycerol, respectively, excitatory current responses were potentiated. URB597-induced potentiation was blocked by CB1 antagonist AM-251 (2 µM). Collectively, this suggests somatostatin-positive oriens interneuron LTP is CB1-dependent.
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Kano, Masanobu, Takako Ohno-Shosaku, Yuki Hashimotodani, Motokazu Uchigashima, and Masahiko Watanabe. "Endocannabinoid-Mediated Control of Synaptic Transmission." Physiological Reviews 89, no. 1 (January 2009): 309–80. http://dx.doi.org/10.1152/physrev.00019.2008.
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The discovery of cannabinoid receptors and subsequent identification of their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on cannabinoid actions in the brain. Then, the discovery in 2001 that endocannabinoids mediate retrograde synaptic signaling has opened up a new era for cannabinoid research and also established a new concept how diffusible messengers modulate synaptic efficacy and neural activity. The last 7 years have witnessed remarkable advances in our understanding of the endocannabinoid system. It is now well accepted that endocannabinoids are released from postsynaptic neurons, activate presynaptic cannabinoid CB1 receptors, and cause transient and long-lasting reduction of neurotransmitter release. In this review, we aim to integrate our current understanding of functions of the endocannabinoid system, especially focusing on the control of synaptic transmission in the brain. We summarize recent electrophysiological studies carried out on synapses of various brain regions and discuss how synaptic transmission is regulated by endocannabinoid signaling. Then we refer to recent anatomical studies on subcellular distribution of the molecules involved in endocannabinoid signaling and discuss how these signaling molecules are arranged around synapses. In addition, we make a brief overview of studies on cannabinoid receptors and their intracellular signaling, biochemical studies on endocannabinoid metabolism, and behavioral studies on the roles of the endocannabinoid system in various aspects of neural functions.
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Ehrenkranz, Joel, and Michael A. Levine. "Bones and Joints: The Effects of Cannabinoids on the Skeleton." Journal of Clinical Endocrinology & Metabolism 104, no. 10 (August 8, 2019): 4683–94. http://dx.doi.org/10.1210/jc.2019-00665.
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Abstract Context The endocannabinoid system uses tissue-specific lipid ligands and G protein‒coupled transmembrane receptors to regulate neurologic, metabolic, and immune responses. Recent studies demonstrate that the endocannabinoid system influences bone metabolism. With the increasing use of endocannabinoid mimetics (e.g., tetrahydrocannabinol and cannabidiol), the involvement of endocannabinoids in bone growth and remodeling has become clinically relevant. Evidence Acquisition This literature review is based on a search of PubMed and Google Scholar databases as of June 2019 for all English-language publications relating to cannabinoids and bone. We evaluated retrieved articles for relevance, experimental design, data acquisition, statistical analysis, and conclusions. Evidence Synthesis Preclinical studies establish a role for endocannabinoids in bone metabolism. These studies yield complex and often contradictory results attributed to differences in the specific experimental model examined. Studies using human cells or subjects are limited. Conclusions In vitro and animal models document that endocannabinoids are involved in bone biology. The relevance of these observations to humans is not clear. The increasing long-term use of medical and recreational cannabis underscores the need to better understand the role of endocannabinoids in human bone metabolism. Moreover, it is important to evaluate the role of endocannabinoids as a therapeutic target to prevent and treat disorders associated with bone loss.
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Wang, Yanqing, and Brian D. Burrell. "Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids." Journal of Neurophysiology 116, no. 2 (August 1, 2016): 619–28. http://dx.doi.org/10.1152/jn.00235.2016.
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Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl−gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana. Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl−export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmechneurons, which are depolarized by GABA due to an elevated Cl−equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl−import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npolyneurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl−import. Consequently, the primary role of elevated EClmay be to protect Npolysynapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npolysynapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmechsynapses. These findings demonstrate a critical role of differences in Cl−gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions.
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Connelly, William M., and Matthew J. Baggott. "Role of Endocannabinoids in 5-HT2 Receptor-Mediated Effects." Journal of Neurophysiology 101, no. 1 (January 2009): 5–7. http://dx.doi.org/10.1152/jn.91054.2008.
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Endocannabinoids are lipid retrograde messengers that can be released by postsynaptic depolarization and/or activation of certain metabotropic receptors. We review a recent report that activation of metabotropic 5-HT2 receptors by endogenous serotonin induces the release of endocannabinoids in the olivary nucleus and suppresses glutamatergic input through a presynaptic action. This serotonin–endocannabinoid interaction has implications in the pathophysiology of pain and mental illness and raises the possibility that drugs targeting the 5-HT2 receptor may act by modulating endocannabinoid release.
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Chicca, Andrea, Simon Nicolussi, Ruben Bartholomäus, Martina Blunder, Alejandro Aparisi Rey, Vanessa Petrucci, Ines del Carmen Reynoso-Moreno, et al. "Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake." Proceedings of the National Academy of Sciences 114, no. 25 (June 5, 2017): E5006—E5015. http://dx.doi.org/10.1073/pnas.1704065114.
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The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derivedN-substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC50= 10 nM) inhibitorN-(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.
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Pertwee, Roger G. "Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications." Proceedings of the Nutrition Society 73, no. 1 (October 18, 2013): 96–105. http://dx.doi.org/10.1017/s0029665113003649.
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The endocannabinoid system consists of cannabinoid CB1 and CB2 receptors, of endogenous agonists for these receptors known as ‘endocannabinoids’, and of processes responsible for endocannabinoid biosynthesis, cellular uptake and metabolism. There is strong evidence first, that this system up-regulates in certain disorders as indicated by an increased release of endocannabinoids onto their receptors and/or by increases in the expression levels or coupling efficiency of these receptors, and second, that this up-regulation often appears to reduce or abolish unwanted effects of these disorders or to slow their progression. This discovery has raised the possibility of developing a medicine that enhances up-regulation of the endocannabinoid system associated with these disorders by inhibiting the cellular uptake or intracellular metabolism of an endocannabinoid following its ‘autoprotective’ endogenous release. For inhibition of endocannabinoid metabolism, research has focused particularly on two highly investigated endocannabinoids, anandamide and 2-arachidonoyl glycerol, and hence on inhibitors of the main anandamide-metabolising enzyme, fatty acid amide hydrolase (FAAH), and of the main 2-arachidonoyl glycerol-metabolising enzyme, monoacylglycerol (MAG) lipase. The resulting data have provided strong preclinical evidence that selective FAAH and MAG lipase inhibitors would ameliorate the unwanted effects of several disorders, when administered alone or with a cyclooxygenase inhibitor, and that the benefit-to-risk ratio of a FAAH inhibitor would exceed that of a MAG lipase inhibitor or dual inhibitor of FAAH and MAG lipase. Promising preclinical data have also been obtained with inhibitors of endocannabinoid cellular uptake. There is now an urgent need for clinical research with these enzyme and uptake inhibitors.
