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Rodrigues RS, Moreira JB, Dias P, Sebastião AM, Xapelli S. The Effects of Exercise-Associated Factors on Hippocampal Progenitor Cell Dynamics Are Mediated by Cannabinoid Type 2 Receptors. J Neurochem 2025; 169:e70091. [PMID: 40405428 DOI: 10.1111/jnc.70091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 04/29/2025] [Accepted: 05/02/2025] [Indexed: 05/24/2025]
Abstract
Neural stem/progenitor cells (NSPCs) operate in specialized niches of the adult mammalian brain, where their proliferative and differentiative potential is modulated by a myriad of factors. Emerging evidence sheds light on the interaction between cannabinoids and neurotrophic factors underlying a major regulatory force of NSPC dynamics. Previous data show that cannabinoid type 2 receptors (CB2Rs) tightly regulate the actions of brain-derived neurotrophic factor (BDNF), a neurotrophic factor highly upregulated during physical exercise. However, further research into the effects of exercise-associated neurotrophic factors in the regulation of NSPCs is still necessary. Therefore, we aimed at exploring the effects of exercise-associated factors in postnatal hippocampal neurogenesis and how CB2Rs regulate this process. By using dentate gyrus-derived neurospheres and treating them with a combination of exercise-associated factors, as an in vitro proxy for exercise, we found that these factors significantly promoted cell proliferation, an action partially reduced when CB2Rs were blocked. Moreover, CB2Rs were shown to be required for the actions of this exercise-mimicking cocktail in early neuronal commitment and differentiation. However, late neuronal differentiation promoted by exercise-associated factors remained unaltered in the presence of CB2R ligands. Together, these data suggest that CB2R actions are preponderant in early stages of hippocampal neurogenesis promoted by exercise. Astroglial late differentiation was also accelerated by a combination of exercise-associated factors, an effect prevented by CB2R blockage. This work provides a deeper understanding of the mechanisms underlying the actions of cannabinoids and exercise on NSPC regulation, highlighting the role of CB2R in modulating exercise-induced hippocampal neurogenesis.
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Affiliation(s)
- R S Rodrigues
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- GIMM - Gulbenkian Institute of Molecular Medicine, Lisbon, Portugal
| | - J B Moreira
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- GIMM - Gulbenkian Institute of Molecular Medicine, Lisbon, Portugal
| | - P Dias
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- GIMM - Gulbenkian Institute of Molecular Medicine, Lisbon, Portugal
| | - A M Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- GIMM - Gulbenkian Institute of Molecular Medicine, Lisbon, Portugal
| | - S Xapelli
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- GIMM - Gulbenkian Institute of Molecular Medicine, Lisbon, Portugal
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Marino M, Di Pietro P, D’Auria R, Lombardi M, Pastorino GMG, Troisi J, Operto FF, Carrizzo A, Vecchione C, Viggiano A, Meccariello R, Santoro A. Adult Neurogenesis Is Regulated by the Endocannabinoid and Kisspeptin Systems. Int J Mol Sci 2025; 26:3977. [PMID: 40362219 PMCID: PMC12071241 DOI: 10.3390/ijms26093977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 04/13/2025] [Accepted: 04/20/2025] [Indexed: 05/15/2025] Open
Abstract
Neurogenesis is considered the most robust form of plasticity in the adult brain. To better decipher this process, we evaluated the potential crosstalk of Kisspeptin and Endocannabinoid Systems (KPS and ECS, respectively) on hippocampal neurogenesis. Male adolescent rats were exposed to kisspeptin-10 (KP10) and the endocannabinoid anandamide (AEA) administered alone or in combination with the type 1 cannabinoid receptor (CB1R) antagonist SR141716A. The expression of Kiss1 and Kisspeptin receptor (Kiss1R) has been characterized for the first time in rat hippocampus together with the expression of the CB1R and the Transient Receptor Potential Vanilloid 1 ion channel receptor (TRPV1). Results show that both systems inhibit neurogenesis by reducing the extracellular signal-regulated kinase (ERK) signaling. Despite little differences in the expression of Kiss1R and CB1R, TRPV1 is enhanced by both KP10 and AEA treatments, suggesting TRPV1 as a common thread. KP10 administration reduces CB1R expression in the dentate gyrus, while AEA does not. KPS, unlike ECS, promotes the expression of estrogen receptor α (ER-α) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), also upregulating sirtuin 1 (SIRT1), brain-derived-neurotrophic factor (BDNF), and c-Jun. These findings suggest that the interaction between ECS and KPS could be involved in the fine-tuning of neurogenesis, highlighting a novel role for KPS.
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Affiliation(s)
- Marianna Marino
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
| | - Paola Di Pietro
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
| | - Raffaella D’Auria
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
| | - Martina Lombardi
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
| | - Grazia Maria Giovanna Pastorino
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
- Child and Adolescent Neuropsychiatry Unit, San Giovanni di Dio Ruggi d’Aragona Hospital, 84131 Salerno, Italy;
| | - Jacopo Troisi
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
- Theoreo S.r.l. Montecorvino Pugliano, 84090 Salerno, Italy
| | - Francesca Felicia Operto
- Child and Adolescent Neuropsychiatry Unit, San Giovanni di Dio Ruggi d’Aragona Hospital, 84131 Salerno, Italy;
- Department of Health Sciences, School of Medicine, University Magna Grecia of Catanzaro, 88100 Catanzaro, Italy
| | - Albino Carrizzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
- Vascular Physiopathology Unit, IRCCS Neuromed Mediterranean Neurological Institute, 86077 Pozzilli, Italy
| | - Carmine Vecchione
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
- Vascular Physiopathology Unit, IRCCS Neuromed Mediterranean Neurological Institute, 86077 Pozzilli, Italy
| | - Andrea Viggiano
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
| | - Rosaria Meccariello
- Department of Medical, Motor and Wellness Sciences, University of Naples Parthenope, 80133 Napoli, Italy;
| | - Antonietta Santoro
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (M.M.); (P.D.P.); (R.D.); (M.L.); (G.M.G.P.); (J.T.); (A.C.); (C.V.); (A.V.)
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Estudillo E, Castillo-Arellano JI, Martínez E, Rangel-López E, López-Ornelas A, Magaña-Maldonado R, Adalid-Peralta L, Velasco I, Escobedo-Ávila I. Modeling the Effect of Cannabinoid Exposure During Human Neurodevelopment Using Bidimensional and Tridimensional Cultures. Cells 2025; 14:70. [PMID: 39851498 PMCID: PMC11763397 DOI: 10.3390/cells14020070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/18/2024] [Accepted: 01/04/2025] [Indexed: 01/26/2025] Open
Abstract
Our knowledge about the consumption of cannabinoids during pregnancy lacks consistent evidence to determine whether it compromises neurodevelopment. Addressing this task is challenging and complex since pregnant women display multiple confounding factors that make it difficult to identify the real effect of cannabinoids' consumption. Recent studies shed light on this issue by using pluripotent stem cells of human origin, which can recapitulate human neurodevelopment. These revolutionary platforms allow studying how exogenous cannabinoids could alter human neurodevelopment without ethical concerns and confounding factors. Here, we review the information to date on the clinical studies about the impact of exogenous cannabinoid consumption on human brain development and how exogenous cannabinoids alter nervous system development in humans using cultured pluripotent stem cells as 2D and 3D platforms to recapitulate brain development.
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Affiliation(s)
- Enrique Estudillo
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (J.I.C.-A.); (E.M.); (E.R.-L.); (R.M.-M.); (L.A.-P.); (I.V.)
| | - Jorge Iván Castillo-Arellano
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (J.I.C.-A.); (E.M.); (E.R.-L.); (R.M.-M.); (L.A.-P.); (I.V.)
| | - Emilio Martínez
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (J.I.C.-A.); (E.M.); (E.R.-L.); (R.M.-M.); (L.A.-P.); (I.V.)
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Edgar Rangel-López
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (J.I.C.-A.); (E.M.); (E.R.-L.); (R.M.-M.); (L.A.-P.); (I.V.)
| | - Adolfo López-Ornelas
- División de Investigación, Hospital Juárez de México, Mexico City 07760, Mexico;
- Hospital Nacional Homeopático, Hospitales Federales de Referencia, Mexico City 06800, Mexico
| | - Roxana Magaña-Maldonado
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (J.I.C.-A.); (E.M.); (E.R.-L.); (R.M.-M.); (L.A.-P.); (I.V.)
| | - Laura Adalid-Peralta
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (J.I.C.-A.); (E.M.); (E.R.-L.); (R.M.-M.); (L.A.-P.); (I.V.)
| | - Iván Velasco
- Laboratorio de Reprogramación Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City 14269, Mexico; (J.I.C.-A.); (E.M.); (E.R.-L.); (R.M.-M.); (L.A.-P.); (I.V.)
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Itzel Escobedo-Ávila
- Instituto de Fisiología Celular-Neurociencias, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
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Monory K, de Azua IR, Lutz B. Genetic Tools in Rodents to Study Cannabinoid Functions. Curr Top Behav Neurosci 2024. [PMID: 39680319 DOI: 10.1007/7854_2024_550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
During the past 30 years, the endocannabinoid system (ECS) has emerged as a major signalling system in the mammalian brain regulating neurotransmission in numerous brain regions and in various cell populations. Endocannabinoids are able to regulate specific physiological functions and thus modify their behavioural manifestations and allostatic alterations of the ECS linked to different pathological conditions. As discussed in detail in other chapters of this book, endocannabinoids are involved in learning and memory, stress, and anxiety, feeding, energy balance, development, and ageing. Likewise, many CNS disorders (e.g. schizophrenia, epilepsy, substance use disorders, and multiple sclerosis) are associated with dysregulation of the ECS. Discerning the physiological functions of the synthetic and degrading enzymes of endocannabinoids and their receptors is a challenging task because of their distinct and complex expression patterns. Techniques of genetic engineering have been able to shed light on a number of complex ECS-related tasks during the past years. In this chapter, first, we take a critical look at the toolbox available to researchers who would like to investigate cannabinoid effects using genetic engineering techniques, then we comprehensively discuss genetically modified rodent models in various neuronal and non-neuronal cell populations, both within and outside the nervous system.
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Affiliation(s)
- Krisztina Monory
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | | | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
- Leibniz Institute for Resilience Research (LIR) gGmbH, Mainz, Germany.
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Rodrigues RJ, Marques JM, Köfalvi A. Cannabis, Endocannabinoids and Brain Development: From Embryogenesis to Adolescence. Cells 2024; 13:1875. [PMID: 39594623 PMCID: PMC11593331 DOI: 10.3390/cells13221875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
The endocannabinoid signalling system (ECS) plays a critical role from the very beginning of embryogenesis. Accordingly, the ECS is engaged early on in nervous system development, starting from neurulation, supported by the identification of ECS components-both receptors and enzymes controlling endocannabinoid metabolism-at these early stages. In particular, regarding the brain, the ECS is involved in the tightly regulated sequence of events that comprise brain development, from neurogenesis to neuronal migration, morphological guidance for neuronal connectivity, and synaptic circuitry refinement. The importance of this broad role of the ECS across various brain development processes is further underscored by the growing understanding of the consequences of cannabis exposure at different developmental stages. Despite the considerable knowledge we have on the role of the ECS in brain development, significant gaps in our understanding remain, particularly regarding the long-term impact and underlying mechanisms of cannabis exposure at different developmental stages. This review provides an overview of the current state of knowledge on the role of the ECS throughout brain development, from embryogenesis to adulthood, and discusses the impact of cannabis exposure, especially during adolescence-a critical period of circuitry maturation and refinement coinciding with an increased risk of cannabis use.
