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Burning mouth syndrome (BMS) is a neuropathic pain disorder associated with a burning sensation on oral mucosal surfaces with frequently reported xerostomia, dysgeusia and tingling or paraesthetic sensations. However, patients present no clinically evident causative lesions. The poor classification of the disorder has resulted in a diagnostic challenge, particularly for the clinician/dentist evaluating these individuals. Major research developments have been made in the BMS field in recent years to address this concern, principally in terms of the pathophysiological mechanisms underlying the disorder, in addition to therapeutic advancements. For the purpose of this review, an update on the pathophysiological mechanisms will be discussed from a neuropathic, immunological, hormonal and psychological perspective. This review will also focus on the many therapeutic strategies that have been explored for BMS, including antidepressants/antipsychotics, non-steroidal anti-inflammatories, hormone replacement therapies, phytotherapeutic compounds and non-pharmacological interventions, overall highlighting the lack of controlled clinical studies to support the effectiveness of such therapeutic avenues. Particular focus is given to the cannabinoid system and the potential of cannabis-based therapeutics in managing BMS patients.
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Síndrome de Boca Ardiente , Cannabinoides , Analgésicos/uso terapéutico , Antidepresivos , Síndrome de Boca Ardiente/tratamiento farmacológico , Síndrome de Boca Ardiente/etiología , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , HumanosRESUMEN
This Special Issue brings an update on some of the advances in research in the cannabinoid field, with focus on the impact of cannabinoids on inflammation [...].
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Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Inflamación/tratamiento farmacológico , Animales , HumanosRESUMEN
The innate immune response to bacterial and viral molecules involves the coordinated production of cytokines, chemokines, and type I interferons (IFNs), which is orchestrated by toll-like receptors (TLRs). TLRs, and their intracellular signalling intermediates, are closely associated with multiple sclerosis (MS) pathogenesis. Recent data from our laboratory reported that the plant-derived cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), regulate viral and bacterial inflammatory signalling pathways controlled by TLR3 and TLR4 in macrophages. The aim of this study was to assess the impact of THC and CBD, when delivered in isolation and in combination (1:1), on TLR3- and TLR4-dependent signalling in peripheral blood mononuclear cells (PBMCs) from people with MS (pwMS; n = 21) and healthy controls (HCs; n = 26). We employed the use of poly(I:C) and lipopolysaccharide (LPS) to induce viral TLR3 and bacterial TLR4 signalling, and PBMCs were pre-exposed to plant-derived highly purified THC (10 µM), CBD (10 µM), or a combination of both phytocannabinoids (1:1 ratio, 10:10 µM), prior to LPS/poly(I:C) exposure. TLR3 stimulation promoted the protein expression of the chemokine CXCL10 and the type I IFN-ß in PBMCs from both cohorts. THC and CBD (delivered in 1:1 combination at 10 µM) attenuated TLR3-induced CXCL10 and IFN-ß protein expression in PBMCs from pwMS and HCs, and this effect was not seen consistently when THC and CBD were delivered alone. In terms of LPS, TLR4 activation promoted TNF-α expression in PBMCs from both cohorts, and, interestingly, CBD when delivered alone at 10 µM, and in combination with THC (in 1:1 combination at 10 µM), exacerbated TLR4-induced TNF-α protein expression in PBMCs from pwMS and HCs. THC and CBD displayed no evidence of toxicity in primary PBMCs. No significant alteration in the relative expression of TLR3 and TLR4 mRNA, or components of the endocannabinoid system, including the cannabinoid receptor CB1 (encoded by CNR1 gene) and CB2 (encoded by CNR2 gene), and endocannabinoid metabolising enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGLL), was determined in PBMCs from pwMS versus HCs. Given their role in inflammation, TLRs are clinical targets, and data herein identify CBD and THC as TLR3 and TLR4 modulating drugs in primary immune cells in vitro. This offers insight on the cellular target(s) of phytocannabinoids in targeting inflammation in the context of MS.