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Malenczyk, Katarzyna, Erik Keimpema, Fabiana Piscitelli, Daniela Calvigioni, Peyman Björklund, Kenneth Mackie, Vincenzo Di Marzo, Tomas G. M. Hökfelt, Agnieszka Dobrzyn, and Tibor Harkany. "Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture." Proceedings of the National Academy of Sciences 112, no. 45 (October 22, 2015): E6185—E6194. http://dx.doi.org/10.1073/pnas.1519040112.
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Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB1 cannabinoid receptor (CB1R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB1Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB1R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB1R−/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.
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Behl, Tapan, Rashita Makkar, Aayush Sehgal, Sukhbir Singh, Hafiz A. Makeen, Mohammed Albratty, Hassan A. Alhazmi, Abdulkarim M. Meraya, and Simona Bungau. "Exploration of Multiverse Activities of Endocannabinoids in Biological Systems." International Journal of Molecular Sciences 23, no. 10 (May 20, 2022): 5734. http://dx.doi.org/10.3390/ijms23105734.
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Over the last 25 years, the human endocannabinoid system (ECS) has come into the limelight as an imperative neuro-modulatory system. It is mainly comprised of endogenous cannabinoid (endocannabinoid), cannabinoid receptors and the associated enzymes accountable for its synthesis and deterioration. The ECS plays a proven role in the management of several neurological, cardiovascular, immunological, and other relevant chronic conditions. Endocannabinoid or endogenous cannabinoid are endogenous lipid molecules which connect with cannabinoid receptors and impose a fashionable impact on the behavior and physiological processes of the individual. Arachidonoyl ethanolamide or Anandamide and 2-arachidonoyl glycerol or 2-AG were the endocannabinoid molecules that were first characterized and discovered. The presence of lipid membranes in the precursor molecules is the characteristic feature of endocannabinoids. The endocannabinoids are released upon rapid enzymatic reactions into the extracellular space via activation through G-protein coupled receptors, which is contradictory to other neurotransmitter that are synthesized beforehand, and stock up into the synaptic vesicles. The current review highlights the functioning, synthesis, and degradation of endocannabinoid, and explains its functioning in biological systems.
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Bhatia-Dey, Naina, and Thomas Heinbockel. "Endocannabinoid-Mediated Neuromodulation in the Olfactory Bulb: Functional and Therapeutic Significance." International Journal of Molecular Sciences 21, no. 8 (April 19, 2020): 2850. http://dx.doi.org/10.3390/ijms21082850.
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Endocannabinoid synthesis in the human body is naturally occurring and on-demand. It occurs in response to physiological and environmental stimuli, such as stress, anxiety, hunger, other factors negatively disrupting homeostasis, as well as the therapeutic use of the phytocannabinoid cannabidiol and recreational use of exogenous cannabis, which can lead to cannabis use disorder. Together with their specific receptors CB1R and CB2R, endocannabinoids are major components of endocannabinoid-mediated neuromodulation in a rapid and sustained manner. Extensive research on endocannabinoid function and expression includes studies in limbic system structures such as the hippocampus and amygdala. The wide distribution of endocannabinoids, their on-demand synthesis at widely different sites, their co-existence in specific regions of the body, their quantitative differences in tissue type, and different pathological conditions indicate their diverse biological functions that utilize specific and overlapping pathways in multiple organ systems. Here, we review emerging evidence of these pathways with a special emphasis on the role of endocannabinoids in decelerating neurodegenerative pathology through neural networks initiated by cells in the main olfactory bulb.
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Meccariello, Rosaria. "Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives." International Journal of Molecular Sciences 21, no. 10 (May 18, 2020): 3549. http://dx.doi.org/10.3390/ijms21103549.
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Kienzl, Melanie, Julia Kargl, and Rudolf Schicho. "The Immune Endocannabinoid System of the Tumor Microenvironment." International Journal of Molecular Sciences 21, no. 23 (November 25, 2020): 8929. http://dx.doi.org/10.3390/ijms21238929.
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Leukocytes are part of the tumor microenvironment (TME) and are critical determinants of tumor progression. Because of the immunoregulatory properties of cannabinoids, the endocannabinoid system (ECS) may have an important role in shaping the TME. Members of the ECS, an entity that consists of cannabinoid receptors, endocannabinoids and their synthesizing/degrading enzymes, have been associated with both tumor growth and rejection. Immune cells express cannabinoid receptors and produce endocannabinoids, thereby forming an “immune endocannabinoid system”. Although in vitro effects of exogenous cannabinoids on immune cells are well described, the role of the ECS in the TME, and hence in tumor development and immunotherapy, is still elusive. This review/opinion discusses the possibility that the “immune endocannabinoid system” can fundamentally influence tumor progression. The widespread influence of cannabinoids on immune cell functions makes the members of the ECS an interesting target that could support immunotherapy.
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Viveros, María-Paz, Eva-María Marco, Ricardo Llorente, and Meritxell López-Gallardo. "Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses." Neural Plasticity 2007 (2007): 1–12. http://dx.doi.org/10.1155/2007/52908.
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The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long- term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.
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Keimpema, Erik, Daniela Calvigioni, and Tibor Harkany. "Endocannabinoid signals in the developmental programming of delayed-onset neuropsychiatric and metabolic illnesses." Biochemical Society Transactions 41, no. 6 (November 20, 2013): 1569–76. http://dx.doi.org/10.1042/bst20130117.