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Affiliation(s)
- Ricardo J. Rodrigues
- CNC-UC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Joana M. Marques
- CNC-UC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Attila Köfalvi
- CNC-UC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal;
- CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
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Peterson CS, Baglot SL, Sallam NA, Mina S, Hill MN, Borgland SL. Oral pre- and early postnatal cannabis exposure disinhibits ventral tegmental area dopamine neuron activity but does not influence cocaine preference in offspring in mice. J Neurosci Res 2024; 102:e25369. [PMID: 39037062 DOI: 10.1002/jnr.25369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 07/01/2024] [Accepted: 07/07/2024] [Indexed: 07/23/2024]
Abstract
Cannabis consumption has increased from 1.5% to 2.5% in Canada between 2012 and 2019. Clinical studies have indicated effects of prenatal cannabis exposure on birth weight, substance use, and neurodevelopmental disorders, but are confounded by several difficult to control variables. Animal models allow for examination of the mechanism of cannabis-induced changes in neurodevelopment and behavior, while controlling dose and timing. Several animal models of prenatal cannabis exposure exist which provide varying levels of construct validity, control of dose, and exposure to maternal stress. Using a voluntary oral consumption model, mouse dams received 5 mg/kg Δ9-tetrahydrocannabinol (THC) whole cannabis oil in peanut butter daily from gestational day 1 (GD1) to postnatal day 10 (PD10). At GD1, GD18, PD1, PD10, and PD15, maternal plasma was collected; pup brains were collected from GD18 onward. Pup brains had higher levels of THC and cannabidiol at each time point, each of which persisted in maternal plasma and pup brains past the end of treatment (PD15). Male and female adolescent offspring were examined for changes to ventral tegmental area (VTA) dopamine neuron activity and cocaine-seeking behavior. Prenatal and early postnatal (GD1-PD10) cannabis-exposed male, but not female mice had decreased gamma-aminobutyric acid (GABAergic) input, depolarized resting membrane potential, and increased spontaneous firing of VTA dopamine neurons. Cannabis-exposed offspring showed faster decay of N-methyl-D-aspartate (NMDA) currents in both sexes. However, no differences in cocaine-seeking behavior were noted. These data characterize a voluntary prenatal cannabis exposure model and demonstrates VTA dopamine neuronal activity is disinhibited in offspring.
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Affiliation(s)
- Colleen S Peterson
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Samantha L Baglot
- Department of Cell Biology and Anatomy, Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Nada A Sallam
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt, Cairo University, Cairo, Egypt
| | - Sarah Mina
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Matthew N Hill
- Department of Cell Biology and Anatomy, Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Stephanie L Borgland
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Dionne O, Abolghasemi A, Corbin F, Çaku A. Implication of the endocannabidiome and metabolic pathways in fragile X syndrome pathophysiology. Psychiatry Res 2024; 337:115962. [PMID: 38763080 DOI: 10.1016/j.psychres.2024.115962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/21/2024]
Abstract
Fragile X Syndrome (FXS) results from the silencing of the FMR1 gene and is the most prevalent inherited cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorder. It is well established that Fragile X individuals are subjected to a wide array of comorbidities, ranging from cognitive, behavioural, and medical origin. Furthermore, recent studies have also described metabolic impairments in FXS individuals. However, the molecular mechanisms linking FMRP deficiency to improper metabolism are still misunderstood. The endocannabinoidome (eCBome) is a lipid-based signalling system that regulates several functions across the body, ranging from cognition, behaviour and metabolism. Alterations in the eCBome have been described in FXS animal models and linked to neuronal hyperexcitability, a core deficit of the disease. However, the potential link between dysregulation of the eCBome and altered metabolism observed in FXS remains unexplored. As such, this review aims to overcome this issue by describing the most recent finding related to eCBome and metabolic dysfunctions in the context of FXS. A better comprehension of this association will help deepen our understanding of FXS pathophysiology and pave the way for future therapeutic interventions.
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Affiliation(s)
- Olivier Dionne
- Biochemistry and Functional Genomic Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada.
| | - Armita Abolghasemi
- Biochemistry and Functional Genomic Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada
| | - François Corbin
- Biochemistry and Functional Genomic Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada
| | - Artuela Çaku
- Biochemistry and Functional Genomic Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada
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Li X, Yennawar M, Wiest A, O'Brien WT, Babrowicz B, White RS, Talos DM, Jensen FE. Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5 R59X knock-in mice. Eur J Neurosci 2024; 59:3337-3352. [PMID: 38654472 DOI: 10.1111/ejn.16350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 02/15/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024]
Abstract
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.
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Affiliation(s)
- Xiaofan Li
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Madhumita Yennawar
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alyssa Wiest
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - William T O'Brien
- Neurobehavior Testing Core, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Bergan Babrowicz
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rachel S White
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Delia M Talos
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Frances E Jensen
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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9
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Baddenhausen S, Lutz B, Hofmann C. Cannabinoid type-1 receptor signaling in dopaminergic Engrailed-1 expressing neurons modulates motivation and depressive-like behavior. Front Mol Neurosci 2024; 17:1379889. [PMID: 38660383 PMCID: PMC11042029 DOI: 10.3389/fnmol.2024.1379889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/21/2024] [Indexed: 04/26/2024] Open
Abstract
The endocannabinoid system comprises highly versatile signaling functions within the nervous system. It is reported to modulate the release of several neurotransmitters, consequently affecting the activity of neuronal circuits. Investigations have highlighted its roles in numerous processes, including appetite-stimulating characteristics, particularly for palatable food. Moreover, endocannabinoids are shown to fine-tune dopamine-signaled processes governing motivated behavior. Specifically, it has been demonstrated that excitatory and inhibitory inputs controlled by the cannabinoid type 1 receptor (CB1) regulate dopaminergic neurons in the mesocorticolimbic pathway. In the present study, we show that mesencephalic dopaminergic (mesDA) neurons in the ventral tegmental area (VTA) express CB1, and we investigated the consequences of specific deletion of CB1 in cells expressing the transcription factor Engrailed-1 (En1). To this end, we validated a new genetic mouse line EN1-CB1-KO, which displays a CB1 knockout in mesDA neurons beginning from their differentiation, as a tool to elucidate the functional contribution of CB1 in mesDA neurons. We revealed that EN1-CB1-KO mice display a significantly increased immobility time and shortened latency to the first immobility in the forced swim test of adult mice. Moreover, the maximal effort exerted to obtain access to chocolate-flavored pellets was significantly reduced under a progressive ratio schedule. In contrast, these mice do not differ in motor skills, anhedonia- or anxiety-like behavior compared to wild-type littermates. Taken together, these findings suggest a depressive-like or despair behavior in an inevitable situation and a lack of motivation to seek palatable food in EN1-CB1-KO mice, leading us to propose that CB1 plays an important role in the physiological functions of mesDA neurons. In particular, our data suggest that CB1 directly modifies the mesocorticolimbic pathway implicated in depressive-like/despair behavior and motivation. In contrast, the nigrostriatal pathway controlling voluntary movement seems to be unaffected.
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Affiliation(s)
- Sarah Baddenhausen
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Leibniz Institute for Resilience Research (LIR), Mainz, Germany
| | - Clementine Hofmann
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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10
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Monsalvo-Maraver LA, Ovalle-Noguez EA, Nava-Osorio J, Maya-López M, Rangel-López E, Túnez I, Tinkov AA, Tizabi Y, Aschner M, Santamaría A. Interactions Between the Ubiquitin-Proteasome System, Nrf2, and the Cannabinoidome as Protective Strategies to Combat Neurodegeneration: Review on Experimental Evidence. Neurotox Res 2024; 42:18. [PMID: 38393521 PMCID: PMC10891226 DOI: 10.1007/s12640-024-00694-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/13/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024]
Abstract
Neurodegenerative disorders are chronic brain diseases that affect humans worldwide. Although many different factors are thought to be involved in the pathogenesis of these disorders, alterations in several key elements such as the ubiquitin-proteasome system (UPS), the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, and the endocannabinoid system (ECS or endocannabinoidome) have been implicated in their etiology. Impairment of these elements has been linked to the origin and progression of neurodegenerative disorders, while their potentiation is thought to promote neuronal survival and overall neuroprotection, as proved with several experimental models. These key neuroprotective pathways can interact and indirectly activate each other. In this review, we summarize the neuroprotective potential of the UPS, ECS, and Nrf2 signaling, both separately and combined, pinpointing their role as a potential therapeutic approach against several hallmarks of neurodegeneration.
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Affiliation(s)
- Luis Angel Monsalvo-Maraver
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, C.U. Coyoacán, 04510, Mexico City, Mexico.
| | - Enid A Ovalle-Noguez
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, C.U. Coyoacán, 04510, Mexico City, Mexico
| | - Jade Nava-Osorio
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, C.U. Coyoacán, 04510, Mexico City, Mexico
| | - Marisol Maya-López
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, C.U. Coyoacán, 04510, Mexico City, Mexico
- Doctorado en Ciencias Biológicas y de La Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Edgar Rangel-López
- Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico
| | - Isaac Túnez
- Instituto de Investigaciones Biomédicas Maimonides de Córdoba (IMIBIC), Departamento de Bioquímica y Biología Molecular, Facultad de Medicina y Enfermería, Universidad de Córdoba, Red Española de Excelencia en Estimulación Cerebral (REDESTIM), Córdoba, Spain
| | - Alexey A Tinkov
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Yaroslavl State University, Yaroslavl, Russia
| | - Yousef Tizabi
- Department of Pharmacology, Howard University College of Medicine, Washington, DC, USA
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Abel Santamaría
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, C.U. Coyoacán, 04510, Mexico City, Mexico.
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11
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Al-Khazaleh AK, Zhou X, Bhuyan DJ, Münch GW, Al-Dalabeeh EA, Jaye K, Chang D. The Neurotherapeutic Arsenal in Cannabis sativa: Insights into Anti-Neuroinflammatory and Neuroprotective Activity and Potential Entourage Effects. Molecules 2024; 29:410. [PMID: 38257323 PMCID: PMC10821245 DOI: 10.3390/molecules29020410] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Cannabis, renowned for its historical medicinal use, harbours various bioactive compounds-cannabinoids, terpenes, and flavonoids. While major cannabinoids like delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have received extensive scrutiny for their pharmacological properties, emerging evidence underscores the collaborative interactions among these constituents, suggesting a collective therapeutic potential. This comprehensive review explores the intricate relationships and synergies between cannabinoids, terpenes, and flavonoids in cannabis. Cannabinoids, pivotal in cannabis's bioactivity, exhibit well-documented analgesic, anti-inflammatory, and neuroprotective effects. Terpenes, aromatic compounds imbuing distinct flavours, not only contribute to cannabis's sensory profile but also modulate cannabinoid effects through diverse molecular mechanisms. Flavonoids, another cannabis component, demonstrate anti-inflammatory, antioxidant, and neuroprotective properties, particularly relevant to neuroinflammation. The entourage hypothesis posits that combined cannabinoid, terpene, and flavonoid action yields synergistic or additive effects, surpassing individual compound efficacy. Recognizing the nuanced interactions is crucial for unravelling cannabis's complete therapeutic potential. Tailoring treatments based on the holistic composition of cannabis strains allows optimization of therapeutic outcomes while minimizing potential side effects. This review underscores the imperative to delve into the intricate roles of cannabinoids, terpenes, and flavonoids, offering promising prospects for innovative therapeutic interventions and advocating continued research to unlock cannabis's full therapeutic potential within the realm of natural plant-based medicine.
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Affiliation(s)
- Ahmad K. Al-Khazaleh
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (X.Z.); (D.J.B.); (G.W.M.); (K.J.)
| | - Xian Zhou
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (X.Z.); (D.J.B.); (G.W.M.); (K.J.)
| | - Deep Jyoti Bhuyan
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (X.Z.); (D.J.B.); (G.W.M.); (K.J.)
- School of Science, Western Sydney University, Penrith, NSW 2751, Australia
| | - Gerald W. Münch
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (X.Z.); (D.J.B.); (G.W.M.); (K.J.)
- Pharmacology Unit, School of Medicine, Western Sydney University, Penrith, NSW 2751, Australia
| | - Elaf Adel Al-Dalabeeh
- Department of Biological Sciences, School of Science, University of Jordan, Amman 11942, Jordan;
| | - Kayla Jaye
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (X.Z.); (D.J.B.); (G.W.M.); (K.J.)
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Penrith, NSW 2751, Australia; (X.Z.); (D.J.B.); (G.W.M.); (K.J.)