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Cannabidiol , Esclerosis Múltiple , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 4/metabolismo , Cannabidiol/farmacología , Dronabinol/farmacología , Humanos , Leucocitos Mononucleares , Esclerosis Múltiple/tratamiento farmacológicoRESUMEN
The objective was to determine plasma levels of pro- (IL-12p70/IL-6) and anti-inflammatory (IL-10) cytokines before and after cycle ergometer training in healthy control (HC) and people with multiple sclerosis (pwMS), and to correlate plasma cytokines with physical/mental health. Study participants cycled for 30 min at 65-75% age-predicted maximal heart rate, twice a week for 8 weeks during supervised sessions. We determined that plasma IL-10 expression was lower in pwMS, compared to HCs, and that exercise augmented IL-10 in pwMS to baseline levels in HCs. Furthermore, plasma isolated from pwMS displayed enhanced expression of the pro-inflammatory cytokines IL-12p70/IL-6. Plasma cytokine signatures correlated with physical/mental health. Overall, this study highlights the potential of a short-term exercise programme to regulate circulating cytokine profiles with relevance to pwMS.
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Ciclismo , Terapia por Ejercicio/métodos , Interleucina-10/sangre , Esclerosis Múltiple/sangre , Esclerosis Múltiple/terapia , Adulto , Ciclismo/fisiología , Ergometría , Humanos , Subunidad p35 de la Interleucina-12/sangre , Interleucina-6/sangreRESUMEN
Following publication the authors informed the Journal that the published version of this article contained a mistake. All occurrences of pg/µl found in the original article should be changed to pg/L. The original article has been corrected. The correction has no impact on the conclusions drawn in the manuscript.
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BACKGROUND: Burning mouth syndrome (BMS) is a neuropathic orofacial pain condition of unknown aetiology that encompasses intra-oral burning pain without abnormal clinical findings. Psychological, neural and inflammatory processes are associated with BMS pathogenesis. Currently, studies characterising plasma cytokine/chemokine profiles with pain and depression in patients with BMS are lacking. Considering that inflammation is associated with the pathophysiology of BMS, and that inflammation is closely associated with pain and depression, we aimed to correlate depressive symptomatology and oral cavity pain with plasma cytokine/chemokine signatures in a cohort of patients with BMS. METHODS: In this study, plasma protein levels of Th1 cytokines (IFN-γ, IL-2, IL-12p70, TNF-α), Th2 cytokines (IL-4, IL-10, IL-6, IL-13) and the chemokine IL-8 were assessed in patients with BMS (n = 10) and healthy volunteers (n = 10), using pro-inflammatory-10-plex assays. Clinical histories, alongside self-rated oral cavity pain intensities and depressive symptomatology were assessed using a visual analogue scale and the 16-item Quick Inventory of Depressive Symptomatology questionnaires, respectively. RESULTS: We present evidence that BMS is associated with increased depressive symptomatology and enhanced oral cavity pain. Plasma isolated from BMS patients display enhanced expression of the pro-inflammatory chemokine IL-8, when compared to plasma from healthy individuals. Plasma IL-8 signature correlates with pain and depressive symptomatology in the study cohort. CONCLUSIONS: Overall, these findings indicate that plasma IL-8 profiles are dysregulated in BMS and that modulation of IL-8 production in the disorder may be a tool in the management of BMS symptomatology.
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Síndrome de Boca Ardiente/fisiopatología , Depresión/inducido químicamente , Depresión/psicología , Interleucina-8/sangre , Dolor/inducido químicamente , Dolor/psicología , Adulto , Anciano , Síndrome de Boca Ardiente/patología , Quimiocinas/sangre , Estudios de Cohortes , Citocinas/sangre , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Boca/fisiopatología , Dimensión del Dolor , Proyectos Piloto , Encuestas y Cuestionarios , Células TH1 , Células Th2RESUMEN
OBJECTIVE: The objective was to measure endocannabinoid (eCB) ligands and non-cannabinoid N-acylethanolamine (NAE) molecules in plasma from individuals with burning mouth syndrome (BMS) and to determine whether plasma eCB/NAE levels correlated with pain, inflammation and depressive symptomatology in this cohort. STUDY DESIGN: Plasma content of the eCBs, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and the NAE molecules, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were assessed in healthy subjects (n = 8) and in a cohort of newly diagnosed BMS patients (n = 9) using liquid chromatography-tandem mass spectrometry. Plasma eCBs and NAE profiles were correlated with self-rated oral cavity pain intensities, depressive symptomatology and plasma IL-8 levels. RESULTS: Plasma levels of PEA, but not OEA, AEA or 2-AG, were significantly elevated in patients with BMS, when compared to plasma from healthy individuals. Plasma PEA, OEA and AEA levels correlated with depressive symptomatology. CONCLUSIONS: This is the first evidence to indicate that circulating eCB/NAE levels are altered in BMS.