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It is increasingly recognized that maternal exposure to metabolic (nutritional) stimuli, infections, illicit or prescription drugs and environmental stressors during pregnancy can predispose affected offspring to developing devastating postnatal illnesses. If detrimental maternal stimuli coincide with critical periods of tissue production and organogenesis then they can permanently derail key cellular differentiation programs. Maternal programming can thus either provoke developmental failure directly (‘direct hit’) or introduce latent developmental errors that enable otherwise sub-threshold secondary stressors to manifest as disease (‘double hit’) postnatally. Accumulating evidence suggests that nervous system development is tightly controlled by maternal metabolic stimuli, and whose synaptic wiring and integrative capacity are adversely affected by dietary and hormonal challenges, infections or episodes of illicit drug use. Endocannabinoids, a family of signal lipids derived from polyunsaturated fatty acids, have been implicated in neuronal fate determination, the control of axonal growth, synaptogenesis and synaptic neurotransmission. Therefore the continuum and interdependence of endocannabinoid actions during the formation and function of synapses together with dynamic changes in focal and circulating endocannabinoid levels upon maternal nutritional imbalance suggest that endocannabinoids can execute the ‘reprogramming’ of specific neuronal networks. In the present paper, we review molecular evidence suggesting that maternal nutrition and metabolism during pregnancy can affect the formation and function of the hippocampus and hypothalamus by altering endocannabinoid signalling such that neuropsychiatric diseases and obesity respectively ensue in affected offspring. Moreover, we propose that the placenta, fetal adipose and nervous tissues interact via endocannabinoid signals. Thus endocannabinoids are hypothesized to act as a molecular substrate of maternal programming.
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Sanson, Benoît, Tao Wang, Jing Sun, Liqun Wang, Martin Kaczocha, Iwao Ojima, Dale Deutsch, and Huilin Li. "Crystallographic study of FABP5 as an intracellular endocannabinoid transporter." Acta Crystallographica Section D Biological Crystallography 70, no. 2 (January 29, 2014): 290–98. http://dx.doi.org/10.1107/s1399004713026795.
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In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocketviahydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels.
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El Manira, A., and A. Kyriakatos. "The Role of Endocannabinoid Signaling in Motor Control." Physiology 25, no. 4 (August 2010): 230–38. http://dx.doi.org/10.1152/physiol.00007.2010.
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Cannabinoid receptors and endocannabinoid signaling are distributed throughout the rostrocaudal neuraxis. Retrograde signaling via endocannabinoid mediates synaptic plasticity in many regions in the central nervous system. Here, we review the role of endocannabinoid signaling in different parts of the vertebrate motor system from networks responsible for the execution of movement to planning centers in the basal ganglia and cortex. The ubiquity of endocannabinoid-mediated plasticity suggests that it plays an important role in producing motion from defined circuitries and also for reconfiguring networks to learn new motor skills. The long-term plasticity induced by endocannabinoids may provide a long-term buffer that stabilizes the organization of motor circuits and their activity.
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Kostrzewa, Magdalena, Ali Mokhtar Mahmoud, Roberta Verde, Federica Scotto di Carlo, Fernando Gianfrancesco, Fabiana Piscitelli, and Alessia Ligresti. "Modulation of Endocannabinoid Tone in Osteoblastic Differentiation of MC3T3-E1 Cells and in Mouse Bone Tissue over Time." Cells 10, no. 5 (May 14, 2021): 1199. http://dx.doi.org/10.3390/cells10051199.
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Bone is a highly complex and metabolically active tissue undergoing a continuous remodeling process, which endures throughout life. A complex cell-signaling system that plays role in regulating different physiological processes, including bone remodeling, is the endocannabinoid system (ECS). Bone mass expresses CB1 and CB2 cannabinoid receptors and enzymatic machinery responsible for the metabolism of their endogenous ligands, endocannabinoids (AEA and 2-AG). Exogenous AEA is reported to increase the early phase of human osteoblast differentiation in vitro. However, regarding this cell context little is known about how endocannabinoids and endocannabinoid-related N-acylethanolamines like PEA and OEA are modulated, in vitro, during cell differentiation and, in vivo, over time up to adulthood. Here we characterized the endocannabinoid tone during the different phases of the osteoblast differentiation process in MC3T3-E1 cells, and we measured endocannabinoid levels in mouse femurs at life cycle stages characterized by highly active bone growth (i.e., of juvenile, young adult, and mature adult bone). Endocannabinoid tone was significantly altered during osteoblast differentiation, with substantial OEA increment, decline in 2-AG and AEA, and consistent modulation of their metabolic enzymes in maturing and mineralized MC3T3-E1 cells. Similarly, in femurs, we found substantial, age-related, decline in 2-AG, OEA, and PEA. These findings can expand existing knowledge underlying physiological bone cell function and contribute to therapeutic strategies for preventing bone-related metabolic changes accruing through lifespan.
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Elphick, Maurice R. "The evolution and comparative neurobiology of endocannabinoid signalling." Philosophical Transactions of the Royal Society B: Biological Sciences 367, no. 1607 (December 5, 2012): 3201–15. http://dx.doi.org/10.1098/rstb.2011.0394.
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CB 1 - and CB 2 -type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB 1 -type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB 1 /CB 2 -type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB 1 /CB 2 -type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB 1 /CB 2 -type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB 1 /CB 2 -mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2-AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids.
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Matias, Isabel, Marie-Paule Gonthier, Pierangelo Orlando, Vassilis Martiadis, Luciano De Petrocellis, Cristina Cervino, Stefania Petrosino, et al. "Regulation, Function, and Dysregulation of Endocannabinoids in Models of Adipose and β-Pancreatic Cells and in Obesity and Hyperglycemia." Journal of Clinical Endocrinology & Metabolism 91, no. 8 (August 1, 2006): 3171–80. http://dx.doi.org/10.1210/jc.2005-2679.
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Abstract Context: Cannabinoid CB1 receptor blockade decreases weight and hyperinsulinemia in obese animals and humans in a way greatly independent from food intake. Objective: The objective of this study was to investigate the regulation and function of the endocannabinoid system in adipocytes and pancreatic β-cells. Design, Setting, and Patients: Mouse 3T3-F442A adipocytes and rat insulinoma RIN-m5F β-cells, pancreas and fat from mice with diet-induced obesity, visceral and sc fat from patients with body mass index equal to or greater than 30 kg/m2, and serum from normoglycemic and type 2 diabetes patients were studied. Main Outcome Measure: Endocannabinoid enzyme and adipocyte protein expression, and endocannabinoid and insulin levels were measured. Results: Endocannabinoids are present in adipocytes with levels peaking before differentiation, and in RIN-m5F β-cells, where they are under the negative control of insulin. Chronic treatment of adipocytes with insulin is accompanied by permanently elevated endocannabinoid signaling, whereas culturing of RIN-m5F β-cells in high glucose transforms insulin down-regulation of endocannabinoid levels into up-regulation. Epididymal fat and pancreas from mice with diet-induced obesity contain higher endocannabinoid levels than lean mice. Patients with obesity or hyperglycemia caused by type 2 diabetes exhibit higher concentrations of endocannabinoids in visceral fat or serum, respectively, than the corresponding controls. CB1 receptor stimulation increases lipid droplets and decreases adiponectin expression in adipocytes, and it increases intracellular calcium and insulin release in RIN-m5F β-cells kept in high glucose. Conclusions: Peripheral endocannabinoid overactivity might explain why CB1 blockers cause weight-loss independent reduction of lipogenesis, of hypoadiponectinemia, and of hyperinsulinemia in obese animals and humans.
