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      The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation—Evidence from In Vivo Studies

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          Abstract

          Neurological disorders such as neurodegenerative diseases or traumatic brain injury are associated with cognitive, motor and behavioural changes that influence the quality of life of the patients. Although different therapeutic strategies have been developed and tried until now to decrease the neurological decline, no treatment has been found to cure these pathologies. In the last decades, the implication of the endocannabinoid system in the neurological function has been extensively studied, and the cannabinoids have been tried as a new promising potential treatment. In this study, we aimed to overview the recent available literature regarding in vivo potential of natural and synthetic cannabinoids with underlying mechanisms of action for protecting against cognitive decline and motor impairments. The results of studies on animal models showed that cannabinoids in traumatic brain injury increase neurobehavioral function, working memory performance, and decrease the neurological deficit and ameliorate motor deficit through down-regulation of pro-inflammatory markers, oedema formation and blood–brain barrier permeability, preventing neuronal cell loss and up-regulating the levels of adherence junction proteins. In neurodegenerative diseases, the cannabinoids showed beneficial effects in decreasing the motor disability and disease progression by a complex mechanism targeting more signalling pathways further than classical receptors of the endocannabinoid system. In light of these results, the use of cannabinoids could be beneficial in traumatic brain injuries and multiple sclerosis treatment, especially in those patients who display resistance to conventional treatment.

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          Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations.

          Two proteins with seven transmembrane-spanning domains typical of guanosine-nucleotide-binding-protein-coupled receptors have been identified as cannabinoid receptors; the central cannabinoid receptor, CB1, and the peripheral cannabinoid receptor, CB2, initially described in rat brain and spleen, respectively. Here, we report the distribution patterns for both CB1 and CB2 transcripts in human immune cells and in several human tissues, as analysed using a highly sensitive and quantitative PCR-based method. CB1 was mainly expressed in the central nervous system and, to a lower extent, in several peripheral tissues such as adrenal gland, heart, lung, prostate, uterus, ovary, testis, bone marrow, thymus and tonsils. In contrast, the CB2 gene, which is not expressed in the brain, was particularly abundant in immune tissues, with an expression level 10-100-fold higher than that of CB1. Although CB2 mRNA was also detected in some other peripheral tissues, its level remained very low. In spleen and tonsils, the CB2 mRNA content was equivalent to that of CB1 mRNA in the central nervous system. Among the main human blood cell subpopulations, the distribution pattern of the CB2 mRNA displayed important variations. The rank order of CB2 mRNA levels in these cells was B-cells > natural killer cells > monocytes > polymorphonuclear neutrophil cells > T8 cells > T4 cells. The same rank order was also established in human cell lines belonging to the myeloid, monocytic and lymphoid lineages. The prevailing expression of the CB2 gene in immune tissues was confirmed by Northern-blot analysis. In addition, the expression of the CB2 protein was demonstrated by an immunohistological analysis performed on tonsil sections using specific anti-(human CB2) IgG; this experiment showed that CB2 expression was restricted to B-lymphocyte-enriched areas of the mantle of secondary lymphoid follicles. These results suggest that (a) CB1 and CB2 can be considered as tissue-selective antigens of the central nervous system and immune system, respectively, and (b) cannabinoids may exert specific receptor-mediated actions on the immune system through the CB2 receptor.
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            Gait and cognition: a complementary approach to understanding brain function and the risk of falling.

            Until recently, clinicians and researchers have performed gait assessments and cognitive assessments separately when evaluating older adults, but increasing evidence from clinical practice, epidemiological studies, and clinical trials shows that gait and cognition are interrelated in older adults. Quantifiable alterations in gait in older adults are associated with falls, dementia, and disability. At the same time, emerging evidence indicates that early disturbances in cognitive processes such as attention, executive function, and working memory are associated with slower gait and gait instability during single- and dual-task testing and that these cognitive disturbances assist in the prediction of future mobility loss, falls, and progression to dementia. This article reviews the importance of the interrelationship between gait and cognition in aging and presents evidence that gait assessments can provide a window into the understanding of cognitive function and dysfunction and fall risk in older people in clinical practice. To this end, the benefits of dual-task gait assessments (e.g., walking while performing an attention-demanding task) as a marker of fall risk are summarized. A potential complementary approach for reducing the risk of falls by improving certain aspects of cognition through nonpharmacological and pharmacological treatments is also presented. Untangling the relationship between early gait disturbances and early cognitive changes may be helpful in identifying older adults at risk of experiencing mobility decline, falls, and progression to dementia. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.
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              A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.

              Endogenous ligands for cannabinoid receptors ("endocannabinoids") include the lipid transmitters anandamide and 2-arachidonoylglycerol (2-AG). Endocannabinoids modulate a diverse set of physiological processes and are tightly regulated by enzymatic biosynthesis and degradation. Termination of anandamide signaling by fatty acid amide hydrolase (FAAH) is well characterized, but less is known about the inactivation of 2-AG, which can be hydrolyzed by multiple enzymes in vitro, including FAAH and monoacylglycerol lipase (MAGL). Here, we have taken a functional proteomic approach to comprehensively map 2-AG hydrolases in the mouse brain. Our data reveal that approximately 85% of brain 2-AG hydrolase activity can be ascribed to MAGL, and that the remaining 15% is mostly catalyzed by two uncharacterized enzymes, ABHD6 and ABHD12. Interestingly, MAGL, ABHD6, and ABHD12 display distinct subcellular distributions, suggesting that they may control different pools of 2-AG in the nervous system.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                27 July 2020
                August 2020
                : 9
                : 8
                : 2395
                Affiliations
                [1 ]Clinical Pharmacy Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
                [2 ]Biochemistry Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; anne_mary_07@ 123456yahoo.com
                [3 ]ENT Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; mihaela.mitroi48@ 123456gmail.com
                [4 ]Department of Toxicology “Akademik Danilo Soldatović”-Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia; aleksandra.buha@ 123456pharmacy.bg.ac.rs
                [5 ]Department of Physiology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; costin.caruntu@ 123456gmail.com (C.C.); cristian.scheau@ 123456umfcd.ro (C.S.)
                [6 ]Department of Dermatology, “Prof. N. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
                [7 ]Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, Mohammed V University in Rabat, 10106 Rabat, Morocco; boyahyaa-90@ 123456hotmail.fr
                [8 ]Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, 10106 Rabat, Morocco
                [9 ]Laboratory of Histology, Embryology and Cytogenetic, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, 10100 Rabat, Morocco; nasrelomari@ 123456gmail.com
                [10 ]Laboratory of Physiology, Pharmacology & Environmental Health, Faculty of Sciences, University Sidi Mohamed Ben Abdellah, 30000 Fez, Morocco; Nawal.ELMENYIY@ 123456usmba.ac.ma
                [11 ]Toxicology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
                Author notes
                [†]

                Equally contributed to the manuscript, thus share the first authorship.

                Author information
                https://orcid.org/0000-0002-1523-9116
                https://orcid.org/0000-0003-0082-6956
                https://orcid.org/0000-0002-6942-7040
                https://orcid.org/0000-0001-7676-6393
                https://orcid.org/0000-0001-9317-1631
                Article
                jcm-09-02395
                10.3390/jcm9082395
                7464236
                32726998
                3b975064-e06b-44af-82a5-d035e5f633aa
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 July 2020
                : 23 July 2020
                Categories
                Review

                cannabinoids,brain injury,neurodegenerative disorders,animal models,molecular mechanisms

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