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12
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Black T, Baccetto SL, Barnard IL, Finch E, McElroy DL, Austin-Scott FVL, Greba Q, Michel D, Zagzoog A, Howland JG, Laprairie RB. Characterization of cannabinoid plasma concentration, maternal health, and cytokine levels in a rat model of prenatal Cannabis smoke exposure. Sci Rep 2023; 13:21070. [PMID: 38030657 PMCID: PMC10687022 DOI: 10.1038/s41598-023-47861-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 11/19/2023] [Indexed: 12/01/2023] Open
Abstract
Cannabis sativa has gained popularity as a "natural substance", leading many to falsely assume that it is not harmful. This assumption has been documented amongst pregnant mothers, many of whom consider Cannabis use during pregnancy as benign. The purpose of this study was to validate a Cannabis smoke exposure model in pregnant rats by determining the plasma levels of cannabinoids and associated metabolites in the dams after exposure to either Cannabis smoke or injected cannabinoids. Maternal and fetal cytokine and chemokine profiles were also assessed after exposure. Pregnant Sprague-Dawley rats were treated daily from gestational day 6-20 with either room air, i.p. vehicle, inhaled high-Δ9-tetrahydrocannabinol (THC) (18% THC, 0.1% cannabidiol [CBD]) smoke, inhaled high-CBD (0.7% THC, 13% CBD) smoke, 3 mg/kg i.p. THC, or 10 mg/kg i.p. CBD. Our data reveal that THC and CBD, but not their metabolites, accumulate in maternal plasma after repeated exposures. Injection of THC or CBD was associated with fewer offspring and increased uterine reabsorption events. For cytokines and chemokines, injection of THC or CBD up-regulated several pro-inflammatory cytokines compared to control or high-THC smoke or high-CBD smoke in placental and fetal brain tissue, whereas smoke exposure was generally associated with reduced cytokine and chemokine concentrations in placental and fetal brain tissue compared to controls. These results support existing, but limited, knowledge on how different routes of administration contribute to inconsistent manifestations of cannabinoid-mediated effects on pregnancy. Smoked Cannabis is still the most common means of human consumption, and more preclinical investigation is needed to determine the effects of smoke inhalation on developmental and behavioural trajectories.
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Affiliation(s)
- Tallan Black
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada
| | - Sarah L Baccetto
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada
| | - Ilne L Barnard
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada
| | - Emma Finch
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada
| | - Dan L McElroy
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada
| | - Faith V L Austin-Scott
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada
| | - Quentin Greba
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada
| | - Deborah Michel
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Ayat Zagzoog
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - John G Howland
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Health Sciences Building, 107 Wiggins Rd, Saskatoon, SK, S7N 5E5, Canada.
| | - Robert B Laprairie
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
- Department of Pharmacology, College of Medicine, Dalhousie University, Halifax, NS, Canada.
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13
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Kouchaeknejad A, Van Der Walt G, De Donato MH, Puighermanal E. Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS. Int J Mol Sci 2023; 24:15829. [PMID: 37958825 PMCID: PMC10648052 DOI: 10.3390/ijms242115829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/26/2023] [Accepted: 10/27/2023] [Indexed: 11/15/2023] Open
Abstract
As central nervous system (CNS)-related disorders present an increasing cause of global morbidity, mortality, and high pressure on our healthcare system, there is an urgent need for new insights and treatment options. The endocannabinoid system (ECS) is a critical network of endogenous compounds, receptors, and enzymes that contribute to CNS development and regulation. Given its multifaceted involvement in neurobiology and its significance in various CNS disorders, the ECS as a whole is considered a promising therapeutic target. Despite significant advances in our understanding of the ECS's role in the CNS, its complex architecture and extensive crosstalk with other biological systems present challenges for research and clinical advancements. To bridge these knowledge gaps and unlock the full therapeutic potential of ECS interventions in CNS-related disorders, a plethora of molecular-genetic tools have been developed in recent years. Here, we review some of the most impactful tools for investigating the neurological aspects of the ECS. We first provide a brief introduction to the ECS components, including cannabinoid receptors, endocannabinoids, and metabolic enzymes, emphasizing their complexity. This is followed by an exploration of cutting-edge imaging tools and genetic models aimed at elucidating the roles of these principal ECS components. Special emphasis is placed on their relevance in the context of CNS and its associated disorders.
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Affiliation(s)
| | | | | | - Emma Puighermanal
- Neuroscience Institute, Autonomous University of Barcelona, 08193 Bellaterra, Spain; (A.K.); (G.V.D.W.); (M.H.D.D.)
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14
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Cinquina V, Keimpema E, Pollak DD, Harkany T. Adverse effects of gestational ω-3 and ω-6 polyunsaturated fatty acid imbalance on the programming of fetal brain development. J Neuroendocrinol 2023; 35:e13320. [PMID: 37497857 PMCID: PMC10909496 DOI: 10.1111/jne.13320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 05/18/2023] [Accepted: 06/10/2023] [Indexed: 07/28/2023]
Abstract
Obesity is a key medical challenge of our time. The increasing number of children born to overweight or obese women is alarming. During pregnancy, the circulation of the mother and her fetus interact to maintain the uninterrupted availability of essential nutrients for fetal organ development. In doing so, the mother's dietary preference determines the amount and composition of nutrients reaching the fetus. In particular, the availability of polyunsaturated fatty acids (PUFAs), chiefly their ω-3 and ω-6 subclasses, can change when pregnant women choose a specific diet. Here, we provide a succinct overview of PUFA biochemistry, including exchange routes between ω-3 and ω-6 PUFAs, the phenotypes, and probable neurodevelopmental disease associations of offspring born to mothers consuming specific PUFAs, and their mechanistic study in experimental models to typify signaling pathways, transcriptional, and epigenetic mechanisms by which PUFAs can imprint long-lasting modifications to brain structure and function. We emphasize that the ratio, rather than the amount of individual ω-3 or ω-6 PUFAs, might underpin physiologically correct cellular differentiation programs, be these for neurons or glia, during pregnancy. Thereupon, the PUFA-driven programming of the brain is contextualized for childhood obesity, metabolic, and endocrine illnesses.
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Affiliation(s)
- Valentina Cinquina
- Department of Molecular NeurosciencesCenter for Brain Research, Medical University of ViennaViennaAustria
| | - Erik Keimpema
- Department of Molecular NeurosciencesCenter for Brain Research, Medical University of ViennaViennaAustria
| | - Daniela D. Pollak
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - Tibor Harkany
- Department of Molecular NeurosciencesCenter for Brain Research, Medical University of ViennaViennaAustria
- Deaprtment of NeuroscienceBiomedicum 7D, Karolinska InstitutetStockholmSweden
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15
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Kovács MV, Charchat-Fichman H, Landeira-Fernandez J, Medina AE, Krahe TE. Combined exposure to alcohol and cannabis during development: Mechanisms and outcomes. Alcohol 2023; 110:1-13. [PMID: 36740025 PMCID: PMC10372841 DOI: 10.1016/j.alcohol.2023.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
Exposure to substances of abuse during pregnancy can have long-lasting effects on offspring. Alcohol is one of the most widely used substances of abuse that leads to the most severe consequences. Recent studies in the United States, Canada, and the United Kingdom showed that between 1% and 7% of all children exhibit signs and symptoms of fetal alcohol spectrum disorder (FASD). Despite preventive campaigns, the rate of children with FASD has not decreased during recent decades. Alcohol consumption often accompanies exposure to such drugs as tobacco, cocaine, opioids, and cannabis. These interactions can be synergistic and exacerbate the deleterious consequences of developmental alcohol exposure. The present review focuses on interactions between alcohol and cannabis exposure and the potential consequences of these interactions.
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Affiliation(s)
- Martina V Kovács
- Departamento de Psicologia, Laboratório de Neurociência do Comportamento, Pontifícia Universidade Católica do Rio de Janeiro, Rua Marquês de São Vicente, 225, Gávea - Rio de Janeiro, RJ, 22451-900, Brazil
| | - Helenice Charchat-Fichman
- Departamento de Psicologia, Laboratório de Neurociência do Comportamento, Pontifícia Universidade Católica do Rio de Janeiro, Rua Marquês de São Vicente, 225, Gávea - Rio de Janeiro, RJ, 22451-900, Brazil
| | - J Landeira-Fernandez
- Departamento de Psicologia, Laboratório de Neurociência do Comportamento, Pontifícia Universidade Católica do Rio de Janeiro, Rua Marquês de São Vicente, 225, Gávea - Rio de Janeiro, RJ, 22451-900, Brazil
| | - Alexandre E Medina
- Department of Pediatrics - School of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, United States.
| | - Thomas E Krahe
- Departamento de Psicologia, Laboratório de Neurociência do Comportamento, Pontifícia Universidade Católica do Rio de Janeiro, Rua Marquês de São Vicente, 225, Gávea - Rio de Janeiro, RJ, 22451-900, Brazil.
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16
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Oddi S, Fiorenza MT, Maccarrone M. Endocannabinoid signaling in adult hippocampal neurogenesis: A mechanistic and integrated perspective. Prog Lipid Res 2023; 91:101239. [PMID: 37385352 DOI: 10.1016/j.plipres.2023.101239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 06/01/2023] [Accepted: 06/25/2023] [Indexed: 07/01/2023]
Abstract
Dentate gyrus of the hippocampus continuously gives rise to new neurons, namely, adult-born granule cells, which contribute to conferring plasticity to the mature brain throughout life. Within this neurogenic region, the fate and behavior of neural stem cells (NSCs) and their progeny result from a complex balance and integration of a variety of cell-autonomous and cell-to-cell-interaction signals and underlying pathways. Among these structurally and functionally diverse signals, there are endocannabinoids (eCBs), the main brain retrograde messengers. These pleiotropic bioactive lipids can directly and/or indirectly influence adult hippocampal neurogenesis (AHN) by modulating, both positively and negatively, multiple molecular and cellular processes in the hippocampal niche, depending on the cell type or stage of differentiation. Firstly, eCBs act directly as cell-intrinsic factors, cell-autonomously produced by NSCs following their stimulation. Secondly, in many, if not all, niche-associated cells, including some local neuronal and nonneuronal elements, the eCB system indirectly modulates the neurogenesis, linking neuronal and glial activity to regulating distinct stages of AHN. Herein, we discuss the crosstalk of the eCB system with other neurogenesis-relevant signal pathways and speculate how the hippocampus-dependent neurobehavioral effects elicited by (endo)cannabinergic medications are interpretable in light of the key regulatory role that eCBs play on AHN.
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Affiliation(s)
- Sergio Oddi
- Department of Veterinary Medicine, University of Teramo, Via R. Balzarini 1, 64100 Teramo, Italy; European Center for Brain Research/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
| | - Maria Teresa Fiorenza
- European Center for Brain Research/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy; Department of Psychology, Division of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, Via dei Sardi 70, 00185 Rome, Italy
| | - Mauro Maccarrone
- European Center for Brain Research/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143 Rome, Italy; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio Snc, 67100 L'Aquila, Italy
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17
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Alam MR, Singh S. Neuromodulation in Parkinson's disease targeting opioid and cannabinoid receptors, understanding the role of NLRP3 pathway: a novel therapeutic approach. Inflammopharmacology 2023:10.1007/s10787-023-01259-0. [PMID: 37318694 DOI: 10.1007/s10787-023-01259-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 05/26/2023] [Indexed: 06/16/2023]
Abstract
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor and non-motor symptoms. Although levodopa is the primary medication for PD, its long-term use is associated with complications such as dyskinesia and drug resistance, necessitating novel therapeutic approaches. Recent research has highlighted the potential of targeting opioid and cannabinoid receptors as innovative strategies for PD treatment. Modulating opioid transmission, particularly through activating µ (MOR) and δ (DOR) receptors while inhibiting κ (KOR) receptors, shows promise in preventing motor complications and reducing L-DOPA-induced dyskinesia. Opioids also possess neuroprotective properties and play a role in neuroprotection and seizure control. Similar to this, endocannabinoid signalling via CB1 and CB2 receptors influences the basal ganglia and may contribute to PD pathophysiology, making it a potential therapeutic target. In addition to opioid and cannabinoid receptor targeting, the NLRP3 pathway, implicated in neuroinflammation and neurodegeneration, emerges as another potential therapeutic avenue for PD. Recent studies suggest that targeting this pathway holds promise as a therapeutic strategy for PD management. This comprehensive review focuses on neuromodulation and novel therapeutic approaches for PD, specifically highlighting the targeting of opioid and cannabinoid receptors and the NLRP3 pathway. A better understanding of these mechanisms has the potential to enhance the quality of life for PD patients.