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Bouchard, Jean-François, Christian Casanova, Bruno Cécyre, and William John Redmond. "Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain." Neural Plasticity 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/9247057.
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Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system. Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoringGi/oprotein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function. In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing. The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far. It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells. The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.
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Zhu, Ping Jun, and David M. Lovinger. "Persistent Synaptic Activity Produces Long-Lasting Enhancement of Endocannabinoid Modulation and Alters Long-Term Synaptic Plasticity." Journal of Neurophysiology 97, no. 6 (June 2007): 4386–89. http://dx.doi.org/10.1152/jn.01228.2006.
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Learning and memory are thought to involve activity-dependent changes in synaptic efficacy such as long-term potentiation (LTP) and long-term depression (LTD). Recent studies have indicated that endocannabinoid-dependent modulation of inhibitory transmission facilitates induction of hippocampal LTP and that endocannabinoids play a key role in certain forms of LTD. Here, we show that repetitive low-frequency synaptic stimulation (LFS) produces persistent up-regulation of endocannabinoid signaling at hippocampal CA1 GABAergic synapses. This LFS also produces LTD of inhibitory synapses and facilitates LTP at excitatory, glutamatergic synapses. These endocannabinoid-mediated plastic changes could contribute to information storage within the brain.
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Dey, Rafik, Pierre Pernin, and Jacques Bodennec. "Endocannabinoids Inhibit the Growth of Free-Living Amoebae." Antimicrobial Agents and Chemotherapy 54, no. 7 (May 17, 2010): 3065–67. http://dx.doi.org/10.1128/aac.01825-09.
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ABSTRACT The cannabinoid Δ9-tetrahydrocannabinol inhibits the growth of some pathogenic amoebae in vitro and exacerbates amoebic encephalitis in animal models. However, the effects of endogenous cannabinoids on amoebae remain unknown. Therefore, we tested several endocannabinoids (N-acyl ethanolamines and 2-O-acyl glycerol) on different genera of amoebae. The results showed that all of the endocannabinoids tested inhibit amoebic growth at subpharmacological doses, with 50% inhibitory concentrations ranging from 15 to 20 μM. A nonhydrolyzable endocannabinoid had similar effects, showing that the inhibition seen results from endocannabinoids per se rather than from a catabolic product.
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Hourani, Wafa, and Stephen P. H. Alexander. "Cannabinoid ligands, receptors and enzymes: Pharmacological tools and therapeutic potential." Brain and Neuroscience Advances 2 (January 2018): 239821281878390. http://dx.doi.org/10.1177/2398212818783908.
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Endocannabinoids have been identified to have roles in numerous physiological and pathological processes. Largely due to the association of the effects of Cannabis administration on mental states, the CNS impact of the endocannabinoid system has been the most intensively studied. Here, we provide a brief summary of the endocannabinoid system, comprising the receptors and the multiple endogenous lipid derivatives which activate them, as well as the enzymes which control the levels of these lipid derivatives. We identify pharmacological tools which may be used to interrogate the endocannabinoid system, as well as current and future options to exploit the system in the clinic.
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Fortin, Dale A., Joseph Trettel, and Eric S. Levine. "Brief Trains of Action Potentials Enhance Pyramidal Neuron Excitability Via Endocannabinoid-Mediated Suppression of Inhibition." Journal of Neurophysiology 92, no. 4 (October 2004): 2105–12. http://dx.doi.org/10.1152/jn.00351.2004.
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Depolarization-induced suppression of inhibition (DSI) is a form of retrograde signaling at GABAergic synapses that is initiated by the calcium- and depolarization-dependent release of endocannabinoids from postsynaptic neurons. In the neocortex, pyramidal neurons (PNs) appear to use DSI as a mechanism for regulating somatic inhibition from a subpopulation of GABAergic inputs that express the type 1 cannabinoid receptor. Although postsynaptic control of afferent inhibition may directly influence the integrative properties of neocortical PNs, little is known about the patterns of activity that evoke endocannabinoid release and the impact such disinhibition may have on the excitability of PNs. Here we provide the first systematic survey of action potential (AP)-induced DSI in the neocortex. The magnitude and time course of DSI was directly related to the number and frequency of postsynaptic APs with significant suppression induced by a 20-Hz train containing as few as three APs. This AP-induced DSI was mediated by endocannabinoids as it was prevented by the cannabinoid receptor antagonist AM251 and potentiated by the endocannabinoid transport inhibitor AM404. We also explored the effects of endocannabinoid-mediated DSI on PN excitability. We found that single AP trains markedly increased PN responsiveness to excitatory synaptic inputs and promoted AP discharge by suppressing GABAergic inhibition. The time course of this effect paralleled DSI expression and was completely blocked by AM251. Taken together, our data suggest a role for endocannabinoids in regulating the output of cortical PNs.
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McDougle, Daniel R., Josephine E. Watson, Amr A. Abdeen, Reheman Adili, Megan P. Caputo, John E. Krapf, Rodney W. Johnson, Kristopher A. Kilian, Michael Holinstat, and Aditi Das. "Anti-inflammatory ω-3 endocannabinoid epoxides." Proceedings of the National Academy of Sciences 114, no. 30 (July 7, 2017): E6034—E6043. http://dx.doi.org/10.1073/pnas.1610325114.