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Síndrome de Boca Ardiente/sangre , Endocannabinoides/sangre , Etanolaminas/sangre , Síndrome de Boca Ardiente/etiología , Femenino , Humanos , Persona de Mediana EdadRESUMEN
In this pilot study, we investigate whether a routine cycle ergometry training programme has therapeutic potential in individuals with multiple sclerosis (MS) by improving quality of life (QOL) and depressive symptomatology, while ameliorating cognitive disturbances. Healthy volunteers and MS patients cycled for 30 min at 65-75% age-predicted maximal heart rate on a recumbent ergometer, with this session repeated twice a week for 8 weeks. QOL, depressive symptomatology and cognitive function were assessed pre- and post-exercise using the MS Quality of Life-54 (MSQOL-54) questionnaire, 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) questionnaire and the Cambridge Neuropsychological Test Automated Battery (CANTAB), respectively. We determined that QOL was lower in MS patients, compared to healthy subjects, with a reduction in physical and mental health summary scores observed. Exercise improved both physical and mental health scores in MS patients. In support of this, exercise was shown to reduce depressive symptomatology in MS patients. Exercise was also associated with an improvement in visual sustained attention, executive function/cognitive flexibility and hippocampal-dependent visuospatial memory in patients. Overall, this study identifies a short-term exercise programme that improves physical and mental health, while reducing depressive symptomatology and cognitive dysfunction in MS.
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Cognición , Depresión/terapia , Terapia por Ejercicio , Esclerosis Múltiple/psicología , Esclerosis Múltiple/terapia , Calidad de Vida , Adulto , Índice de Masa Corporal , Peso Corporal , Depresión/fisiopatología , Ejercicio Físico/psicología , Terapia por Ejercicio/instrumentación , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , Esclerosis Múltiple/fisiopatología , Pruebas Neuropsicológicas , Aptitud Física , Proyectos Piloto , Resultado del TratamientoRESUMEN
The central nervous system, once thought to be a site of immunological privilege, has since been found to harbour immunocompetent cells and to communicate with the peripheral nervous system. In the central nervous system (CNS), glial cells display immunological responses to pathological and physiological stimuli through pro- and anti-inflammatory cytokine and chemokine signalling, antigen presentation and the clearing of cellular debris through phagocytosis. While this neuroinflammatory signalling can act to reduce neuronal damage and comprises a key facet of CNS homeostasis, persistent inflammation or auto-antigen-mediated immunoreactivity can induce a positive feedback cycle of neuroinflammation that ultimately results in necrosis of glia and neurons. Persistent neuroinflammation has been recognised as a major pathological component of virtually all neurodegenerative diseases and has also been a focus of research into the pathology underlying psychiatric disorders. Thus, pharmacological strategies to curb the pathological effects of persistent neuroinflammation are of interest for many disorders of the CNS. Accumulating evidence suggests that GABAergic activities are closely bound to immune processes and signals, and thus the GABAergic neurotransmitter system might represent an important therapeutic target in modulating neuroinflammation. Here, we review evidence that inflammation induces changes in the GABA neurotransmitter system in the CNS and that GABAergic signalling exerts a reciprocal influence over neuroinflammatory processes. Together, the data support the hypothesis that the GABA system is a potential therapeutic target in the modulation of central inflammation.