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Affiliation(s)
- Md Reyaz Alam
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
| | - Shamsher Singh
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India.
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18
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Bockmann EC, Brito R, Madeira LF, da Silva Sampaio L, de Melo Reis RA, França GR, Calaza KDC. The Role of Cannabinoids in CNS Development: Focus on Proliferation and Cell Death. Cell Mol Neurobiol 2023; 43:1469-1485. [PMID: 35925507 PMCID: PMC11412427 DOI: 10.1007/s10571-022-01263-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/15/2022] [Indexed: 11/26/2022]
Abstract
The active principles of Cannabis sativa are potential treatments for several diseases, such as pain, seizures and anorexia. With the increase in the use of cannabis for medicinal purposes, a more careful assessment of the possible impacts on embryonic development becomes necessary. Surveys indicate that approximately 3.9% of pregnant women use cannabis in a recreational and/or medicinal manner. However, although the literature has already described the presence of endocannabinoid system components since the early stages of CNS development, many of their physiological effects during this stage have not yet been established. Moreover, it is still uncertain how the endocannabinoid system can be altered in terms of cell proliferation and cell fate, neural migration, neural differentiation, synaptogenesis and particularly cell death. In relation to cell death in the CNS, knowledge about the effects of cannabinoids is scarce. Thus, the present work aims to review the role of the endocannabinoid system in different aspects of CNS development and discuss possible side effects or even opportunities for treating some conditions in the development of this tissue.
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Affiliation(s)
- Eduardo Cosendey Bockmann
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
| | - Rafael Brito
- Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
| | - Lucianne Fragel Madeira
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
| | - Luzia da Silva Sampaio
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ricardo Augusto de Melo Reis
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Guilherme Rapozeiro França
- Departamento de Ciências Fisiológicas, Instituto Biomédico, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Karin da Costa Calaza
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
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19
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Hippocampal expression of the cannabinoid receptor type 1 in canine epilepsy. Sci Rep 2023; 13:3138. [PMID: 36823232 PMCID: PMC9950490 DOI: 10.1038/s41598-023-29868-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 02/11/2023] [Indexed: 02/25/2023] Open
Abstract
Canine drug-resistant epilepsy is a prevailing issue in veterinary neurology. Alternative or additional treatment with cannabinoids is showing promising results in seizure management. A crucial component of the endocannabinoid system, cannabinoid receptor type 1 (CB1R), is heavily involved in the control of neurotransmitter release. Knowledge of its distribution in the epileptic brain would serve a better understanding of disease pathology and application of cannabinoids in dogs with epilepsy. CB1R distribution was assessed in sub-regions of hippocampus of dogs with idiopathic epilepsy, structural epilepsy and without cerebral pathology. In dogs with idiopathic epilepsy, significantly decreased CB1R expression compared to control animals was observed in CA1. In dogs with structural epilepsy, a significant increase in CB1R signal intensity in comparison to controls was observed. CB1R expression was higher in the structural group as compared to the idiopathic. Double immunofluorescence showed co-localization between CB1R and an astrocytic marker in about 50% of cells, regardless of the diagnosis. In summary, CB1R expression in canine hippocampus undergoes modification by the epileptic process and the direction of this change depends on the etiology of the disease. The distinct disease-associated CB1R expression needs to be considered in new treatment development for dogs with epilepsy.
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Cáceres D, Ochoa M, González-Ortiz M, Bravo K, Eugenín J. Effects of Prenatal Cannabinoids Exposure upon Placenta and Development of Respiratory Neural Circuits. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1428:199-232. [PMID: 37466775 DOI: 10.1007/978-3-031-32554-0_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
Cannabis use has risen dangerously during pregnancy in the face of incipient therapeutic use and a growing perception of safety. The main psychoactive compound of the Cannabis sativa plant is the phytocannabinoid delta-9-tetrahydrocannabinol (A-9 THC), and its status as a teratogen is controversial. THC and its endogenous analogues, anandamide (AEA) and 2-AG, exert their actions through specific receptors (eCBr) that activate intracellular signaling pathways. CB1r and CB2r, also called classic cannabinoid receptors, together with their endogenous ligands and the enzymes that synthesize and degrade them, constitute the endocannabinoid system. This system is distributed ubiquitously in various central and peripheral tissues. Although the endocannabinoid system's most studied role is controlling the release of neurotransmitters in the central nervous system, the study of long-term exposure to cannabinoids on fetal development is not well known and is vital for understanding environmental or pathological embryo-fetal or postnatal conditions. Prenatal exposure to cannabinoids in animal models has induced changes in placental and embryo-fetal organs. Particularly, cannabinoids could influence both neural and nonneural tissues and induce embryo-fetal pathological conditions in critical processes such as neural respiratory control. This review aims at the acute and chronic effects of prenatal exposure to cannabinoids on placental function and the embryo-fetal neurodevelopment of the respiratory pattern. The information provided here will serve as a theoretical framework to critically evaluate the teratogen effects of the consumption of cannabis during pregnancy.
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Affiliation(s)
- Daniela Cáceres
- Laboratorio de Sistemas Neurales, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Martín Ochoa
- Laboratorio de Sistemas Neurales, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Marcelo González-Ortiz
- Laboratorio de Investigación Materno-Fetal (LIMaF), Departamento de Obstetricia y Ginecología, Facultad de Medicina, Universidad de Concepción, Concepción, Chile
| | - Karina Bravo
- Laboratorio de Sistemas Neurales, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
- Facultad de Ingeniería, Universidad Autónoma de Chile, Providencia, Chile
| | - Jaime Eugenín
- Laboratorio de Sistemas Neurales, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.
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21
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Costas‐Insua C, Guzmán M. Endocannabinoid signaling in glioma. Glia 2023; 71:127-138. [PMID: 35322459 PMCID: PMC9790654 DOI: 10.1002/glia.24173] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/16/2022] [Accepted: 03/17/2022] [Indexed: 12/30/2022]
Abstract
High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB1 and CB2 receptors, as well as other elements of the endocannabinoid system. Accruing preclinical evidence supports that pharmacological activation of cannabinoid receptors located on glioma cells exerts overt anti-tumoral effects by modulating key intracellular signaling pathways. The mechanism of this cannabinoid receptor-evoked anti-tumoral activity in experimental models of glioma is intricate and may involve an inhibition not only of cancer cell survival/proliferation, but also of invasiveness, angiogenesis, and the stem cell-like properties of cancer cells, thereby affecting the complex tumor microenvironment. However, the precise biological role of the endocannabinoid system in the generation and progression of glioma seems very context-dependent and remains largely unknown. Increasing our basic knowledge on how (endo)cannabinoids act on glioma cells could help to optimize experimental cannabinoid-based anti-tumoral therapies, as well as the preliminary clinical testing that is currently underway.
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Affiliation(s)
- Carlos Costas‐Insua
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain,Department of Biochemistry and Molecular BiologyInstituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityMadridSpain,Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
| | - Manuel Guzmán
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain,Department of Biochemistry and Molecular BiologyInstituto Universitario de Investigación Neuroquímica (IUIN), Complutense UniversityMadridSpain,Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)MadridSpain
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22
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Xiao J, Zhou Y, Sun L, Wang H. Role of integrating cannabinoids and the endocannabinoid system in neonatal hypoxic-ischaemic encephalopathy. Front Mol Neurosci 2023; 16:1152167. [PMID: 37122621 PMCID: PMC10130673 DOI: 10.3389/fnmol.2023.1152167] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 03/16/2023] [Indexed: 05/02/2023] Open
Abstract
Neonatal hypoxic-ischaemic events, which can result in long-term neurological impairments or even cell death, are among the most significant causes of brain injury during neurodevelopment. The complexity of neonatal hypoxic-ischaemic pathophysiology and cellular pathways make it difficult to treat brain damage; hence, the development of new neuroprotective medicines is of great interest. Recently, numerous neuroprotective medicines have been developed to treat brain injuries and improve long-term outcomes based on comprehensive knowledge of the mechanisms that underlie neuronal plasticity following hypoxic-ischaemic brain injury. In this context, understanding of the medicinal potential of cannabinoids and the endocannabinoid system has recently increased. The endocannabinoid system plays a vital neuromodulatory role in numerous brain regions, ensuring appropriate control of neuronal activity. Its natural neuroprotection against adult brain injury or acute brain injury also clearly demonstrate the role of endocannabinoid signalling in modulating neuronal activity in the adult brain. The goal of this review is to examine how cannabinoid-derived compounds can be used to treat neonatal hypoxic-ischaemic brain injury and to assess the critical function of the endocannabinoid system and its potential for use as a new neuroprotective treatment for neonatal hypoxic-ischaemic brain injury.
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Affiliation(s)
- Jie Xiao
- Department of Pathology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China
| | - Yue Zhou
- Department of Pharmacy, Xindu District People’s Hospital of Chengdu, Chengdu, China
| | - Luqiang Sun
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Haichuan Wang
- Department of Paediatrics, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- *Correspondence: Haichuan Wang,
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23
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Ruiz-Contreras HA, Santamaría A, Arellano-Mendoza MG, Sánchez-Chapul L, Robles-Bañuelos B, Rangel-López E. Modulatory Activity of the Endocannabinoid System in the Development and Proliferation of Cells in the CNS. Neurotox Res 2022; 40:1690-1706. [PMID: 36522511 DOI: 10.1007/s12640-022-00592-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/21/2022] [Accepted: 10/08/2022] [Indexed: 12/23/2022]
Abstract
The Endocannabinoid System (ECS, also known as Endocannabinoidome) plays a key role in the function of the Central Nervous System, though the participation of this system on the early development - specifically in neuroprotection and proliferation of nerve cells - has been poorly studied. Here, we collect and describe evidence regarding how cannabinoid receptors CB1R and CB2R regulate several cell markers related to proliferation. While CB1R participates in the modulation of neuronal and glial proliferation, CB2R is involved in the proliferation of glial cells. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) exert significant effects on nerve cell proliferation. AEA generated during embryogenesis induces major effects on the differentiation of neuronal progenitor cells, whereas 2-AG participates in modulating cell migration events rather than affecting the neural proliferation rate. However, although the ECS has been demonstrated to participate in neuroprotection, more characterization on its role in neuronal and glial proliferation and differentiation is needed, especially in brain areas with recognized high neurogenesis rates. This has encouraged scientists to elucidate and propose specific mechanisms related with these cell proliferation mechanisms to better understand some neurodegenerative disorders such as Parkinson, Huntington and Alzheimer diseases, in which neuronal loss and poor neurogenesis are crucial factors for their onset and progression. In this review, we collect and present recent evidence published pointing to an active role of the ECS in the development and proliferation of nerve cells.
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Affiliation(s)
- Hipolito A Ruiz-Contreras
- Maestría en Ciencias en Farmacología, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Abel Santamaría
- Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular Y Nanotecnología, Instituto Nacional de Neurología Y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, 14269, Mexico City, Mexico.
| | - Mónica G Arellano-Mendoza
- Laboratorio de Investigación en Enfermedades Crónico Degenerativas, Sección de Estudios de Posgrado E Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Laura Sánchez-Chapul
- Laboratorio de Enfermedades Neuromusculares, División de Neurociencias Clínicas, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City, Mexico
| | - Benjamín Robles-Bañuelos
- Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular Y Nanotecnología, Instituto Nacional de Neurología Y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, 14269, Mexico City, Mexico
| | - Edgar Rangel-López
- Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular Y Nanotecnología, Instituto Nacional de Neurología Y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, 14269, Mexico City, Mexico.