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Clinical studies suggest that diets rich in ω-3 polyunsaturated fatty acids (PUFAs) provide beneficial anti-inflammatory effects, in part through their conversion to bioactive metabolites. Here we report on the endogenous production of a previously unknown class of ω-3 PUFA–derived lipid metabolites that originate from the crosstalk between endocannabinoid and cytochrome P450 (CYP) epoxygenase metabolic pathways. The ω-3 endocannabinoid epoxides are derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to form epoxyeicosatetraenoic acid-ethanolamide (EEQ-EA) and epoxydocosapentaenoic acid-ethanolamide (EDP-EA), respectively. Both EEQ-EAs and EDP-EAs are endogenously present in rat brain and peripheral organs as determined via targeted lipidomics methods. These metabolites were directly produced by direct epoxygenation of the ω-3 endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) by activated BV-2 microglial cells, and by human CYP2J2. Neuroinflammation studies revealed that the terminal epoxides 17,18-EEQ-EA and 19,20-EDP-EA dose-dependently abated proinflammatory IL-6 cytokines while increasing anti-inflammatory IL-10 cytokines, in part through cannabinoid receptor-2 activation. Furthermore the ω-3 endocannabinoid epoxides 17,18-EEQ-EA and 19,20-EDP-EA exerted antiangiogenic effects in human microvascular endothelial cells (HMVEC) and vasodilatory actions on bovine coronary arteries and reciprocally regulated platelet aggregation in washed human platelets. Taken together, the ω-3 endocannabinoid epoxides’ physiological effects are mediated through both endocannabinoid and epoxyeicosanoid signaling pathways. In summary, the ω-3 endocannabinoid epoxides are found at concentrations comparable to those of other endocannabinoids and are expected to play critical roles during inflammation in vivo; thus their identification may aid in the development of therapeutics for neuroinflammatory and cerebrovascular diseases.
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Kasatkina, Ludmila A., Sonja Rittchen, and Eva M. Sturm. "Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation." International Journal of Molecular Sciences 22, no. 11 (May 21, 2021): 5431. http://dx.doi.org/10.3390/ijms22115431.
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Endocannabinoids (eCBs) are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB1/2, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines (NAEs), which together with N-acylneurotransmitters, lipoamino acids and primary fatty acid amides comprise expanded endocannabinoid/endovanilloid signaling systems. Most of these compounds do not bind CB1/2, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)-α and non-cannabinoid G-protein coupled receptors (GPRs) to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy.
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Sun, Hai-Jing, Yan Lu, Hao-Wei Wang, Hao Zhang, Shuang-Ran Wang, Wen-Yun Xu, Hai-Long Fu, Xue-Ya Yao, Feng Yang, and Hong-Bin Yuan. "Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–18. http://dx.doi.org/10.1155/2017/2186383.
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Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.
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Rakotoarivelo, Volatiana, Jyoti Sihag, and Nicolas Flamand. "Role of the Endocannabinoid System in the Adipose Tissue with Focus on Energy Metabolism." Cells 10, no. 6 (May 21, 2021): 1279. http://dx.doi.org/10.3390/cells10061279.
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The endocannabinoid system is involved in a wide range of processes including the control of energy acquisition and expenditure. Endocannabinoids and their receptors are present in the central nervous system but also in peripheral tissues, notably the adipose tissues. The endocannabinoid system interacts with two main hormones regulating appetite, namely leptin and ghrelin. The inhibitory effect of the cannabinoid receptor 1 (CB1) antagonist rimonabant on fat mass suggested that the endocannabinoid system can also have a peripheral action in addition to its effect on appetite reduction. Thus, several investigations have focused on the peripheral role of the endocannabinoid system in the regulation of metabolism. The white adipose tissue stores energy as triglycerides while the brown adipose tissue helps to dissipate energy as heat. The endocannabinoid system regulates several functions of the adipose tissues to favor energy accumulation. In this review we will describe the presence of the endocannabinoid system in the adipose tissue. We will survey the role of the endocannabinoid system in the regulation of white and brown adipose tissue metabolism and how the eCB system participates in obesity and metabolic diseases.
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Siegmund, Sören V., and Robert F. Schwabe. "Endocannabinoids and Liver Disease. II. Endocannabinoids in the pathogenesis and treatment of liver fibrosis." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 2 (February 2008): G357—G362. http://dx.doi.org/10.1152/ajpgi.00456.2007.
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Hepatic fibrosis is the response of the liver to chronic injury and is associated with portal hypertension, progression to hepatic cirrhosis, liver failure, and high incidence of hepatocellular carcinoma. On a molecular level, a large number of signaling pathways have been shown to contribute to the activation of fibrogenic cell types and the subsequent accumulation of extracellular matrix in the liver. Recent evidence suggests that the endocannabinoid system is an important part of this complex signaling network. In the injured liver, the endocannabinoid system is upregulated both at the level of endocannabinoids and at the endocannabinoid receptors CB1 and CB2. The hepatic endocannabinoid system mediates both pro- and antifibrogenic effects by activating distinct signaling pathways that differentially affect proliferation and death of fibrogenic cell types. Here we will summarize current findings on the role of the hepatic endocannabinoid system in liver fibrosis and discuss emerging options for its therapeutic exploitation.
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Schelling, Gustav, Daniela Hauer, Shahnaz Christina Azad, Martin Schmoelz, Alexander Chouker, Michael Schmidt, Cyrill Hornuss, et al. "Effects of General Anesthesia on Anandamide Blood Levels in Humans." Anesthesiology 104, no. 2 (February 1, 2006): 273–77. http://dx.doi.org/10.1097/00000542-200602000-00012.
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Background The endocannabinoid system includes G-protein-coupled cannabinoid receptors, the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and multiple enzymes involved in the biosynthesis and degradation of endocannabinoids, including the anandamide metabolizing enzyme fatty acid amide hydrolase. Endocannabinoids play an important role in the physiologic control of sleep, pain processing, and emesis. The authors therefore investigated the effects of general anesthesia on the endocannabinoid system in humans. Methods The authors measured whole blood levels of anandamide in 12 patients after induction of general anesthesia with etomidate (an agent shown to have no effect on anandamide levels) and maintenance of anesthesia with the volatile agent sevoflurane as well as in 12 patients undergoing total intravenous anesthesia with propofol, a known inhibitor of fatty acid amide hydrolase in the mouse brain. Anandamide levels were measured using high-performance liquid chromatography-tandem mass spectrometry at four time points (before and at 10, 20, 30, and 40 min after induction of anesthesia). Results Patients of the sevoflurane group showed a significant decline in anandamide levels from induction of anesthesia to 40 min after induction, whereas anandamide levels in patients of the propofol group remained unchanged (type III sum of squares = 1725.66, F = 162.60, P < 0.001, repeated-measures analysis of variance). Conclusion General anesthesia influences the endocannabinoid system in a drug-dependent way, which may explain side effects of general anesthetics such as psychomimetic and antiemetic properties of propofol and the high incidence of postoperative nausea and vomiting after volatile anesthetics. These findings suggest new targets for anesthetic drug development.
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Viggiano, D., L. A. Ruocco, M. Pignatelli, G. Grammatikopoulos, and A. G. Sadile. "Prenatal elevation of endocannabinois corrects the unbalance between dopamine systems and reduces activity in the Naples High Excitability rats." Neuroscience & Biobehavioral Reviews 27, no. 1-2 (January 2003): 129–39. http://dx.doi.org/10.1016/s0149-7634(03)00015-0.
