scholarly journals Immunomodulatory Potential of Cannabidiol in Multiple Sclerosis: a Systematic Review

2021 ◽  
Author(s):  
Alessia Furgiuele ◽  
Marco Cosentino ◽  
Marco Ferrari ◽  
Franca Marino
Keyword(s):  
Multiple Sclerosis ◽  
Systematic Review ◽  
Cannabis Sativa ◽  
Ex Vivo ◽  
Unmet Need ◽  
Autoimmune Encephalomyelitis ◽  
Dosing Regimens ◽  
The Central Nervous System ◽  
High Doses

AbstractMultiple sclerosis (MS) is the most common chronic autoimmune disease of the central nervous system. Efficacy of treatments for MS is associated with risk of adverse effects, and effective and well-tolerated drugs remain a major unmet need. Cannabis (Cannabis sativa L., fam. Cannabaceae) and cannabinoids are popular among MS patients to treat spasticity and pain. Cannabinoids are endowed with remarkable immunomodulating properties, and in particular the non-psychotropic cannabinoid cannabidiol (CBD) is increasingly recognized as anti-inflammatory and immunosuppressive, nevertheless with excellent tolerability even at high doses. In this systematic review, we retrieved and critically evaluated available evidence regarding the immune and disease-modifying effects of CBD in experimental autoimmune encephalomyelitis (EAE) and in MS. Evidence in rodent models of EAE strongly supports CBD as effective, while clinical evidence is still limited and usually negative, due to paucity of studies and possibly to the use of suboptimal dosing regimens. Better characterization of targets acted upon by CBD in MS should be obtained in ex vivo/in vitro studies in human immune cells, and higher doses should be tested in well-designed clinical trials with clinically relevant efficacy endpoints.

scholarly journals IFP35 family proteins promote neuroinflammation and multiple sclerosis

2021 ◽  
Vol 118 (32) ◽  
pp. e2102642118
Author(s):  
Xizhong Jing ◽  
Yongjie Yao ◽  
Danning Wu ◽  
Hao Hong ◽  
Xu Feng ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Immune Cells ◽  
Neutralizing Antibodies ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Multiple Cells ◽  
Excessive Activation ◽  
Experimental Autoimmune

Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B–dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi−/−, Ifp35−/−, or administration of neutralizing antibodies against IFP35 alleviated the immune cells’ infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.

scholarly journals Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 15
Author(s):  
Paweł Piatek ◽  
Magdalena Namiecinska ◽  
Małgorzata Domowicz ◽  
Marek Wieczorek ◽  
Sylwia Michlewska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cumulative Effect ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Cns Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d+CD154+ lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d+CD154+ lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d+CD154+ lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d+CD154+ lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d+CD154+ cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG35-55) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d+/CD154+ cells were found to be co-localized with O4+ cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d+CD154+ lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.

scholarly journals IL-9 as a mediator of Th17-driven inflammatory disease

2009 ◽  
Vol 206 (8) ◽  
pp. 1653-1660 ◽  
Author(s):  
Elizabeth C. Nowak ◽  
Casey T. Weaver ◽  
Henrietta Turner ◽  
Sakhina Begum-Haque ◽  
Burkhard Becher ◽  
...  
Keyword(s):  
Inflammatory Disease ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Autoimmune Encephalomyelitis ◽  
Regional Lymph Nodes ◽  
Functional Consequences ◽  
The Central Nervous System

We report that like other T cells cultured in the presence of transforming growth factor (TGF) β, Th17 cells also produce interleukin (IL) 9. Th17 cells generated in vitro with IL-6 and TGF-β as well as purified ex vivo Th17 cells both produced IL-9. To determine if IL-9 has functional consequences in Th17-mediated inflammatory disease, we evaluated the role of IL-9 in the development and progression of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. The data show that IL-9 neutralization and IL-9 receptor deficiency attenuates disease, and this correlates with decreases in Th17 cells and IL-6–producing macrophages in the central nervous system, as well as mast cell numbers in the regional lymph nodes. Collectively, these data implicate IL-9 as a Th17-derived cytokine that can contribute to inflammatory disease.

scholarly journals DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation

2019 ◽  
Vol 116 (18) ◽  
pp. 8985-8994 ◽  
Author(s):  
Massimo Costanza ◽  
Pietro L. Poliani ◽  
Paola Portararo ◽  
Barbara Cappetti ◽  
Silvia Musio ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Sterile Inflammation ◽  
Autoimmune Encephalomyelitis ◽  
Priming Phase ◽  
The Central Nervous System