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24
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The Cytotoxic Effects of Cannabidiol and Cannabigerol on Glioblastoma Stem Cells May Mostly Involve GPR55 and TRPV1 Signalling. Cancers (Basel) 2022; 14:cancers14235918. [PMID: 36497400 PMCID: PMC9738061 DOI: 10.3390/cancers14235918] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/18/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
Glioblastoma (GBM) is one of the most aggressive cancers, comprising 60-70% of all gliomas. The large G-protein-coupled receptor family includes cannabinoid receptors CB1, CB2, GPR55, and non-specific ion receptor protein transporters TRPs. First, we found up-regulated CNR1, GPR55, and TRPV1 expression in glioma patient-derived tissue samples and cell lines compared with non-malignant brain samples. CNR1 and GPR55 did not correlate with glioma grade, whereas TRPV1 negatively correlated with grade and positively correlated with longer overall survival. This suggests a tumour-suppressor role of TRPV1. With respect to markers of GBM stem cells, preferred targets of therapy, TRPV1 and GPR55, but not CNR1, strongly correlated with different sets of stemness gene markers: NOTCH, OLIG2, CD9, TRIM28, and TUFM and CD15, SOX2, OCT4, and ID1, respectively. This is in line with the higher expression of TRPV1 and GPR55 genes in GSCs compared with differentiated GBM cells. Second, in a panel of patient-derived GSCs, we found that CBG and CBD exhibited the highest cytotoxicity at a molar ratio of 3:1. We suggest that this mixture should be tested in experimental animals and clinical studies, in which currently used Δ9-tetrahydrocannabinol (THC) is replaced with efficient and non-psychoactive CBG in adjuvant standard-of-care therapy.
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25
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Blando S, Raffaele I, Chiricosta L, Valeri A, Gugliandolo A, Silvestro S, Pollastro F, Mazzon E. Cannabidiol Promotes Neuronal Differentiation Using Akt and Erk Pathways Triggered by Cb1 Signaling. Molecules 2022; 27:molecules27175644. [PMID: 36080415 PMCID: PMC9457834 DOI: 10.3390/molecules27175644] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
Recently, the scientific community has started to focus on the neurogenic potential of cannabinoids. The phytocompound cannabidiol (CBD) shows different mechanism of signaling on cannabinoid receptor 1 (CB1), depending on its concentration. In this study, we investigated if CBD may induce in vitro neuronal differentiation after treatment at 5 µM and 10 µM. For this purpose, we decided to use the spinal cord × neuroblastoma hybrid cell line (NSC-34) because of its proliferative and undifferentiated state. The messenger RNAs (mRNAs) expression profiles were tested using high-throughput sequencing technology and Western blot assay was used to determine the number of main proteins in different pathways. Interestingly, the treatment shows different genes associated with neurodifferentiation statistically significant, such as Rbfox3, Tubb3, Pax6 and Eno2. The CB1 signaling pathway is responsible for neuronal differentiation at 10 µM, as suggested by the presence of p-ERK and p-AKT, but not at 5 µM. A new correlation between CBD, neurodifferentiation and retinoic acid receptor-related orphan receptors (RORs) has been observed.
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Affiliation(s)
- Santino Blando
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy,
| | - Ivana Raffaele
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy,
| | - Luigi Chiricosta
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy,
| | - Andrea Valeri
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy,
| | - Agnese Gugliandolo
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy,
| | - Serena Silvestro
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy,
| | - Federica Pollastro
- Department of Pharmaceutical Sciences, University of Eastern Piedmont, Largo Donegani 2, 28100 Novara, Italy
| | - Emanuela Mazzon
- IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy,
- Correspondence:
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26
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Park Y, Watkins BA. Dietary PUFAs and Exercise Dynamic Actions on Endocannabinoids in Brain: Consequences for Neural Plasticity and Neuroinflammation. Adv Nutr 2022; 13:1989-2001. [PMID: 35675221 PMCID: PMC9526838 DOI: 10.1093/advances/nmac064] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 10/15/2021] [Accepted: 06/02/2022] [Indexed: 01/28/2023] Open
Abstract
The brain and peripheral nervous system provide oversight to muscle physiology and metabolism. Muscle is the largest organ in the body and critical for glucose sensitivity, prevention of diabetes, and control of obesity. The central nervous system produces endocannabinoids (eCBs) that play a role in brain neurobiology, such as inflammation and pain. Interestingly, studies in humans and rodents show that a moderate duration of exercise increases eCBs in the brain and blood and influences cannabinoid receptors. Cannabinoid actions in the nervous system have advanced our understanding of pain, well-being, and disease. Nutrition is an important aspect of brain and eCB physiology because eCBs are biosynthesized from PUFAs. The primary eCB metabolites are derived from arachidonic acid, a 20:4n-6 (ω-6) PUFA, and the n-3 (ω-3) PUFAs, EPA and DHA. The eCBs bind to cannabinoid receptors CB1 and CB2 to exert a wide range of activities, such as stimulating appetite, influencing energy metabolism, supporting the immune system, and facilitating neuroplasticity. A diet containing different essential n-6 and n-3 PUFAs will dominate the formation of specific eCBs, and subsequently their actions as ligands for CB1 and CB2. The eCBs also function as substrates for cyclooxygenase enzymes, including potential substrates for the oxylipins (OxLs), which can be proinflammatory. Together, the eCBs and OxLs act as modulators of neuroinflammation. Thus, dietary PUFAs have implications for exercise responses via synthesis of eCBs and their effects on neuroinflammation. Neurotrophins also participate in interactions between diet and the eCBs, specifically brain-derived neurotrophic factor (BDNF). BDNF supports neuroplasticity in cooperation with the endocannabinoid system (ECS). This review will describe the role of PUFAs in eCB biosynthesis, discuss the ECS and OxLs in neuroinflammation, highlight the evidence for exercise effects on eCBs, and describe eCB and BDNF actions on neuroplasticity.
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27
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Ramon-Duaso C, Conde-Moro AR, Busquets-Garcia A. Astroglial cannabinoid signaling and behavior. Glia 2022; 71:60-70. [PMID: 35293647 DOI: 10.1002/glia.24171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 11/11/2022]
Abstract
In neuroscience, the explosion of innovative and advanced technical accomplishments is fundamental to understanding brain functioning. For example, the possibility to distinguish glial and neuronal activities at the synaptic level and/or the appearance of new genetic tools to specifically monitor and manipulate astroglial functions revealed that astrocytes are involved in several facets of behavioral control. In this sense, the discovery of functional presence of type-1 cannabinoid receptors in astrocytes has led to identify important behavioral responses mediated by this specific pool of cannabinoid receptors. Thus, astroglial type-1 cannabinoid receptors are in the perfect place to play a role in a complex scenario in which astrocytes sense neuronal activity, release gliotransmitters and modulate the activity of other neurons, ultimately controlling behavioral responses. In this review, we will describe the known behavioral implications of astroglial cannabinoid signaling and highlight exciting unexplored research avenues on how astroglial cannabinoid signaling could affect behavior.
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Affiliation(s)
- Carla Ramon-Duaso
- Cell-Type Mechanisms in Normal and Pathological Behavior Research Group, Neuroscience Programme, IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Ana Rocio Conde-Moro
- Cell-Type Mechanisms in Normal and Pathological Behavior Research Group, Neuroscience Programme, IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Arnau Busquets-Garcia
- Cell-Type Mechanisms in Normal and Pathological Behavior Research Group, Neuroscience Programme, IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain
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28
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Simone JJ, Green MR, McCormick CM. Endocannabinoid system contributions to sex-specific adolescent neurodevelopment. Prog Neuropsychopharmacol Biol Psychiatry 2022; 113:110438. [PMID: 34534603 DOI: 10.1016/j.pnpbp.2021.110438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/13/2021] [Accepted: 09/08/2021] [Indexed: 01/08/2023]
Abstract
With an increasing number of countries and states adopting legislation permitting the use of cannabis for medical purposes, there is a growing interest among health and research professionals into the system through which cannabinoids principally act, the endocannabinoid system (ECS). Much of the seminal research into the ECS dates back only 30 years and, although there has been tremendous development within the field during this time, many questions remain. More recently, investigations have emerged examining the contributions of the ECS to normative development and the effect of altering this system during important critical periods. One such period is adolescence, a unique period during which brain and behaviours are maturing and reorganizing in preparation for adulthood, including shifts in endocannabinoid biology. The purpose of this review is to discuss findings to date regarding the maturation of the ECS during adolescence and the consequences of manipulations of the ECS during this period to normative neurodevelopmental processes, as well as highlight sex differences in ECS function, important technical considerations, and future directions. Because most of what we know is derived from preclinical studies on rodents, we provide relevant background of this model and some commentary on the translational relevance of the research in this area.
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Affiliation(s)
- Jonathan J Simone
- Department of Biological Sciences, 1812 Sir Isaac Brock Way, Brock University, St. Catharines, ON L2S 3A1, Canada; Centre for Neuroscience, 1812 Sir Isaac Brock Way, Brock University, St. Catharines, ON L2S 3A1, Canada; Huxley Health Inc., 8820 Jane St., Concord, ON, L4K 2M9, Canada; eCB Consulting Inc., PO Box 652, 3 Cameron St. W., Cannington, ON L0E 1E0, Canada; Medical Cannabis Canada, 601-3500 Lakeshore Rd. W., Oakville, ON L6L 0B4, Canada.
| | - Matthew R Green
- eCB Consulting Inc., PO Box 652, 3 Cameron St. W., Cannington, ON L0E 1E0, Canada; Medical Cannabis Canada, 601-3500 Lakeshore Rd. W., Oakville, ON L6L 0B4, Canada.
| | - Cheryl M McCormick
- Department of Biological Sciences, 1812 Sir Isaac Brock Way, Brock University, St. Catharines, ON L2S 3A1, Canada; Centre for Neuroscience, 1812 Sir Isaac Brock Way, Brock University, St. Catharines, ON L2S 3A1, Canada; Department of Psychology, 1812 Sir Isaac Brock Way, Brock University, St. Catharines, ON L2S 3A1, Canada.
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29
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Almeida MM, Dias-Rocha CP, Calviño C, Trevenzoli IH. Lipid endocannabinoids in energy metabolism, stress and developmental programming. Mol Cell Endocrinol 2022; 542:111522. [PMID: 34843899 DOI: 10.1016/j.mce.2021.111522] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 11/09/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022]
Abstract
The endocannabinoid system (ECS) regulates brain development and function, energy metabolism and stress in a sex-, age- and tissue-dependent manner. The ECS comprises mainly the bioactive lipid ligands anandamide (AEA) and 2-aracdonoylglycerol (2-AG), cannabinoid receptors 1 and 2 (CB1 and CB2), and several metabolizing enzymes. The endocannabinoid tonus is increased in obesity, stimulating food intake and a preference for fat, reward, and lipid accumulation in peripheral tissues, as well as favoring a positive energy balance. Energy balance and stress responses share adaptive mechanisms regulated by the ECS that seem to underlie the complex relationship between feeding and emotional behavior. The ECS is also a key regulator of development. Environmental insults (diet, toxicants, and stress) in critical periods of developmental plasticity, such as gestation, lactation and adolescence, alter the ECS and may predispose individuals to the development of chronic diseases and behavioral changes in the long term. This review is focused on the ECS and the developmental origins of health and disease (DOHaD).
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Affiliation(s)
- Mariana Macedo Almeida
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, RJ, Brazil
| | | | - Camila Calviño
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, RJ, Brazil
| | - Isis Hara Trevenzoli
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, RJ, Brazil.