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Fonseca, B. M., G. Correia-da-Silva, A. H. Taylor, P. M. W. Lam, T. H. Marczylo, J. C. Konje, S. C. Bell, and N. A. Teixeira. "N-Acylethanolamine Levels and Expression of Their Metabolizing Enzymes during Pregnancy." Endocrinology 151, no. 8 (June 9, 2010): 3965–74. http://dx.doi.org/10.1210/en.2009-1424.
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Decidualization is essential for a successful pregnancy and is a tightly regulated process influenced by the local microenvironment. Lipid-based mediators, such as the endocannabinoid anandamide, and other compounds that have cannabimimetic actions may act on the decidua during early pregnancy. In this study, the levels of N-arachidonoylethanolamine (anandamide) and two other N-acylethanolamines, N-oleoylethanolamine and N-palmitoylethanolamine, were measured in rat plasma and maternal tissues between d 8 and 19 of pregnancy by ultraperformance liquid chromatography tandem mass spectrometry. The spatiotemporal expression of N-acylethanolamine metabolizing enzymes in implantation units were also determined by quantitative PCR, Western blot, and immunohistochemistry and shown to vary with gestation being mainly localized in decidual cells. The data also indicated that plasma and tissues levels of all three N-acylethanolamines fluctuate throughout pregnancy. Tissue levels of endocannabinoids did not correlate with plasma, suggesting that during pregnancy, maternal tissue levels of endocannabinoids are primarily regulated by in situ production and degradation to create endocannabinoid gradients conducive to successful pregnancy.
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Forteza, Fabiola, Giada Giorgini, and Frédéric Raymond. "Neurobiological Processes Induced by Aerobic Exercise through the Endocannabinoidome." Cells 10, no. 4 (April 17, 2021): 938. http://dx.doi.org/10.3390/cells10040938.
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Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this relationship. The eCBome includes several endocannabinoid-like mediators such as N-acylethanolamines and 2-monoacylglycerols, the enzymes involved in their biosynthesis and degradation, and the receptors they affect. This review aims to relate the functional interactions between aerobic exercise, and the molecular and cellular pathways related to endocannabinoids, in the hypothalamus, hippocampus, and the periphery, with special attention given to associations with emotional state, cognition, and mental health. Given the well-documented roles of many eCBome members in regulating stress and neurological processes, we posit that the eCBome is an important effector of exercise-induced central and peripheral adaptive mechanisms that benefit mental health. Gut microbiota imbalance, affecting the gut-brain axis and metabolism, also influences certain eCBome-modulated inflammation pathways. The integrity of the gut microbiota could thus be crucial in the onset of neuroinflammation and mental conditions. Further studies on how the modulation by exercise of the peripheral eCBome affects brain functions could reveal to be key elements in the prevention and treatment of neuropsychological disorders.
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Cascio, Maria Grazia. "PUFA-derived endocannabinoids: an overview." Proceedings of the Nutrition Society 72, no. 4 (September 11, 2013): 451–59. http://dx.doi.org/10.1017/s0029665113003418.
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Following on from the discovery of cannabinoid receptors, of their endogenous agonists (endocannabinoids) and of the biosynthetic and metabolic enzymes of the endocannabinoids, significant progress has been made towards the understanding of the role of the endocannabinoid system in both physiological and pathological conditions. Endocannabinoids are mainly n-6 long-chain PUFA (LCPUFA) derivatives that are synthesised by neuronal cells and inactivated via a two-step process that begins with their transport from the extracellular to the intracellular space and culminates in their intracellular degradation by hydrolysis or oxidation. Although the enzymes responsible for the biosynthesis and metabolism of endocannabinoids have been well characterised, the processes involved in their cellular uptake are still a subject of debate. Moreover, little is yet known about the roles of endocannabinoids derived from n-3 LCPUFA such as EPA and DHA. Here, I provide an overview of what is currently known about the mechanisms for the biosynthesis and inactivation of endocannabinoids, together with a brief analysis of the involvement of the endocannabinoids in both food intake and obesity. Owing to limited space, recent reviews will be often cited instead of original papers.
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Di Blasio, Anna Maria, Michele Vignali, and Davide Gentilini. "The endocannabinoid pathway and the female reproductive organs." Journal of Molecular Endocrinology 50, no. 1 (November 23, 2012): R1—R9. http://dx.doi.org/10.1530/jme-12-0182.
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Endocannabinoids are endogenous ligands of cannabinoid, vanilloid and peroxisome proliferator-activated receptors that activate multiple signal transduction pathways. Together with their receptor and the enzymes responsible for their synthesis and degradation, these compounds constitute the endocannabinoid system that has been recently shown to play, in humans, an important role in modulating several central and peripheral functions including reproduction. Given the relevance of the system, drugs that are able to interfere with the activity of endocannabinoids are currently considered as candidates for the treatment of various diseases. In this review, we will summarise the current knowledge regarding the effects of endocannabinoids in female reproductive organs. In particular, we will focus on some newly reported mechanisms that can affect endometrial plasticity both in physiological and in pathological conditions.
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Zueva, I., K. I. Vanaeva, and E. V. Shlyakhto. "The cognitive dysfunction in patients with obesity. Role of the endocannabinoids." "Arterial’naya Gipertenziya" ("Arterial Hypertension") 18, no. 2 (April 28, 2012): 126–35. http://dx.doi.org/10.18705/1607-419x-2012-18-2-126-135.
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The endocannabinoid system plays an important role in different physiological processes including memory and learning. Its activation can affect cognitive function and cause cognitive deficit in obese patients. Objective. To assess the association between cognitive function and activity of the endocannabinoid system in obese patients. Design and methods. 32 subjects (18 females and 14 males) aged 35-55 years old (mean age — 47,8 ± 2,3 years) were included in the study. All participants underwent neuropsychological testing, assessment of cognitive evoked potentials and plasma level of the endocannabinoids. Results. Our study showed that obese patients demonstrate cognitive dysfunction. Cognitive evoked potential is an objective and early sing of cognitive dysfunction. Activation of the endocannabinoid system is associated with cognitive deficit in obese patients.
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Pagotto, Uberto, Giovanni Marsicano, Daniela Cota, Beat Lutz, and Renato Pasquali. "The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance." Endocrine Reviews 27, no. 1 (November 23, 2005): 73–100. http://dx.doi.org/10.1210/er.2005-0009.
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During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.