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Neuroinmunomodulación/inmunología , Receptores de GABA/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacología , Animales , Antiinflamatorios/uso terapéutico , Agonistas del GABA/metabolismo , Antagonistas del GABA/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Receptores de GABA/inmunología , Ácido gamma-Aminobutírico/inmunologíaRESUMEN
Accumulating evidence continues to underpin the role of the innate immune system in pathologies associated with neuroinflammation. Innate immunity is regulated by pattern recognition receptors that detect pathogens, and in the case of Gram-positive bacteria, binding of bacterial lipopeptides to toll-like receptor (TLR)2 is emerging as an important mechanism controlling glial cell activation. In the present study, we employed the use of the synthetic bacterial lipoprotein and a selective TLR2 agonist, Pam3CSK4, to induce inflammatory signaling in microglia and astrocytes. The adaptor proteins, downstream of kinase (Dok)1 and Dok2, are known to have a role in negatively regulating the Ras-ERK signaling cascade, with downstream consequences on pro-inflammatory cytokine expression. Data presented herein demonstrate that TLR2 enhanced the tyrosine phosphorylation of Dok1 and Dok2 in astrocytes and microglia, and that knockdown of these adaptors using small interfering RNA robustly elevated TLR2-induced ERK activation. Importantly, TLR2-induced NF-κB activation, and IL-6 production was exacerbated in astrocytes transfected with Dok1 and Dok2 siRNA, indicating that both Dok proteins negatively regulate TLR2-induced inflammatory signaling in astrocytes. In contrast, Dok1 knockdown attenuated TLR2-induced NF-κB activation and IL-6 production in microglia, while Dok2 siRNA failed to affect TLR2-induced NF-κB activity and subsequent cytokine expression in this cell type. Overall, this indicates that Dok1 and Dok2 are novel adaptors for TLR2 in glial cells and importantly indicates that Dok1 and Dok2 differentially regulate TLR2-induced pro-inflammatory signaling in astrocytes and microglia.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Astrocitos/metabolismo , Proteínas de Unión al ADN/metabolismo , Sistema de Señalización de MAP Quinasas , Microglía/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Unión al ARN/metabolismo , Receptor Toll-Like 2/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Células Cultivadas , Proteínas de Unión al ADN/genética , Inflamación/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopéptidos/farmacología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosfoproteínas/genética , Proteínas de Unión al ARN/genética , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 2/genéticaRESUMEN
Toll-like receptors (TLRs) have become a focus in biomedicine and biomedical research given the roles of this unique family of innate immune proteins in immune activation, infection, and autoimmunity. It is evident that TLR dysregulation, and subsequent alterations in TLR-mediated inflammatory signalling, can contribute to disease pathogenesis, and TLR targeted therapies are in development. This review highlights evidence that cannabinoids are key regulators of TLR signalling. Cannabinoids include component of the plant Cannabis sativa L. (C. sativa), synthetic and endogenous ligands, and overall represent a class of compounds whose therapeutic potential and mechanism of action continues to be elucidated. Cannabinoid-based medicines are in the clinic, and are furthermore under intense investigation for broad clinical development to manage symptoms of a range of disorders. In this review, we present an overview of research evidence that signalling linked to a range of TLRs is targeted by cannabinoids, and such cannabinoid mediated effects represent therapeutic avenues for further investigation. First, we provide an overview of TLRs, adaptors and key signalling events, alongside a summary of evidence that TLRs are linked to disease pathologies. Next, we discuss the cannabinoids system and the development of cannabinoid-based therapeutics. Finally, for the bulk of this review, we systematically outline the evidence that cannabinoids (plant-derived cannabinoids, synthetic cannabinoids, and endogenous cannabinoid ligands) can cross-talk with innate immune signalling governed by TLRs, focusing specifically on each member of the TLR family. Cannabinoids should be considered as key regulators of signalling controlled by TLRs, and such regulation should be a major focus in terms of the anti-inflammatory propensity of the cannabinoid system.