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30
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Jayanthi S, Peesapati R, McCoy MT, Ladenheim B, Cadet JL. Footshock-Induced Abstinence from Compulsive Methamphetamine Self-administration in Rat Model Is Accompanied by Increased Hippocampal Expression of Cannabinoid Receptors (CB1 and CB2). Mol Neurobiol 2022; 59:1238-1248. [PMID: 34978045 PMCID: PMC8857101 DOI: 10.1007/s12035-021-02656-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/17/2021] [Indexed: 01/06/2023]
Abstract
Methamphetamine (METH) use disorder (MUD) is characterized by compulsive and repeated drug taking despite negative life consequences. Large intake of METH in humans and animals is accompanied by dysfunctions in learning and memory processes. The endocannabinoid system (ECS) is known to modulate synaptic plasticity and cognitive functions. In addition, the ECS has been implicated in some of the manifestations of substance use disorders (SUDs). We therefore sought to identify potential changes in the expression of various enzymes and of the receptors (CB1 and CB2) that are members of that system. Herein, we used a model of METH self-administration (SA) that includes a punishment phase (footshocks) that helps to separate rats into a compulsive METH phenotype (compulsive) that continues to take METH and a non-compulsive METH (abstinent) group that suppressed or stopped taking METH. Animals were euthanized 2 h after the last METH SA session and their hippocampi were used to measure mRNA levels of cannabinoid receptors (CB/Cnr), as well as those of synthesizing (DAGL-A, DAGL-B, NAPEPLD) and metabolizing (MGLL, FAAH, PTGS2) enzymes of the endocannabinoid cascade. Non-compulsive rats exhibited significant increased hippocampal expression of CB1/Cnr1 and CB2/Cnr2 mRNAs. mRNA levels of the synthesizing enzyme, DAGL-A, and of the metabolic enzymes, MGLL and FAAH, were also increased. Non-compulsive rats also exhibited a significant decrease in hippocampal Ptgs2 mRNA levels. Taken together, these observations implicate the hippocampal endocannabinoid system in the suppression of METH intake in the presence of adverse consequences.
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Affiliation(s)
- Subramaniam Jayanthi
- Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Ritvik Peesapati
- Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Michael T McCoy
- Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Bruce Ladenheim
- Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Jean Lud Cadet
- Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
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31
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Papa A, Pasquini S, Contri C, Gemma S, Campiani G, Butini S, Varani K, Vincenzi F. Polypharmacological Approaches for CNS Diseases: Focus on Endocannabinoid Degradation Inhibition. Cells 2022; 11:cells11030471. [PMID: 35159280 PMCID: PMC8834510 DOI: 10.3390/cells11030471] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/21/2022] [Accepted: 01/27/2022] [Indexed: 01/27/2023] Open
Abstract
Polypharmacology breaks up the classical paradigm of “one-drug, one target, one disease” electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy. ECS is an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 and type 2 (CB1 and CB2), and the main catabolic enzymes involved in the endocannabinoid inactivation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The multiple connections of the ECS with other signaling pathways in the CNS allows the consideration of the ECS as an optimal source of inspiration in the development of innovative polypharmacological compounds. In this review, we focused our attention on the reported polypharmacological examples in which FAAH and MAGL inhibitors are involved.
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Affiliation(s)
- Alessandro Papa
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; (A.P.); (S.G.); (G.C.)
| | - Silvia Pasquini
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy; (S.P.); (C.C.); (K.V.); (F.V.)
| | - Chiara Contri
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy; (S.P.); (C.C.); (K.V.); (F.V.)
| | - Sandra Gemma
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; (A.P.); (S.G.); (G.C.)
| | - Giuseppe Campiani
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; (A.P.); (S.G.); (G.C.)
| | - Stefania Butini
- Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; (A.P.); (S.G.); (G.C.)
- Correspondence: ; Tel.: +39-0577-234161
| | - Katia Varani
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy; (S.P.); (C.C.); (K.V.); (F.V.)
| | - Fabrizio Vincenzi
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy; (S.P.); (C.C.); (K.V.); (F.V.)
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Molecular Findings Guiding the Modulation of the Endocannabinoid System as a Potential Target to Treat Schizophrenia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1400:89-103. [DOI: 10.1007/978-3-030-97182-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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Gallego-Landin I, García-Baos A, Castro-Zavala A, Valverde O. Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression. Front Pharmacol 2021; 12:762738. [PMID: 34938182 PMCID: PMC8685322 DOI: 10.3389/fphar.2021.762738] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/11/2021] [Indexed: 01/04/2023] Open
Abstract
Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.
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Affiliation(s)
- Ines Gallego-Landin
- Neurobiology of Behaviour Research Group (GReNeC—NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Alba García-Baos
- Neurobiology of Behaviour Research Group (GReNeC—NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Adriana Castro-Zavala
- Neurobiology of Behaviour Research Group (GReNeC—NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Olga Valverde
- Neurobiology of Behaviour Research Group (GReNeC—NeuroBio), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
- Neuroscience Research Programme, IMIM-Hospital del Mar Research Institute, Barcelona, Spain
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Valeri A, Mazzon E. Cannabinoids and Neurogenesis: The Promised Solution for Neurodegeneration? Molecules 2021; 26:molecules26206313. [PMID: 34684894 PMCID: PMC8541184 DOI: 10.3390/molecules26206313] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/14/2021] [Accepted: 10/16/2021] [Indexed: 01/02/2023] Open
Abstract
The concept of neurons as irreplaceable cells does not hold true today. Experiments and evidence of neurogenesis, also, in the adult brain give hope that some compounds or drugs can enhance this process, helping to reverse the outcomes of diseases or traumas that once were thought to be everlasting. Cannabinoids, both from natural and artificial origins, already proved to have several beneficial effects (e.g., anti-inflammatory, anti-oxidants and analgesic action), but also capacity to increase neuronal population, by replacing the cells that were lost and/or regenerate a damaged nerve cell. Neurogenesis is a process which is not highly represented in literature as neuroprotection, though it is as important as prevention of nervous system damage, because it can represent a possible solution when neuronal death is already present, such as in neurodegenerative diseases. The aim of this review is to resume the experimental evidence of phyto- and synthetic cannabinoids effects on neurogenesis, both in vitro and in vivo, in order to elucidate if they possess also neurogenetic and neurorepairing properties.
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Isaac AR, de Velasco PC, Fraga KYD, Tavares-do-Carmo MDG, Campos RMP, Iannotti FA, Verde R, Martins DBG, Santos TA, Ferreira BK, de Mello FG, Di Marzo V, Andrade-da-Costa BLDS, de Melo Reis RA. Maternal omega-3 intake differentially affects the endocannabinoid system in the progeny`s neocortex and hippocampus: Impact on synaptic markers. J Nutr Biochem 2021; 96:108782. [PMID: 34038760 DOI: 10.1016/j.jnutbio.2021.108782] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 03/16/2021] [Accepted: 04/29/2021] [Indexed: 12/16/2022]
Abstract
Omega-3 (n-3) polyunsaturated fatty acids (PUFA) and the endocannabinoid system (ECS) modulate several functions through neurodevelopment including synaptic plasticity mechanisms. The interplay between n-3PUFA and the ECS during the early stages of development, however, is not fully understood. This study investigated the effects of maternal n-3PUFA supplementation (n-3Sup) or deficiency (n-3Def) on ECS and synaptic markers in postnatal offspring. Female rats were fed with a control, n-3Def, or n-3Sup diet from 15 days before mating and during pregnancy. The cerebral cortex and hippocampus of mothers and postnatal 1-2 days offspring were analyzed. In the mothers, a n-3 deficiency reduced CB1 receptor (CB1R) protein levels in the cortex and increased CB2 receptor (CB2R) in both cortex and hippocampus. In neonates, a maternal n-3 deficiency reduced the hippocampal CB1R amount while it increased CB2R. Additionally, total GFAP isoform expression was increased in both cortex and hippocampus in neonates of the n-3Def group. Otherwise, maternal n-3 supplementation increased the levels of n-3-derived endocannabinoids, DHEA and EPEA, in the cortex and hippocampus and reduced 2-arachidonoyl-glycerol (2-AG) concentrations in the cortex of the offspring. Furthermore, maternal n-3 supplementation also increased PKA phosphorylation in the cortex and ERK phosphorylation in the hippocampus. Synaptophysin immunocontent in both regions was also increased. In vitro assays showed that the increase of synaptophysin in the n-3Sup group was independent of CB1R activation. The findings show that variations in maternal dietary omega-3 PUFA levels may impact differently on the ECS and molecular markers in the cerebral cortex and hippocampus of the progeny.
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Affiliation(s)
- Alinny Rosendo Isaac
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
| | | | - Karla Yasmin Dias Fraga
- Instituto de Nutrição Josué de Castro (INJC), Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria das Graças Tavares-do-Carmo
- Instituto de Nutrição Josué de Castro (INJC), Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Raquel Maria Pereira Campos
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fabio Arturo Iannotti
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale delle Ricerche (CNR), Pozzuoli (NA), Italy
| | - Roberta Verde
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale delle Ricerche (CNR), Pozzuoli (NA), Italy
| | - Danyelly Bruneska Gondim Martins
- Grupo de Bioinformática e prospecção molecular, Laboratório de Imunopatologia Keizo Asami, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Thaysa Aragão Santos
- Grupo de Bioinformática e prospecção molecular, Laboratório de Imunopatologia Keizo Asami, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
| | - Bruna Klippel Ferreira
- Departamento de Bioquímica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernando Garcia de Mello
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale delle Ricerche (CNR), Pozzuoli (NA), Italy; Canada Exellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, CRIUCPQ and NUTRISS-INAF Universitè Laval, Quebec City, Canada
| | | | - Ricardo Augusto de Melo Reis
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Tveden-Nyborg P. Vitamin C Deficiency in the Young Brain-Findings from Experimental Animal Models. Nutrients 2021; 13:1685. [PMID: 34063417 PMCID: PMC8156420 DOI: 10.3390/nu13051685] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 12/17/2022] Open
Abstract
Severe and long-term vitamin C deficiency can lead to fatal scurvy, which is fortunately considered rare today. However, a moderate state of vitamin C (vitC) deficiency (hypovitaminosis C)-defined as a plasma concentration below 23 μM-is estimated to affect up to 10% of the population in the Western world, albeit clinical hallmarks in addition to scurvy have not been linked to vitC deficiency. The brain maintains a high vitC content and uniquely high levels during deficiency, supporting vitC's importance in the brain. Actions include both antioxidant and co-factor functions, rendering vitamin C deficiency likely to affect several targets in the brain, and it could be particularly significant during development where a high cellular metabolism and an immature antioxidant system might increase sensitivity. However, investigations of a non-scorbutic state of vitC deficiency and effects on the developing young brain are scarce. This narrative review provides a comprehensive overview of the complex mechanisms that regulate vitC homeostasis in vivo and in the brain in particular. Functions of vitC in the brain and the potential consequences of deficiency during brain development are highlighted, based primarily on findings from experimental animal models. Perspectives for future investigations of vitC are outlined.
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Affiliation(s)
- Pernille Tveden-Nyborg
- Section of Experimental Animal Models, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Copenhagen, Denmark
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Efficacy of Phytocannabinoids in Epilepsy Treatment: Novel Approaches and Recent Advances. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18083993. [PMID: 33920188 PMCID: PMC8070313 DOI: 10.3390/ijerph18083993] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/29/2022]
Abstract
Epilepsy is a neurological disorder mainly characterised by recurrent seizures that affect the entire population diagnosed with the condition. Currently, there is no cure for the disease and a significant proportion of patients have been deemed to have treatment-resistant epilepsy (TRE). A patient is deemed to have TRE if two or more antiepileptic drugs (AEDs) fail to bring about seizure remission. This inefficacy of traditional AEDs, coupled with their undesirable side effect profile, has led to researchers considering alternative forms of treatment. Phytocannabinoids have long served as therapeutics with delta-9-THC (Δ9-THC) receiving extensive focus to determine its therapeutic potential. This focus on Δ9-THC has been to the detriment of analysing the plethora of other phytocannabinoids found in the cannabis plant. The overall aim of this review is to explore other novel phytocannabinoids and their place in epilepsy treatment. The current review intends to achieve this aim via an exploration of the molecular targets underlying the anticonvulsant capabilities of cannabidiol (CBD), cannabidavarin (CBDV), delta-9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Further, this review will provide an exploration of current pre-clinical and clinical data as it relates to the aforementioned phytocannabinoids and the treatment of epilepsy symptoms. With specific reference to epilepsy in young adult and adolescent populations, the exploration of CBD, CBDV, Δ9-THCV and CBG in both preclinical and clinical environments can guide future research and aid in the further understanding of the role of phytocannabinoids in epilepsy treatment. Currently, much more research is warranted in this area to be conclusive.
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Song CG, Kang X, Yang F, Du WQ, Zhang JJ, Liu L, Kang JJ, Jia N, Yue H, Fan LY, Wu SX, Jiang W, Gao F. Endocannabinoid system in the neurodevelopment of GABAergic interneurons: implications for neurological and psychiatric disorders. Rev Neurosci 2021; 32:803-831. [PMID: 33781002 DOI: 10.1515/revneuro-2020-0134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 02/20/2021] [Indexed: 02/07/2023]
Abstract
In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.