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Fride, Ester, Tatyana Bregman, and Tim C. Kirkham. "Endocannabinoids and Food Intake: Newborn Suckling and Appetite Regulation in Adulthood." Experimental Biology and Medicine 230, no. 4 (April 2005): 225–34. http://dx.doi.org/10.1177/153537020523000401.
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The appetite-stimulating effects of the cannabis plant (Cannabis sativa) have been known since ancient times, and appear to be effected through the incentive and rewarding properties of foods. Investigations into the biological basis of the multiple effects of cannabis have yielded important breakthroughs in recent years: the discovery of two cannabinoid receptors in brain and peripheral organ systems, and endogenous ligands (endocannabinoids) for these receptors. These advances have greatly increased our understanding of how appetite is regulated through these endocannabinoid receptor systems. The presence of endocannabinoids in the developing brain and in maternal milk have led to evidence for a critical role for CB, receptors in oral motor control of suckling during neonatal development. The endocannabinoids appear to regulate energy balance and food intake at four functional levels within the brain and periphery: (i) limbic system (for hedonic evaluation of foods), (ii) hypothalamus and hindbrain (integrative functions), (iii) intestinal system, and (iv) adipose tissue. At each of these levels, the endocannabinoid system interacts with a number of better known molecules involved in appetite and weight regulation, including leptin, ghrelin, and the melanocortins. Therapeutically, appetite stimulation by cannabinoids has been studied for several decades, particularly in relation to cachexia and malnutrition associated with cancer, acquired immunodeficiency syndrome, or anorexia nervosa. The recent advances in cannabinoid pharmacology may lead to improved treatments for these conditions or, conversely, for combating excessive appetite and body weight, such as CB, receptor antagonists as antiobesity medications. In conclusion, the exciting progress in the understanding of how the endocannabinoid CB receptor systems influence appetite and body weight is stimulating the development of therapeutic orexigenic and anorectic agents. Furthermore, the role of cannabinoid CB, receptor activation for milk suckling in newborns may open new doors toward understanding nonorganic failure-to-thrive in infants, who display growth failure without known organic cause.
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Angyal, Ágnes, Zsófia Pénzes, Shahrzad Alimohammadi, Dorottya Horváth, Lili Takács, György Vereb, Barbara Zsebik, et al. "Anandamide Concentration-Dependently Modulates Toll-Like Receptor 3 Agonism or UVB-Induced Inflammatory Response of Human Corneal Epithelial Cells." International Journal of Molecular Sciences 22, no. 15 (July 21, 2021): 7776. http://dx.doi.org/10.3390/ijms22157776.
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Photodamage-induced and viral keratitis could benefit from treatment with novel nonsteroid anti-inflammatory agents. Therefore, we determined whether human corneal epithelial cells (HCECs) express members of the endocannabinoid system (ECS), and examined how the endocannabinoid anandamide (AEA, N-arachidonoyl ethanolamine) influences the Toll-like receptor 3 (TLR3) agonism- or UVB irradiation-induced inflammatory response of these cells. Other than confirming the presence of cannabinoid receptors, we show that endocannabinoid synthesizing and catabolizing enzymes are also expressed in HCECs in vitro, as well as in the epithelial layer of the human cornea in situ, proving that they are one possible source of endocannabinoids. p(I:C) and UVB irradiation was effective in promoting the transcription and secretion of inflammatory cytokines. Surprisingly, when applied alone in 100 nM and 10 μM, AEA also resulted in increased pro-inflammatory cytokine production. Importantly, AEA further increased levels of these cytokines in the UVB model, whereas its lower concentration partially prevented the transcriptional effect of p(I:C), while not decreasing the p(I:C)-induced cytokine release. HCECs express the enzymatic machinery required to produce endocannabinoids both in vitro and in situ. Moreover, our data show that, despite earlier reports about the anti-inflammatory potential of AEA in murine cornea, its effects on the immune phenotype of human corneal epithelium may be more complex and context dependent.
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Kilaru, Aruna, and Kent D. Chapman. "The endocannabinoid system." Essays in Biochemistry 64, no. 3 (July 10, 2020): 485–99. http://dx.doi.org/10.1042/ebc20190086.
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Abstract Thirty years ago, the discovery of a cannabinoid (CB) receptor that interacts with the psychoactive compound in Cannabis led to the identification of anandamide, an endogenous receptor ligand or endocannabinoid. Research on endocannabinoids has since exploded, and additional receptors along with their lipid mediators and signaling pathways continue to be revealed. Specifically, in humans, the release of endocannabinoids from membrane lipids occurs on demand and the signaling process is rapidly attenuated by the breakdown of the ligand suggesting a tight regulation of the endocannabinoid system (ECS). Additionally, the varying distribution of CB receptors between the central nervous system and other tissues allows for the ECS to participate in a wide range of cognitive and physiological processes. Select plant-derived ‘phyto’cannabinoids such as Δ-9-tetrahydrocannabinol (Δ9-THC) bind to the CB receptors and trigger the ECS, and in the case of Δ9-THC, while it has therapeutic value, can also produce detrimental effects. Current research is aimed at the identification of additional phytocannabinoids with minimal psychotropic effects with potential for therapeutic development. Although decades of research on the ECS and its components have expanded our understanding of the mechanisms and implications of endocannabinoid signaling in mammals, it continues to evolve. Here, we provide a brief overview of the ECS and its overlap with other related lipid-mediated signaling pathways.
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Kunos, George, and Douglas Osei-Hyiaman. "Endocannabinoids and Liver Disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 5 (May 2008): G1101—G1104. http://dx.doi.org/10.1152/ajpgi.00057.2008.
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Endocannabinoids are endogenous lipid mediators that interact with the same receptors as plant-derived cannabinoids to produce similar biological effects. The well-known appetitive effect of smoking marijuana has prompted inquiries into the possible role of endocannabinoids in the control of food intake and body weight. This brief review surveys recent evidence that endocannabinoids and their receptors are involved at multiple levels in the control of energy homeostasis. Endocannabinoids are orexigenic mediators and are part of the leptin-regulated central neural circuitry that controls energy intake. In addition, they act at multiple peripheral sites including adipose tissue, liver, and skeletal muscle to promote lipogenesis and limit fat elimination. Their complex actions could be viewed as anabolic, increasing energy intake and storage and decreasing energy expenditure, as components of an evolutionarily conserved system that has insured survival under conditions of starvation. In the era of plentiful food and limited physical activity, pharmacological inhibition of endocannabinoid activity offers benefits in the treatment of obesity and its hormonal/metabolic consequences.