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Cannabinoides , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Cannabinoides/metabolismo , Receptores Toll-Like , Transducción de Señal , Endocannabinoides , Moduladores de Receptores de Cannabinoides , Ligandos , Receptores de CannabinoidesRESUMEN
Cannflavin A (CFL-A), a flavonoid present in the hemp plant Cannabis sativa L. (C. sativa), has anti-inflammatory and neuroprotective capacity. Research continues to elucidate the anti-inflammatory effects of components of C. sativa, with evidence that plant-derived cannabinoids and terpenes can mediate anti-inflammatory activity by targeting toll-like receptor (TLR) signalling, the sensors of pathogen-associated molecules. This study set out to determine if TLR-mediated inflammatory signalling is a CFL-A target using the endotoxin lipopolysaccharide (LPS) to induce TLR4 signalling in human THP-1-derived macrophages. TLR4 activation promoted the production of the chemokine CXCL10 and cytokines IL-1ß and TNFα. Treatment with CFL-A dose-dependently attenuated TLR4-induced CXCL10 and IL-1ß secretion, with our findings also indicating that the inhibitory effects of CFL-A on chemokine/cytokine secretion are in line with an NF-κB inhibitor. This study highlights TLR4 signalling as a cannflavin target in macrophages.
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We have demonstrated that R(+)WIN55,212-2, a synthetic cannabinoid that possesses cannabimimetic properties, acts as a novel regulator of Toll-like receptor 3 (TLR3) signaling to interferon (IFN) regulatory factor 3 (IRF3) activation and IFN-ß expression, and this is critical for manifesting its protective effects in a murine multiple sclerosis model. Here we investigated the role of peroxisome proliferator-activated receptor-α (PPARα) in mediating the effects of R(+)WIN55,212-2 on this pathway. Data herein demonstrate that the TLR3 agonist poly(I:C) promotes IFN-ß expression and R(+)WIN55,212-2 enhances TLR3-induced IFN-ß expression in a stereoselective manner via PPARα. R(+)WIN55,212-2 promotes increased transactivation and expression of PPARα. Using the PPARα antagonist GW6471, we demonstrate that R(+)WIN55,212-2 acts via PPARα to activate JNK, activator protein-1, and positive regulatory domain IV to transcriptionally regulate the IFN-ß promoter. Furthermore, GW6471 ameliorated the protective effects of R(+)WIN55,212-2 during the initial phase of experimental autoimmune encephalomyelitis. Overall, these findings define PPARα as an important mediator in manifesting the effects of R(+)WIN55,212-2 on the signaling cascade regulating IFN-ß expression. The study adds to our molecular appreciation of potential therapeutic effects of R(+)WIN55,212-2 in multiple sclerosis.
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Analgésicos/farmacología , Benzoxazinas/farmacología , Cannabinoides/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Interferón beta/biosíntesis , Morfolinas/farmacología , Naftalenos/farmacología , PPAR alfa/metabolismo , Animales , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Regulación de la Expresión Génica/genética , Células HEK293 , Humanos , Inductores de Interferón/farmacología , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Interferón beta/genética , Ratones , Oxazoles/farmacología , PPAR alfa/agonistas , PPAR alfa/genética , Poli I-C/farmacología , Tirosina/análogos & derivados , Tirosina/farmacologíaRESUMEN
Human embryology is a complex topic that brings together core components of anatomy and physiology to describe the developmental process from fertilisation to birth. Embryonic development is a challenging topic of study that is core to the curricula for health science students. There are challenges ingrained in teaching and learning embryology, due to the three-dimensional dynamic processes that occur as the embryo develops. This study aimed to develop and assess two newly developed animations depicting key processes in embryology, namely gastrulation and neurulation, as supplemental learning aids for students. Indeed, animated teaching tools to enhance the learning of gastrulation and neurulation are not widely available. A multi-disciplinary team of physiologists, biochemists, anatomists, and a computer scientist developed the animation sets. A student cohort of 81 first-year health science students were enrolled in this study over a period of three academic years. Both animations are in line with the course content of the first-year health science students undertaking the Human Health and Disease BSc at Trinity College Dublin, who were the study participants. Participants were randomly assigned to a non-animation control group and an animation group. Each set of animated teaching aids was broken down into individual clips which were given identifiable headings to allow the user to interchange between clips to facilitate a more personal learning experience. The animation group had open access to the animations for a three-week period. Questionnaires were designed to assess participants' attitude to the animations and their knowledge of embryology, both at the start of the study and three weeks later following access to the animations. Data presented herein indicate that students incorporated the animated teaching aids into digital home study and that the use of the animations acted as a supplemental tool that increased student knowledge in key areas of human embryology. From a qualitative point of view, students described the animations as enjoyable and helpful in visualising complex processes. This study indicates that the development of gastrulation and neurulation animated learning tools allow for a more engaging learning experience, facilitating student's engagement with academically challenging concepts in human embryology.
