The endocannabinoid system

2020 ◽  
Vol 64 (3) ◽  
pp. 485-499
Author(s):  
Aruna Kilaru ◽  
Kent D. Chapman
Keyword(s):  
Signaling Pathways ◽  
Membrane Lipids ◽  
Endocannabinoid System ◽  
Physiological Processes ◽  
Therapeutic Value ◽  
Wide Range ◽  
Therapeutic Development ◽  
The Central Nervous System ◽  
Psychotropic Effects ◽  
Signaling Process

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.

scholarly journals Drugs modulating the L-arginine:NO:cGMP pathway – current use in therapy

2016 ◽  
Vol 29 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Magdalena Polakowska ◽  
Jolanta Orzelska-Gorka ◽  
Sylwia Talarek
Keyword(s):  
Nitric Oxide ◽  
Central Nervous System ◽  
Nervous System ◽  
Cardiovascular Diseases ◽  
Significant Role ◽  
Current Understanding ◽  
Physiological Processes ◽  
Wide Range ◽  
The Central Nervous System ◽  
Pharmacological Profiles

AbstractNitric oxide (NO) is a relatively novel messenger that plays a significant role in a wide range of physiological processes. Currently, it is known that, both, lack and excess of NO can cause diseases, thus a lot of substances have been discovered and utilized which can change the concentration of this molecule within the organism. The aim of the present work is to provide an overview of currently used agents modulating the L-arginine:NO:cGMP pathway, as well as to summarize current understanding of their pharmacological profiles. Nowadays, most of these agents are employed particularly in the treatment of cardiovascular diseases. Further studies can hold promise for enhancing the therapeutic equipment for a variety of other impairments, such as osteoporosis, and also in treatments of the central nervous system.

scholarly journals Systems-level neurophysiological state characteristics for drug evaluation in an animal model of levodopa-induced dyskinesia

2016 ◽  
Vol 115 (3) ◽  
pp. 1713-1729 ◽  
Author(s):  
Martin Tamtè ◽  
Ivani Brys ◽  
Ulrike Richter ◽  
Nedjeljka Ivica ◽  
Pär Halje ◽  
...  
Keyword(s):  
Large Scale ◽  
Drug Evaluation ◽  
Brain Structures ◽  
Significant Information ◽  
Animal Models Of Disease ◽  
Physiological Processes ◽  
Wide Range ◽  
The Central Nervous System ◽  
Neurophysiological Mechanisms ◽  
Models Of Disease

Disorders affecting the central nervous system have proven particularly hard to treat, and disappointingly few novel therapies have reached the clinics in recent decades. A better understanding of the physiological processes in the brain underlying various symptoms could therefore greatly improve the rate of progress in this field. We here show how systems-level descriptions of different brain states reliably can be obtained through a newly developed method based on large-scale recordings in distributed neural networks encompassing several different brain structures. Using this technology, we characterize the neurophysiological states associated with parkinsonism and levodopa-induced dyskinesia in a rodent model of Parkinson's disease together with pharmacological interventions aimed at reducing dyskinetic symptoms. Our results show that the obtained electrophysiological data add significant information to conventional behavioral evaluations and hereby elucidate the underlying effects of treatments in greater detail. Taken together, these results potentially open up for studies of neurophysiological mechanisms underlying symptoms in a wide range of neurological and psychiatric conditions that until now have been very hard to investigate in animal models of disease.

scholarly journals Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 918 ◽  
Author(s):  
Kinga Tóth ◽  
Dorottya Ádám ◽  
Tamás Bíró ◽  
Attila Oláh
Keyword(s):  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
The Body ◽  
Future Research ◽  
Research Directions ◽  
Physiological Processes ◽  
Barrier Formation ◽  
The Central Nervous System ◽  
Future Research Directions ◽  
Pigmentation Disorders

The endocannabinoid system (ECS) has lately been proven to be an important, multifaceted homeostatic regulator, which influences a wide-variety of physiological processes all over the body. Its members, the endocannabinoids (eCBs; e.g., anandamide), the eCB-responsive receptors (e.g., CB1, CB2), as well as the complex enzyme and transporter apparatus involved in the metabolism of the ligands were shown to be expressed in several tissues, including the skin. Although the best studied functions over the ECS are related to the central nervous system and to immune processes, experimental efforts over the last two decades have unambiguously confirmed that cutaneous cannabinoid (“c[ut]annabinoid”) signaling is deeply involved in the maintenance of skin homeostasis, barrier formation and regeneration, and its dysregulation was implicated to contribute to several highly prevalent diseases and disorders, e.g., atopic dermatitis, psoriasis, scleroderma, acne, hair growth and pigmentation disorders, keratin diseases, various tumors, and itch. The current review aims to give an overview of the available skin-relevant endo- and phytocannabinoid literature with a special emphasis on the putative translational potential, and to highlight promising future research directions as well as existing challenges.

scholarly journals Novel Ex Vivo Zymography Approach for Assessment of Protease Activity in Tissues with Activatable Antibodies