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Affiliation(s)
- Chang-Geng Song
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China.,Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Xin Kang
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Fang Yang
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Wan-Qing Du
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Jia-Jia Zhang
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Long Liu
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Jun-Jun Kang
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Ning Jia
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Hui Yue
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Lu-Yu Fan
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Sheng-Xi Wu
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Wen Jiang
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, 127 Chang Le Xi Road, Xi'an710032, Shaanxi, China
| | - Fang Gao
- Department of Neurobiology and Institute of Neurosciences, Collaborative Innovation Center for Brain Science, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an710032, Shaanxi, China
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Endocannabinoids and aging-Inflammation, neuroplasticity, mood and pain. VITAMINS AND HORMONES 2021; 115:129-172. [PMID: 33706946 DOI: 10.1016/bs.vh.2020.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Aging is associated with changes in hormones, slowing of metabolism, diminished physiological processes, chronic inflammation and high exposure to oxidative stress factors, generally described as the biological cost of living. Lifestyle interventions of diet and exercise can improve the quality of life during aging and lower diet-related chronic disease. The endocannabinoid system (ECS) has important effects on systemic metabolism and physiological systems, including the central and peripheral nervous systems. Exercise can reduce the loss of muscle mass and improve strength, and increase the levels of endocannabinoids (eCB) in brain and blood. Although the ECS exerts controls on multiple systems throughout life it affords benefits to natural aging. The eCB are synthesized from polyunsaturated fatty acids (PUFA) and the primary ones are produced from arachidonic acid (n-6 PUFA) and others from the n-3 PUFA, namely eicosapentaenoic and docosahexaenoic acids. The eCB ligands bind to their receptors, CB1 and CB2, with effects on appetite stimulation, metabolism, immune functions, and brain physiology and neuroplasticity. Dietary families of PUFA are a primary factor that can influence the types and levels of eCB and as a consequence, the downstream actions when the ligands bind to their receptors. Furthermore, the association of eCB with the synthesis of oxylipins (OxL) is a connection between the physiological actions of eCB and the lipid derived immunological OxL mediators of inflammation. OxL are ubiquitous and influence neuroinflammation and inflammatory processes. The emerging actions of eCB on neuroplasticity, well-being and pain are important to aging. Herein, we present information about the ECS and its components, how exercise and diet affects specific eCB, their role in neuroplasticity, neuroinflammation, pain, mood, and relationship to OxL. Poor nutrition status and low nutrient intakes observed with many elderly are reasons to examine the role of dietary PUFA actions on the ECS to improve health.
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Durieux LJA, Gilissen SRJ, Arckens L. Endocannabinoids and cortical plasticity: CB1R as a possible regulator of the excitation/inhibition balance in health and disease. Eur J Neurosci 2021; 55:971-988. [PMID: 33427341 DOI: 10.1111/ejn.15110] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 12/27/2022]
Abstract
The endocannabinoid system has been linked to neurological disorders in which the excitation inhibition (E/I) balance in the neocortex is dysregulated, such as schizophrenia. The main endocannabinoid receptor type 1 of the central nervous system-CB1R-is expressed on different cell types, that when activated, modulate the cortical E/I balance. Here we review how CB1R signalling contributes to phases of heightened plasticity of the neocortex. We review the major role of the CB1R in cortical plasticity throughout life, including the early life sensory critical periods, the later maturation phase of the association cortex in adolescence, and the adult phase of sensory deprivation-induced cortical plasticity. Endocannabinoid-mediated long-term potentiation and depression of synapse strength fine-tune the E/I balance in visual, somatosensory and association areas. We emphasize how a distinct set of key endocannabinoid-regulated elements such as GABA and glutamate release, basket parvalbumin interneurons, somatostatin interneurons and astrocytes, are essential for normal cortical plasticity and dysregulated in schizophrenia. Even though a lot of data has been gathered, mechanistic knowledge about the exact CB1R-based modulation of excitation and/or inhibition is still lacking depending on cortical area and maturation phase in life. We emphasize the importance of creating such detailed knowledge for a better comprehension of what underlies the dysregulation of the neocortex in schizophrenic patients in adulthood. We propose that taking age, brain area and cell type into consideration when modulating the cortical E/I imbalance via cannabinoid-based pharmacology may pave the way for better patient care.
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Affiliation(s)
- Lucas J A Durieux
- KU Leuven, Department of Biology, Laboratory of Neuroplasticity and Neuroproteomics, Leuven, Belgium.,Leuven Brain Institute, Leuven, Belgium
| | - Sara R J Gilissen
- KU Leuven, Department of Biology, Laboratory of Neuroplasticity and Neuroproteomics, Leuven, Belgium.,Leuven Brain Institute, Leuven, Belgium
| | - Lutgarde Arckens
- KU Leuven, Department of Biology, Laboratory of Neuroplasticity and Neuroproteomics, Leuven, Belgium.,Leuven Brain Institute, Leuven, Belgium
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Neurodevelopmental signatures of narcotic and neuropsychiatric risk factors in 3D human-derived forebrain organoids. Mol Psychiatry 2021; 26:7760-7783. [PMID: 34158620 PMCID: PMC8873021 DOI: 10.1038/s41380-021-01189-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/20/2021] [Accepted: 06/01/2021] [Indexed: 02/06/2023]
Abstract
It is widely accepted that narcotic use during pregnancy and specific environmental factors (e.g., maternal immune activation and chronic stress) may increase risk of neuropsychiatric illness in offspring. However, little progress has been made in defining human-specific in utero neurodevelopmental pathology due to ethical and technical challenges associated with accessing human prenatal brain tissue. Here we utilized human induced pluripotent stem cells (hiPSCs) to generate reproducible organoids that recapitulate dorsal forebrain development including early corticogenesis. We systemically exposed organoid samples to chemically defined "enviromimetic" compounds to examine the developmental effects of various narcotic and neuropsychiatric-related risk factors within tissue of human origin. In tandem experiments conducted in parallel, we modeled exposure to opiates (μ-opioid agonist endomorphin), cannabinoids (WIN 55,212-2), alcohol (ethanol), smoking (nicotine), chronic stress (human cortisol), and maternal immune activation (human Interleukin-17a; IL17a). Human-derived dorsal forebrain organoids were consequently analyzed via an array of unbiased and high-throughput analytical approaches, including state-of-the-art TMT-16plex liquid chromatography/mass-spectrometry (LC/MS) proteomics, hybrid MS metabolomics, and flow cytometry panels to determine cell-cycle dynamics and rates of cell death. This pipeline subsequently revealed both common and unique proteome, reactome, and metabolome alterations as a consequence of enviromimetic modeling of narcotic use and neuropsychiatric-related risk factors in tissue of human origin. However, of our 6 treatment groups, human-derived organoids treated with the cannabinoid agonist WIN 55,212-2 exhibited the least convergence of all groups. Single-cell analysis revealed that WIN 55,212-2 increased DNA fragmentation, an indicator of apoptosis, in human-derived dorsal forebrain organoids. We subsequently confirmed induction of DNA damage and apoptosis by WIN 55,212-2 within 3D human-derived dorsal forebrain organoids. Lastly, in a BrdU pulse-chase neocortical neurogenesis paradigm, we identified that WIN 55,212-2 was the only enviromimetic treatment to disrupt newborn neuron numbers within human-derived dorsal forebrain organoids. Cumulatively this study serves as both a resource and foundation from which human 3D biologics can be used to resolve the non-genomic effects of neuropsychiatric risk factors under controlled laboratory conditions. While synthetic cannabinoids can differ from naturally occurring compounds in their effects, our data nonetheless suggests that exposure to WIN 55,212-2 elicits neurotoxicity within human-derived developing forebrain tissue. These human-derived data therefore support the long-standing belief that maternal use of cannabinoids may require caution so to avoid any potential neurodevelopmental effects upon developing offspring in utero.
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Gomes TM, Dias da Silva D, Carmo H, Carvalho F, Silva JP. Epigenetics and the endocannabinoid system signaling: An intricate interplay modulating neurodevelopment. Pharmacol Res 2020; 162:105237. [PMID: 33053442 DOI: 10.1016/j.phrs.2020.105237] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 09/16/2020] [Accepted: 10/02/2020] [Indexed: 01/08/2023]
Abstract
The endocannabinoid (eCB) system is a complex system comprising endogenous cannabinoids (eCBs), their synthesis and degradation enzymes, and cannabinoid receptors. These elements crucially regulate several biological processes during neurodevelopment, such as proliferation, differentiation, and migration. Recently, eCBs were also reported to have an epigenetic action on genes that play key functions in the neurotransmitter signaling, consequently regulating their expression. In turn, epigenetic modifications (e.g. DNA methylation, histone modifications) may also modulate the function of eCB system's elements. For example, the expression of the cnr gene in the central nervous system may be epigenetically regulated (e.g. DNA methylation, histone modifications), thus altering the function of the cannabinoid receptor type-1 (CB1R). Considering the importance of the eCB system during neurodevelopment, it is thus reasonable to expect that alterations in this interaction between the eCB system and epigenetic modifications may give rise to neurodevelopmental disorders. Here, we review key concepts related to the regulation of neuronal function by the eCB system and the different types of epigenetic modifications. In particular, we focus on the mechanisms involved in the intricate interplay between both signaling systems and how they control cell fate during neurodevelopment. Noteworthy, such mechanistic understanding assumes high relevance considering the implications of the dysregulation of key neurogenic processes towards the onset of neurodevelopment-related disorders. Moreover, considering the increasing popularity of cannabis and its synthetic derivatives among young adults, it becomes of utmost importance to understand how exogenous cannabinoids may epigenetically impact neurodevelopment.
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Affiliation(s)
- Telma Marisa Gomes
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Diana Dias da Silva
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Helena Carmo
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Félix Carvalho
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
| | - João Pedro Silva
- UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
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Morozov YM, Mackie K, Rakic P. Cannabinoid Type 1 Receptor is Undetectable in Rodent and Primate Cerebral Neural Stem Cells but Participates in Radial Neuronal Migration. Int J Mol Sci 2020; 21:ijms21228657. [PMID: 33212822 PMCID: PMC7696736 DOI: 10.3390/ijms21228657] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/13/2020] [Accepted: 11/15/2020] [Indexed: 12/14/2022] Open
Abstract
Cannabinoid type 1 receptor (CB1R) is expressed and participates in several aspects of cerebral cortex embryonic development as demonstrated with whole-transcriptome mRNA sequencing and other contemporary methods. However, the cellular location of CB1R, which helps to specify molecular mechanisms, remains to be documented. Using three-dimensional (3D) electron microscopic reconstruction, we examined CB1R immunolabeling in proliferating neural stem cells (NSCs) and migrating neurons in the embryonic mouse (Mus musculus) and rhesus macaque (Macaca mulatta) cerebral cortex. We found that the mitotic and postmitotic ventricular and subventricular zone (VZ and SVZ) cells are immunonegative in both species while radially migrating neurons in the intermediate zone (IZ) and cortical plate (CP) contain CB1R-positive intracellular vesicles. CB1R immunolabeling was more numerous and more extensive in monkeys compared to mice. In CB1R-knock out mice, projection neurons in the IZ show migration abnormalities such as an increased number of lateral processes. Thus, in radially migrating neurons CB1R provides a molecular substrate for the regulation of cell movement. Undetectable level of CB1R in VZ/SVZ cells indicates that previously suggested direct CB1R-transmitted regulation of cellular proliferation and fate determination demands rigorous re-examination. More abundant CB1R expression in monkey compared to mouse suggests that therapeutic or recreational cannabis use may be more distressing for immature primate neurons than inferred from experiments with rodents.
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Affiliation(s)
- Yury M. Morozov
- Department of Neuroscience, Kavli Institute for Neuroscience, Yale School of Medicine, Yale University, New Haven, CT 6510, USA
- Correspondence: (Y.M.M.); (P.R.)
| | - Ken Mackie
- Gill Center for Biomolecular Science, Indiana University, Bloomington, IN 47405-2204, USA;
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405-2204, USA
| | - Pasko Rakic
- Department of Neuroscience, Kavli Institute for Neuroscience, Yale School of Medicine, Yale University, New Haven, CT 6510, USA
- Correspondence: (Y.M.M.); (P.R.)