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Khavandi, Marzie, Praveen P. N. Rao, and Michael A. Beazely. "Differential Effects of Endocannabinoids on Amyloid-Beta Aggregation and Toxicity." International Journal of Molecular Sciences 24, no. 2 (January 4, 2023): 911. http://dx.doi.org/10.3390/ijms24020911.
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The regulation and metabolism of the endocannabinoid system has received extensive attention for their potential neuroprotective effect in neurodegenerative diseases such as Alzheimer’s disease (AD), which is characterized by amyloid β (Aβ) -induced cell toxicity, inflammation, and oxidative stress. Using in vitro techniques and two cell lines, the mouse hippocampus-derived HT22 cells and Chinese hamster ovary (CHO) cells expressing human cannabinoid receptor type 1 (CB1), we investigated the ability of endocannabinoids to inhibit Aβ aggregation and protect cells against Aβ toxicity. The present study provides evidence that endocannabinoids N-arachidonoyl ethanol amide (AEA), noladin and O-arachidonoyl ethanolamine (OAE) inhibit Aβ42 aggregation. They were able to provide protection against Aβ42 induced cytotoxicity via receptor-mediated and non-receptor-mediated mechanisms in CB1-CHO and HT22 cells, respectively. The aggregation kinetic experiments demonstrate the anti-Aβ aggregation activity of some endocannabinoids (AEA, noladin). These data demonstrate the potential role and application of endocannabinoids in AD pathology and treatment.
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Maia, J., BM Fonseca, N. Teixeira, and G. Correia-da-Silva. "The fundamental role of the endocannabinoid system in endometrium and placenta: implications in pathophysiological aspects of uterine and pregnancy disorders." Human Reproduction Update 26, no. 4 (April 29, 2020): 586–602. http://dx.doi.org/10.1093/humupd/dmaa005.
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Abstract BACKGROUND The endocannabinoid system (ECS) consists of the cannabinoid receptors CB1 and CB2, the main endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their metabolic enzymes N-acylphosphatidylethanolamine-specific phospholipase D, fatty acid amide hydrolase, diacylglycerol lipase and monoacylglycerol lipase. This system is involved in the modulation of essential physiological processes. Its role in the reproductive system has become significantly important in recent years, given its major role in events such as gametogenesis, decidualisation, implantation and placentation. OBJECTIVE AND RATIONALE In this paper, we review the literature and summarize the role of the ECS elements in reproduction and their potential as early markers for diagnosis of reproductive disorders or as pharmacological targets for treatment. SEARCH METHODS Original research and review papers published from 1964 to June 2019 were selected in terms of relevance, reliability and quality by searching PubMed, MEDLINE and Web of Science, using the following search terms: endocannabinoid system and endometriosis; endocannabinoid system and ectopic pregnancy; endocannabinoid system and miscarriage; endocannabinoid system and pre-eclampsia; endocannabinoid system and endometrial cancer; endocannabinoid system and reproduction; endocannabinoid, endometrium; placenta; N-acylethanolamines; anandamide; 2-arachidonoylglycerol; and cannabinoids. OUTCOMES This review demonstrates relevant information concerning ECS alterations in endometriosis, ectopic pregnancy, miscarriage, pre-eclampsia and endometrial cancer. We highlight the importance of the endocannabinoids in endometrial and placental physiology and pathophysiology, from studies in vitro and in vivo and in clinical observations. The most studied of the endogenous cannabinoids is AEA. The levels of AEA were increased in plasma of patients with endometriosis and miscarriage, as well as in the fallopian tube of women with ectopic pregnancy and in endometrial biopsies of endometrial cancer. Changes in the pattern of expression of the cannabinoid receptor CB1 were also observed in endometrial biopsies of endometriosis, fallopian tube and decidua of patients with ectopic pregnancy and pre-eclamptic placenta. Moreover, alterations in CB2 expression have been reported in association with endometrial cancer. In general, studies on the cannabinoid signalling through CB2 and on the biological activities of the other major endocannabinoid, namely 2-AG, as well as its metabolic enzymes are scarce and avidly required. WIDER IMPLICATIONS The pathophysiological mechanisms involved in the described endometrial and placental pathologies are still unclear and lack the means for an early diagnosis. Based on current evidence, though alterations in ECS are demonstrated at tissue level, it is difficult to associate plasmatic changes in AEA with specific endometrial and placental diseases. Thus, pairing alterations in AEA levels with 2-AG and/or other endocannabinoid-like molecules may provide more accurate and early diagnoses. In addition, patients may benefit from new therapies that target the ECS and endocannabinoid signalling.
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Guha, Sujay, Serafina Calarco, M. Salomé Gachet, and Jürg Gertsch. "Juniperonic Acid Biosynthesis is Essential in Caenorhabditis elegans Lacking Δ6 Desaturase (fat-3) and Generates New ω-3 Endocannabinoids." Cells 9, no. 9 (September 19, 2020): 2127. http://dx.doi.org/10.3390/cells9092127.
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In eukaryotes, the C20:4 polyunsaturated fatty acid arachidonic acid (AA) plays important roles as a phospholipid component, signaling molecule and precursor of the endocannabinoid-prostanoid axis. Accordingly, the absence of AA causes detrimental effects. Here, compensatory mechanisms involved in AA deficiency in Caenorhabditis elegans were investigated. We show that the ω-3 C20:4 polyunsaturated fatty acid juniperonic acid (JuA) is generated in the C. elegans fat-3(wa22) mutant, which lacks Δ6 desaturase activity and cannot generate AA and ω-3 AA. JuA partially rescued the loss of function of AA in growth and development. Additionally, we observed that supplementation of AA and ω-3 AA modulates lifespan of fat-3(wa22) mutants. We described a feasible biosynthetic pathway that leads to the generation of JuA from α-linoleic acid (ALA) via elongases ELO-1/2 and Δ5 desaturase which is rate-limiting. Employing liquid chromatography mass spectrometry (LC-MS/MS), we identified endocannabinoid-like ethanolamine and glycerol derivatives of JuA and ω-3 AA. Like classical endocannabinoids, these lipids exhibited binding interactions with NPR-32, a G protein coupled receptor (GPCR) shown to act as endocannabinoid receptor in C. elegans. Our study suggests that the eicosatetraenoic acids AA, ω-3 AA and JuA share similar biological functions. This biosynthetic plasticity of eicosatetraenoic acids observed in C. elegans uncovers a possible biological role of JuA and associated ω-3 endocannabinoids in Δ6 desaturase deficiencies, highlighting the importance of ALA.