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1390
Author(s):  
Bruce Howng ◽  
Michael B. Winter ◽  
Carol LePage ◽  
Irina Popova ◽  
Michael Krimm ◽  
...  
Keyword(s):  
Protease Activity ◽  
Ex Vivo ◽  
Human Tumor ◽  
Cancer Therapeutics ◽  
Biological Tissues ◽  
Clinical Samples ◽  
Reliable Technique ◽  
Physiological Processes ◽  
Wide Range ◽  
Therapeutic Development

Proteases are involved in the control of numerous physiological processes, and their dysregulation has been identified in a wide range of pathologies, including cancer. Protease activity is normally tightly regulated post-translationally and therefore cannot be accurately estimated based on mRNA or protein expression alone. While several types of zymography approaches to estimate protease activity exist, there remains a need for a robust and reliable technique to measure protease activity in biological tissues. We present a novel quantitative ex vivo zymography (QZ) technology based on Probody® therapeutics (Pb-Tx), a novel class of protease-activated cancer therapeutics that contain a substrate linker cleavable by tumor-associated proteases. This approach enables the measurement and comparison of protease activity in biological tissues via the detection of Pb-Tx activation. By exploiting substrate specificity and selectivity, cataloguing and differentiating protease activities is possible, with further refinement achieved using protease-specific inhibitors. Using the QZ assay and human tumor xenografts, patient tumor tissues, and patient plasma, we characterized protease activity in preclinical and clinical samples. The QZ assay offers the potential to increase our understanding of protease activity in tissues and inform diagnostic and therapeutic development for diseases, such as cancer, that are characterized by dysregulated proteolysis.

scholarly journals Lipid Signaling in Ocular Neovascularization

2020 ◽  
Vol 21 (13) ◽  
pp. 4758 ◽  
Author(s):  
Ryo Terao ◽  
Hiroki Kaneko
Keyword(s):  
Signaling Pathways ◽  
Membrane Lipids ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Vascular Diseases ◽  
Corneal Neovascularization ◽  
Lipid Mediators ◽  
Lipid Signaling ◽  
Ocular Neovascularization ◽  
Wide Range

Vasculogenesis and angiogenesis play a crucial role in embryonic development. Pathological neovascularization in ocular tissues can lead to vision-threatening vascular diseases, including proliferative diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, choroidal neovascularization, and corneal neovascularization. Neovascularization involves various cellular processes and signaling pathways and is regulated by angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF). Modulating these circuits may represent a promising strategy to treat ocular neovascular diseases. Lipid mediators derived from membrane lipids are abundantly present in most tissues and exert a wide range of biological functions by regulating various signaling pathways. In particular, glycerophospholipids, sphingolipids, and polyunsaturated fatty acids exert potent pro-angiogenic or anti-angiogenic effects, according to the findings of numerous preclinical and clinical studies. In this review, we summarize the current knowledge regarding the regulation of ocular neovascularization by lipid mediators and their metabolites. A better understanding of the effects of lipid signaling in neovascularization may provide novel therapeutic strategies to treat ocular neovascular diseases and other human disorders.

scholarly journals Glutamate-Gated NMDA Receptors: Insights into the Function and Signaling in the Kidney

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1051
Author(s):  
José M. Valdivielso ◽  
Àuria Eritja ◽  
Maite Caus ◽  
Milica Bozic
Keyword(s):  
Signaling Pathways ◽  
Current Knowledge ◽  
Receptor Activation ◽  
Whole Body ◽  
Ionotropic Receptor ◽  
Glomerular Function ◽  
Endocrine Organ ◽  
Downstream Signaling ◽  
Wide Range ◽  
The Central Nervous System

N-Methyl-d-aspartate receptor (NMDAR) is a glutamate-gated ionotropic receptor that intervenes in most of the excitatory synaptic transmission within the central nervous system (CNS). Aside from being broadly distributed in the CNS and having indispensable functions in the brain, NMDAR has predominant roles in many physiological and pathological processes in a wide range of non-neuronal cells and tissues. The present review outlines current knowledge and understanding of the physiological and pathophysiological functions of NMDAR in the kidney, an essential excretory and endocrine organ responsible for the whole-body homeostasis. The review also explores the recent findings regarding signaling pathways involved in NMDAR-mediated responses in the kidney. As established from diverse lines of research reviewed here, basal levels of receptor activation within the kidney are essential for the maintenance of healthy tubular and glomerular function, while a disproportionate activation can lead to a disruption of NMDAR’s downstream signaling pathways and a myriad of pathophysiological consequences.

scholarly journals Aberrant signaling pathways in medulloblastomas: a stem cell connection

2010 ◽  
Vol 68 (6) ◽  
pp. 947-952 ◽  
Author(s):  
Carolina Oliveira Rodini ◽  
Daniela Emi Suzuki ◽  
Adriana Miti Nakahata ◽  
Márcia Cristina Leite Pereira ◽  
Luciana Janjoppi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Signaling Pathways ◽  
Tumor Development ◽  
Current Treatment ◽  
Molecular Alterations ◽  
Tumorigenic Potential ◽  
Therapeutic Development ◽  
Future Drug ◽  
The Central Nervous System ◽  
Pediatric Brain

Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFβ, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers.