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Instrucción por Computador , Humanos , Neurulación , Gastrulación , Estudiantes , Aprendizaje , EnseñanzaRESUMEN
ß-Interferons (IFN-ßs) represent one of the first line treatments for relapsing-remitting multiple sclerosis, slowing disease progression while reducing the frequency of relapses. Despite this, more effective, well tolerated therapeutic strategies are needed. Cannabinoids palliate experimental autoimmune encephalomyelitis (EAE) symptoms and have therapeutic potential in MS patients although the precise molecular mechanism for these effects is not understood. Toll-like receptor (TLR) signaling controls innate immune responses and TLRs are implicated in MS. Here we demonstrate that the synthetic cannabinoid R(+)WIN55,212-2 is a novel regulator of TLR3 and TLR4 signaling by inhibiting the pro-inflammatory signaling axis triggered by TLR3 and TLR4, whereas selectively augmenting TLR3-induced activation of IFN regulatory factor 3 (IRF3) and expression of IFN-ß. We present evidence that R(+)WIN55,212-2 strongly promotes the nuclear localization of IRF3. The potentiation of IFN-ß expression by R(+)WIN55,212-2 is critical for manifesting its protective effects in the murine MS model EAE as evidenced by its reduced therapeutic efficacy in the presence of an anti-IFN-ß antibody. R(+)WIN55,212-2 also induces IFN-ß expression in MS patient peripheral blood mononuclear cells, whereas down-regulating inflammatory signaling in these cells. These findings identify R(+)WIN55,212-2 as a novel regulator of TLR3 signaling to IRF3 activation and IFN-ß expression and highlights a new mechanism that may be open to exploitation in the development of new therapeutics for the treatment of MS.
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Analgésicos/farmacología , Benzoxazinas/farmacología , Cannabinoides/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Factor 3 Regulador del Interferón/biosíntesis , Interferón beta/biosíntesis , Morfolinas/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Naftalenos/farmacología , Adulto , Animales , Línea Celular Tumoral , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Células HEK293 , Humanos , Factor 3 Regulador del Interferón/genética , Interferón beta/genética , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
BACKGROUND: The interaction between the membrane glycoprotein, CD200 and its cognate receptor CD200 receptor (CD200R), has been shown to play a role in maintaining microglia in a quiescent state. There is evidence of increased activation under resting and stimulated conditions in microglia prepared from CD200-deficient mice compared with wild-type mice, whereas activation of the receptor by CD200 fusion protein (CD200Fc) ameliorates inflammatory changes which are evident in the central nervous system (CNS) of the mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) and also in the hippocampus of aged rats. Additionally, an inverse relationship between microglial activation and expression of CD200 has been observed in animals treated with lipopolysaccharide (LPS) or amyloid-ß (Aß). METHODS: We assessed the effect of CD200R activation by CD200Fc on Aß-induced production of the pro-inflammatory cytokines, interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNFα) and the expression of microglial activation markers, CD68 and CD40 in cultured glia. The role played by downstream of tyrosine kinase 2 (Dok2) phosphorylation in mediating the effects of CD200R activation was evaluated by siRNA knockdown of Dok2. To further examine the impact of inflammatory changes on synaptic plasticity, the effect of CD200Fc on Aß-induced impairment of long-term potentiation (LTP) in the CA1 region of hippocampal slices was also investigated. RESULTS: We demonstrate that Aß-induced increases in IL-1ß, TNFα, CD68 and CD40 were inhibited by CD200Fc. The evidence suggests that Dok2 phosphorylation is a key factor in mediating the effect of CD200Fc, since Dok2 knockdown by siRNA abrogated its effects on microglial activation and inflammatory cytokine production. Consistent with evidence that inflammatory changes negatively impact on LTP, we show that the Aß-induced impairment of LTP was attenuated by CD200Fc. CONCLUSIONS: The findings suggest that activation of CD200R and Dok2 is a valuable strategy for modulating microglial activation and may have therapeutic potential in neurodegenerative conditions.