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44
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Haspula D, Clark MA. Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. Int J Mol Sci 2020; 21:E7693. [PMID: 33080916 PMCID: PMC7590033 DOI: 10.3390/ijms21207693] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/14/2020] [Accepted: 10/15/2020] [Indexed: 12/16/2022] Open
Abstract
The identification of the human cannabinoid receptors and their roles in health and disease, has been one of the most significant biochemical and pharmacological advancements to have occurred in the past few decades. In spite of the major strides made in furthering endocannabinoid research, therapeutic exploitation of the endocannabinoid system has often been a challenging task. An impaired endocannabinoid tone often manifests as changes in expression and/or functions of type 1 and/or type 2 cannabinoid receptors. It becomes important to understand how alterations in cannabinoid receptor cellular signaling can lead to disruptions in major physiological and biological functions, as they are often associated with the pathogenesis of several neurological, cardiovascular, metabolic, and inflammatory diseases. This review focusses mostly on the pathophysiological roles of type 1 and type 2 cannabinoid receptors, and it attempts to integrate both cellular and physiological functions of the cannabinoid receptors. Apart from an updated review of pre-clinical and clinical studies, the adequacy/inadequacy of cannabinoid-based therapeutics in various pathological conditions is also highlighted. Finally, alternative strategies to modulate endocannabinoid tone, and future directions are also emphasized.
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Affiliation(s)
- Dhanush Haspula
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA;
| | - Michelle A. Clark
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33314, USA
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45
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Lourenço DM, Ribeiro-Rodrigues L, Sebastião AM, Diógenes MJ, Xapelli S. Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy. Int J Mol Sci 2020; 21:E7309. [PMID: 33022963 PMCID: PMC7582633 DOI: 10.3390/ijms21197309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 01/18/2023] Open
Abstract
Epilepsy is one of the most common brain diseases worldwide, having a huge burden in society. The main hallmark of epilepsy is the occurrence of spontaneous recurrent seizures, having a tremendous impact on the lives of the patients and of their relatives. Currently, the therapeutic strategies are mostly based on the use of antiepileptic drugs, and because several types of epilepsies are of unknown origin, a high percentage of patients are resistant to the available pharmacotherapy, continuing to experience seizures overtime. Therefore, the search for new drugs and therapeutic targets is highly important. One key aspect to be targeted is the aberrant adult hippocampal neurogenesis (AHN) derived from Neural Stem Cells (NSCs). Indeed, targeting seizure-induced AHN may reduce recurrent seizures and shed some light on the mechanisms of disease. The endocannabinoid system is a known modulator of AHN, and due to the known endogenous antiepileptic properties, it is an interesting candidate for the generation of new antiepileptic drugs. However, further studies and clinical trials are required to investigate the putative mechanisms by which cannabinoids can be used to treat epilepsy. In this manuscript, we will review how cannabinoid-induced modulation of NSCs may promote neural plasticity and whether these drugs can be used as putative antiepileptic treatment.
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Affiliation(s)
- Diogo M. Lourenço
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (D.M.L.); (L.R.-R.); (A.M.S.); (M.J.D.)
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Leonor Ribeiro-Rodrigues
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (D.M.L.); (L.R.-R.); (A.M.S.); (M.J.D.)
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Ana M. Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (D.M.L.); (L.R.-R.); (A.M.S.); (M.J.D.)
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Maria J. Diógenes
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (D.M.L.); (L.R.-R.); (A.M.S.); (M.J.D.)
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
| | - Sara Xapelli
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; (D.M.L.); (L.R.-R.); (A.M.S.); (M.J.D.)
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal
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Abstract
The endocannabinoid system (ECS) is a highly versatile signaling system within the nervous system. Despite its widespread localization, its functions within the context of distinct neural processes are very well discernable and specific. This is remarkable, and the question remains as to how such specificity is achieved. One key player in the ECS is the cannabinoid type 1 receptor (CB1), a G protein-coupled receptor characterized by the complexity of its cell-specific expression, cellular and subcellular localization, and its adaptable regulation of intracellular signaling cascades. CB1 receptors are involved in different synaptic and cellular plasticity processes and in the brain's bioenergetics in a context-specific manner. CB2 receptors are also important in several processes in neurons, glial cells, and immune cells of the brain. As polymorphisms in ECS components, as well as external impacts such as stress and metabolic challenges, can both lead to dysregulated ECS activity and subsequently to possible neuropsychiatric disorders, pharmacological intervention targeting the ECS is a promising therapeutic approach. Understanding the neurobiology of cannabinoid receptor signaling in depth will aid optimal design of therapeutic interventions, minimizing unwanted side effects.
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Affiliation(s)
- Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
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Abstract
ABSTRACT:Cannabidiol (CBD) has been generating increasing interest in medicine due to its therapeutic properties and an apparent lack of negative side effects. Research has suggested that high dosages of CBD can be taken acutely and chronically with little to no risk. This review focuses on the neuroprotective effects of a CBD, with an emphasis on its implications for recovering from a mild traumatic brain injury (TBI) or concussion. CBD has been shown to influence the endocannabinoid system, both by affecting cannabinoid receptors and other receptors involved in the endocannabinoid system such as vanilloid receptor 1, adenosine receptors, and 5-hydroxytryptamine via cannabinoid receptor-independent mechanisms. Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species. Double-blind randomized controlled trials are still required to validate the use of CBD as medication following mild TBIs, such as concussion.
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48
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Han QW, Yuan YH, Chen NH. The therapeutic role of cannabinoid receptors and its agonists or antagonists in Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry 2020; 96:109745. [PMID: 31442553 DOI: 10.1016/j.pnpbp.2019.109745] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 08/19/2019] [Accepted: 08/19/2019] [Indexed: 12/16/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease and its characteristic is the progressive degeneration of dopaminergic neurons within the substantia nigra (SN) of the midbrain. There is hardly any clinically proven efficient therapeutics for its cure in several recent preclinical advances proposed to treat PD. Recent studies have found that the endocannabinoid signaling system in particular the comprised two receptors, CB1 and CB2 receptors, has a significant regulatory function in basal ganglia and is involved in the pathogenesis of PD. Therefore, adding new insights into the biochemical interactions between cannabinoids and other signaling pathways may help develop new pharmacological strategies. Factors of the endocannabinoid system (ECS) are abundantly expressed in the neural circuits of basal ganglia, where they interact interactively with glutamatergic, γ-aminobutyric acid-ergic (GABAergic), and dopaminergic signaling systems. Although preclinical studies on PD are promising, the use of cannabinoids at the clinical level has not been thoroughly studied. In this review, we evaluated the available evidence and reviewed the involvement of ECS in etiologies, symptoms and treatments related to PD. Since CB1 and CB2 receptors are the two main receptors of endocannabinoids, we primarily put the focus on the therapeutic role of CB1 and CB2 receptors in PD. We will try to determine future research clues that will help understand the potential therapeutic benefits of the ECS in the treatment of PD, aiming to open up new strategies and ideas for the treatment of PD.
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Affiliation(s)
- Qi-Wen Han
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica& Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yu-He Yuan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica& Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Nai-Hong Chen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica& Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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49
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Buceta I, Elezgarai I, Rico‐Barrio I, Gerrikagoitia I, Puente N, Grandes P. Deletion of the cannabinoid CB
1
receptor impacts on the ultrastructure of the cerebellar parallel fiber‐Purkinje cell synapses. J Comp Neurol 2019; 528:1041-1052. [DOI: 10.1002/cne.24808] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 10/09/2019] [Accepted: 10/31/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Ianire Buceta
- Department of Neurosciences, Faculty of Medicine and Nursing University of the Basque Country UPV/EHU Leioa Spain
- Achucarro Basque Center for Neuroscience Science Park of the University of the Basque Country UPV/EHU Leioa Spain
| | - Izaskun Elezgarai
- Department of Neurosciences, Faculty of Medicine and Nursing University of the Basque Country UPV/EHU Leioa Spain
- Achucarro Basque Center for Neuroscience Science Park of the University of the Basque Country UPV/EHU Leioa Spain
| | - Irantzu Rico‐Barrio
- Department of Neurosciences, Faculty of Medicine and Nursing University of the Basque Country UPV/EHU Leioa Spain
- Achucarro Basque Center for Neuroscience Science Park of the University of the Basque Country UPV/EHU Leioa Spain
| | - Inmaculada Gerrikagoitia
- Department of Neurosciences, Faculty of Medicine and Nursing University of the Basque Country UPV/EHU Leioa Spain
- Achucarro Basque Center for Neuroscience Science Park of the University of the Basque Country UPV/EHU Leioa Spain
| | - Nagore Puente
- Department of Neurosciences, Faculty of Medicine and Nursing University of the Basque Country UPV/EHU Leioa Spain
- Achucarro Basque Center for Neuroscience Science Park of the University of the Basque Country UPV/EHU Leioa Spain
| | - Pedro Grandes
- Department of Neurosciences, Faculty of Medicine and Nursing University of the Basque Country UPV/EHU Leioa Spain
- Achucarro Basque Center for Neuroscience Science Park of the University of the Basque Country UPV/EHU Leioa Spain
- Division of Medical Sciences University of Victoria Victoria British Columbia Canada
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50
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Zimmermann T, Maroso M, Beer A, Baddenhausen S, Ludewig S, Fan W, Vennin C, Loch S, Berninger B, Hofmann C, Korte M, Soltesz I, Lutz B, Leschik J. Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus. Cereb Cortex 2019; 28:4454-4471. [PMID: 30307491 PMCID: PMC6215469 DOI: 10.1093/cercor/bhy258] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Indexed: 12/19/2022] Open
Abstract
Neural stem cells (NSCs) in the adult mouse hippocampus occur in a specific neurogenic niche, where a multitude of extracellular signaling molecules converges to regulate NSC proliferation as well as fate and functional integration. However, the underlying mechanisms how NSCs react to extrinsic signals and convert them to intracellular responses still remains elusive. NSCs contain a functional endocannabinoid system, including the cannabinoid type-1 receptor (CB1). To decipher whether CB1 regulates adult neurogenesis directly or indirectly in vivo, we performed NSC-specific conditional inactivation of CB1 by using triple-transgenic mice. Here, we show that lack of CB1 in NSCs is sufficient to decrease proliferation of the stem cell pool, which consequently leads to a reduction in the number of newborn neurons. Furthermore, neuronal differentiation was compromised at the level of dendritic maturation pointing towards a postsynaptic role of CB1 in vivo. Deteriorated neurogenesis in NSC-specific CB1 knock-outs additionally resulted in reduced long-term potentiation in the hippocampal formation. The observed cellular and physiological alterations led to decreased short-term spatial memory and increased depression-like behavior. These results demonstrate that CB1 expressed in NSCs and their progeny controls neurogenesis in adult mice to regulate the NSC stem cell pool, dendritic morphology, activity-dependent plasticity, and behavior.
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Affiliation(s)
- Tina Zimmermann
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Mattia Maroso
- Department of Neurosurgery, Stanford University, USA
| | - Annika Beer
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Sarah Baddenhausen
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Susann Ludewig
- Zoological Institute, Division Cellular Neurobiology, TU Braunschweig, Germany
| | - Wenqiang Fan
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Constance Vennin
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany.,German Resilience Center (DRZ), Mainz
| | - Sebastian Loch
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Benedikt Berninger
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany.,Institute of Psychiatry, Psychology & Neuroscience, Centre for Developmental Neurobiology and MRC Centre for Neurodevelopmental Disorders, King's College London, UK
| | - Clementine Hofmann
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
| | - Martin Korte
- Zoological Institute, Division Cellular Neurobiology, TU Braunschweig, Germany.,Helmholtz Centre for Infection Research, Research group Neuroinflammation and Neurodegeneration, Braunschweig, Germany
| | - Ivan Soltesz
- Department of Neurosurgery, Stanford University, USA
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany.,German Resilience Center (DRZ), Mainz
| | - Julia Leschik
- Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
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