The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

2018 ◽  
Vol 15 (13) ◽  
pp. 1191-1212 ◽  
Author(s):  
Botond Penke ◽  
Gábor Paragi ◽  
János Gera ◽  
Róbert Berkecz ◽  
Zsolt Kovács ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Membrane Lipids ◽  
Specific Protein ◽  
Dietary Factors ◽  
Lipid Signaling ◽  
Special Role ◽  
Aβ Peptides

Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important factors in the initiation of Alzheimer’s disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids to AD. In addition, lipid signaling pathways have a crucial role in the cellular homeostasis and depend on specific protein-lipid interactions. The current review focuses on pathological alterations of membrane lipids (cholesterol, glycerophospholipids, sphingolipids) and lipid metabolism in AD and provides insight in the current understanding of biological membranes, their lipid structures and functions, as well as their role as potential therapeutic targets. Novel methods for studying the membrane structure and lipid composition will be reviewed in a broad sense whereas the use of lipid biomarkers for early diagnosis of AD will be shortly summarized. Interactions of Aβ peptides with the cell membrane and different subcellular organelles are reviewed. Next, the details of the most important lipid signaling pathways, including the role of the plasma membrane as stress sensor and its therapeutic applications are given. 4-hydroxy-2-nonenal may play a special role in the initiation of the pathogenesis of AD and thus the “calpain-cathepsin hypothesis” of AD is highlighted. Finally, the most important lipid dietary factors and their possible use and efficacy in the prevention of AD are discussed.

The Influence of Ultra-Low Concentrations of Potassium Anphen on the Bioenergetic Characteristics of Mitochondria

2020 ◽  
Vol 16 (4) ◽  
pp. 537-542
Author(s):  
Zhigacheva Irina ◽  
Volodkin Aleksandr ◽  
Rasulov Maksud
Keyword(s):  
Functional State ◽  
Membrane Lipids ◽  
Biological Effects ◽  
Dose Dependence ◽  
Stress Factors ◽  
Mitochondrial Membranes ◽  
Oxidation Rates ◽  
Pea Seedlings ◽  
Low Concentrations ◽  
Wide Range

Background: One of the main sources of ROS in stress conditions is the mitochondria. Excessive generation of ROS leads to oxidation of thiol groups of proteins, peroxidation of membrane lipids and swelling of the mitochondria. In this regard, there is a need to search for preparationsadaptogens that increase the body's resistance to stress factors. Perhaps, antioxidants can serve as such adaptogens. This work aims at studying the effect of antioxidant; the potassium anphen in a wide range of concentrations on the functional state of 6 day etiolated pea seedlings mitochondria (Pisum sativum L). Methods: The functional state of mitochondria was studied per rates of mitochondria respiration, by the level of lipid peroxidation and study of fatty acid composition of mitochondrial membranes by chromatography technique. Results: Potassium anphen in concentrations of 10-5 - 10-8 M and 10-13-10-16 prevented the activation of LPO in the mitochondrial membranes of pea seedlings, increased the oxidation rates of NAD-dependent substrates and succinate in the respiratory chain of mitochondria that probably pointed to the anti-stress properties of the drug. Indeed, the treatment of pea seeds with the preparation in concentrations of 10-13 M prevented the inhibition of growth of seedlings in conditions of water deficiency. Conclusion: It is assumed that the dose dependence of the biological effects of potassium anphen and the manifestation of these effects in ultra-low concentrations are due to its ability in water solutions to form a hydrate containing molecular ensembles (structures).

Bioprospecting Cryptogams as Potential Source of Unique Biodynamic Phytochemicals with Diverse Pharmaceutical Applications

2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Brahma N. Singh ◽  
Garima Pandey ◽  
Prateeksha ◽  
J. Kumar
Keyword(s):  
Secondary Metabolites ◽  
Higher Plants ◽  
New Drugs ◽  
Terrestrial Plants ◽  
Pharmacological Activities ◽  
Therapeutic Drugs ◽  
Potential Source ◽  
Therapeutic Value ◽  
Wide Range ◽  
Novel Structures

With the advent of green pharmaceuticals, the secondary metabolites derived from plants have provided numerous leads for the development of a wide range of therapeutic drugs; however the discovery of new drugs with novel structures has declined in the past few years. Cryptogams including lichens, bryophytes, and pteridophytes represent a group of small terrestrial plants that remain relatively untouched in the drug discovery process though some have been used as ethnomedicines by various tribes worldwide. Studies of their secondary metabolites are recent but reveal unique secondary metabolites which are not synthesized by higher plants. These compounds can have the potential to develop more potential herbal drugs for prevention and treatment of diseases The present article . deals with the secondary metabolites and pharmacological activities of cryptogams with an objective to bring them forth as potential source of biodynamic compounds of therapeutic value.

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