The extrusion of DNA traps contributes to a key mechanism in which innate immune cells clear pathogens or induce sterile inflammation. Here we provide evidence that CD4+ T cells, a critical regulator of adaptive immunity, release extracellular threads of DNA on activation. These DNA extrusions convey autocrine costimulatory signals to T lymphocytes and can be detected in lymph nodes isolated during the priming phase of experimental autoimmune encephalomyelitis (EAE), a CD4+ T cell-driven mouse model of multiple sclerosis. Pharmacologic inhibition of mitochondrial reactive oxygen species (mtROS) abolishes the extrusion of DNA by CD4+ T cells, reducing cytokine production in vitro and T cell priming against myelin in vivo. Moreover, mtROS blockade during established EAE markedly ameliorates disease severity, dampening autoimmune inflammation of the central nervous system. Taken together, these experimental results elucidate a mechanism of intrinsic immune costimulation mediated by DNA threads released by activated T helper cells, and identify a potential therapeutic target for such disorders as multiple sclerosis, neuromyelitis optica, and CD4+ T cell-mediated disorders.

The protease inhibitor, Bowman-Birk Inhibitor, suppresses experimental autoimmune encephalomyelitis: a potential oral therapy for multiple sclerosis

2006 ◽  
Vol 12 (6) ◽  
pp. 688-697 ◽  
Author(s):  
B Gran ◽  
N Tabibzadeh ◽  
A Martin ◽  
E S Ventura ◽  
J H Ware ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Protease Inhibitor ◽  
Ex Vivo ◽  
Disease Onset ◽  
Autoimmune Encephalomyelitis ◽  
Treatment Protocols ◽  
Soybean Extract ◽  
Experimental Autoimmune

Available treatments for multiple sclerosis (MS) require frequent injections and have significant side effects. Proteases generated during inflammation are involved in the induction of tissue damage during inflammatory demyelination in the central nervous system (CNS). The Bowman-Birk Inhibitor (BBI), a soy-derived protease inhibitor with anti-carcinogenic and anti-inflammatory properties, has been shown to be well tolerated in clinical trials for pre-cancerous conditions, such as oral leukoplakia and the inflammatory disease, ulcerative colitis. We hypothesized that BBI may modulate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The BBI concentrate (BBIC), a soybean extract enriched in BBI, was administered to myelin basic protein (MBP)-immunized Lewis rats by gastric gavage in different treatment regimens, during the induction or the effector phase of disease. BBIC significantly delayed disease onset and suppressed disease severity, clinically and pathologically, in all treatment protocols. Both in vitro and ex vivo, BBIC inhibited MBP-specific proliferation of lymph node cells. BBIC reduced the activity of matrix metalloproteinase (MMP)-2 and -9 in spleen cell supernatants and was detected in the CNS of treated rats. BBIC suppresses EAE, it can be administered orally, and it is safe and relatively inexpensive. It may have a therapeutic role in patients with MS.

Cannabis Therapeutic Applications - Review

2020 ◽  
Vol 30 (Supplement_2) ◽  
Author(s):  
J Faim ◽  
J Balteiro
Keyword(s):  
Multiple Sclerosis ◽  
Systematic Review ◽  
Cannabis Sativa ◽  
Scientific Interest ◽  
Medical Cannabis ◽  
Therapeutic Application ◽  
Anti Tumour Activity ◽  
The Central Nervous System ◽  
Full Analysis ◽  
Tumour Activity

Abstract Introduction Medical cannabis refers to the use of cannabis or cannabinoids as medical therapy to treat disease or alleviate symptoms. Cannabinoids can be given orally, sublingually or topically, can be smoked, inhaled, mixed with food or made into tea. Objectives Elaboration of a systematic literature review about cannabis’s medicinal and therapeutic properties. It is intended to characterize the plant and its properties, highlighting the proven therapeutic evidence published in the area of oncology and diseases of the central nervous system. Methodology The selection of articles was based on the reading and analysis of the title and the abstract; only articles published in the last 15 years have been considered. After full analysis of the selected articles, it was concluded that 64 scientific articles were relevant to the study. Results With this systematic review, we can conclude that its therapeutic application in areas such as epilepsy, multiple sclerosis and in the relief of some cancer patient’s symptoms is promising. Its apparent anti-tumour activity in various types of cancer is of increasing scientific interest as current treatments in these situations are scarce. Conclusion The future of cannabis therapy is getting closer. It is therefore necessary to study and develop new synthetic analogues of THC, with better separation between therapeutic and side effects. Scientific advances show that Cannabis sativa is a treatment option for many conditions. With this systematic review we can conclude that its therapeutic application in areas such as epilepsy, multiple sclerosis and in the relief of some symptoms in cancer patients is promising. Its apparent anti-tumour activity in various types of cancer is also of increasing scientific interest.