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Péptidos beta-Amiloides/farmacología , Inmunoglobulina G/farmacología , Neuroglía/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Fosfoproteínas/metabolismo , Análisis de Varianza , Animales , Animales Recién Nacidos , Antígenos CD/genética , Antígenos CD/metabolismo , Proteínas de Arabidopsis/metabolismo , Encéfalo/citología , Células Cultivadas , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Transferasas Intramoleculares/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/genética , Ratones , Ratones Endogámicos C57BL , Técnicas de Placa-Clamp , Fosforilación/efectos de los fármacos , Interferencia de ARN/fisiología , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The biologically active components of cannabis have therapeutic potential in neuroinflammatory disorders due to their anti-inflammatory propensity. Cannabinoids influence immune function in both the peripheral and the central nervous system (CNS), and the components of the cannabinoid system, the cannabinoid receptors and their endogenous ligands (endocannabinoids), have been detected on immune cells as well as in brain glia. Neuroinflammation is the complex innate immune response of neural tissue to control infection and eliminate pathogens, and Toll-like receptors (TLRs), a major family of pattern recognition receptors (PRRs) that mediate innate immunity, have emerged as players in the neuroinflammatory processes underpinning various CNS diseases. This review will highlight evidence that cannabinoids interact with the immune system by impacting TLR-mediated signaling events, which may provide cues for devising novel therapeutic approaches for cannabinoid ligands.
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Cannabinoides/uso terapéutico , Inmunidad Innata , Inflamación/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Receptores Toll-Like/fisiología , Humanos , Inflamación/inmunología , Enfermedades del Sistema Nervioso/inmunologíaRESUMEN
Cannabidiol (CBD), one of the primary non-euphoric components in the Cannabis sativa L. plant, has undergone clinical development over the last number of years as a therapeutic for patients with Lennox-Gastaut syndrome and Dravet syndromes. This phytocannabinoid demonstrates functional and pharmacological diversity, and research data indicate that CBD is a comparable antioxidant to common antioxidants. This review gathers the latest knowledge regarding the impact of CBD on oxidative signalling, with focus on the proclivity of CBD to regulate antioxidants and control the production of reactive oxygen species. CBD is considered an attractive therapeutic agent for neuroimmune disorders, and a body of literature indicates that CBD can regulate redox function at multiple levels, with a range of downstream effects on cells and tissues. However, pro-oxidant capacity of CBD has also been reported, and hence caution must be applied when considering CBD from a therapeutic standpoint. Such pro- and antioxidant functions of CBD may be cell- and model-dependent and may also be influenced by CBD dose, the duration of CBD treatment and the underlying pathology.
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BACKGROUND AND PURPOSE: Cannabidiol (CBD) has been shown to differentially regulate the mechanistic target of rapamycin complex 1 (mTORC1) in preclinical models of disease, where it reduces activity in models of epilepsies and cancer and increases it in models of multiple sclerosis (MS) and psychosis. Here, we investigate the effects of phytocannabinoids on mTORC1 and define a molecular mechanism. EXPERIMENTAL APPROACH: A novel mechanism for phytocannabinoids was identified using the tractable model system, Dictyostelium discoideum. Using mouse embryonic fibroblasts, we further validate this new mechanism of action. We demonstrate clinical relevance using cells derived from healthy individuals and from people with MS (pwMS). KEY RESULTS: Both CBD and the more abundant cannabigerol (CBG) enhance mTORC1 activity in D. discoideum. We identify a mechanism for this effect involving inositol polyphosphate multikinase (IPMK), where elevated IPMK expression reverses the response to phytocannabinoids, decreasing mTORC1 activity upon treatment, providing new insight on phytocannabinoids' actions. We further validated this mechanism using mouse embryonic fibroblasts. Clinical relevance of this effect was shown in primary human peripheral blood mononuclear cells, where CBD and CBG treatment increased mTORC1 activity in cells derived from healthy individuals and decreased mTORC1 activity in cells derived from pwMS. CONCLUSION AND IMPLICATIONS: Our findings suggest that both CBD and the abundant CBG differentially regulate mTORC1 signalling through a mechanism dependent on the activity of the upstream IPMK signalling pathway, with potential relevance to the treatment of mTOR-related disorders, including MS.