Reduction of free radicals in multiple sclerosis: effect of glatiramer acetate (Copaxone®)

2008 ◽  
Vol 14 (6) ◽  
pp. 739-748 ◽  
Author(s):  
C Iarlori ◽  
D Gambi ◽  
A Lugaresi ◽  
A Patruno ◽  
M Felaco ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Free Radicals ◽  
Glatiramer Acetate ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Brain Lesions ◽  
Therapeutic Mechanism ◽  
The Central Nervous System ◽  
High Concentrations

Free radicals have been found in high concentrations within inflammatory multiple sclerosis (MS) lesions. The superoxide anion (O2–) reacts rapidly with nitric oxide (NO), producing peroxynitrite (ONOO–). Glatiramer acetate (GA) is a specific MS immunomodulator that induces the synthesis of Th2 cytokines, and reduces the frequency of relapses and the formation of active brain lesions. Proinflammatory cytokines could play a role in free radicals production in the peripheral immune system as well as in the central nervous system (CNS). The effect of GA on iNOS, superoxide radicals (O2–) and 3-nitrotyrosine production by peripheral blood adherent mononuclear cells (PBAMs) was assessed. Our findings demonstrate that in vitro GA reduced spontaneous and LPS-induced iNOS, 3-nitrotyrosine, NO and O2– production, and that similar inhibition can be demonstrated ex vivo in mononuclear cells obtained from GA-treated patients. The inhibition of the production of free radicals in PBAMs may represent a new therapeutic mechanism against inflammation during MS.

In Vivo Effect of Suloctidil as an Antiplatelet Agent

1979 ◽  
Vol 41 (03) ◽  
pp. 465-474 ◽  
Author(s):  
Marcia R Stelzer ◽  
Thomas S Burns ◽  
Robert N Saunders
Keyword(s):  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Ratio Method ◽  
Platelet Aggregate ◽  
Permanent Effect ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

Effects of Two Different Doses of Hirudin on APTT, Determined with Eight Different Reagents

1995 ◽  
Vol 73 (02) ◽  
pp. 219-222 ◽  
Author(s):  
Manuel Monreal ◽  
Luis Monreal ◽  
Rafael Ruiz de Gopegui ◽  
Yvonne Espada ◽  
Ana Maria Angles ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
In Vitro Study ◽  
Ex Vivo Model ◽  
Suitable Candidate ◽  
Significant Prolongation ◽  
High Doses ◽  
Different Doses

SummaryThe APTT has been considered the most suitable candidate to monitor the anticoagulant activity of hirudin. However, its use is hampered by problems of standardization, which make the results heavily dependent on the responsiveness of the reagent used. Our aim was to investigate if this different responsiveness of different reagents when added in vitro is to be confirmed in an ex vivo study.Two different doses of r-hirudin (CGP 39393), 0.3 mg/kg and 1 mg/kg, were administered subcutaneously to 20 New Zealand male rabbits, and the differences in prolongation of APTT 2 and 12 h later were compared, using 8 widely used commercial reagents. All groups exhibited a significant prolongation of APTT 2 h after sc administration of hirudin, both at low and high doses. But this prolongation persisted 12 h later only when the PTTa reagent (Boehringer Mannheim) was used. In general, hirudin prolonged the APTT most with the silica- based reagents.In a further study, we compared the same APTT reagents in an in vitro study in which normal pooled plasma was mixed with increasing amount of hirudin. We failed to confirm a higher sensitivity for silica- containing reagents. Thus, we conclude that subcutaneous administration of hirudin prolongs the APTT most with the silica-based reagents, but this effect is exclusive for the ex vivo model.

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

2021 ◽  
Author(s):  
William E. Barclay ◽  
M. Elizabeth Deerhake ◽  
Makoto Inoue ◽  
Toshiaki Nonaka ◽  
Kengo Nozaki ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Animal Model ◽  
Cell Death ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

ABSTRACTInflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.

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