How CBD Reduces Multiple Sclerosis Symptoms Has Now Been Revealed
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Multiple Sclerosis (MS) is a chronic, sometimes debilitating,autoimmune diseasewhich affects the brain and spinal cord. Symptoms, and the severity of those symptoms, can vary dramatically over time with many sufferers reporting symptoms worsening steadily over time, or going through periods of relapse and remission where symptoms come and go.
The disease is most commonly characterized by issues with mobility, ranging anywhere from numbness in one or more limbs, to paralysis. People with MS also report experiencing one, or a combination of, the following symptoms: problems with their vision, pain or muscle spasms, cognitive impairment, and fatigue.
Though it isstill unknownexactly causes MS, studies on animals with experimental autoimmune encephalomyelitis (EAE), the animal model for MS in humans, revealedantigen-specific T cells crossing the blood-brain barrierwhich triggered neuroinflammation. This led to the destruction of myelinated neuronal cells and produced symptoms of paralysis as a result of this demyelination.
A commercial cannabis-based treatment for MS
Cannabidiol (CBD), the main non-psychoactive component of cannabis, is known to exhibit bothanti-inflammatoryandneuroprotectiveeffects against known and suspected autoimmune diseases, such as ulcerative colitis andAlzheimer’s disease. Given what little is known about the etiology of MS, it was theorized that medicinal CBD could also be of benefit to MS patients. Drugs such asSativex, a cannabis oil consisting mainly of CBD and Δ9-tetrahydrocannabinol (THC), can now be prescribed to MS patients living in countries and states with medicinal cannabis programs who feel that their symptoms are not being relieved by traditional pharmaceuticals.
While clinical studies show that patients receiving Sativex doreport a better quality of life and lower spasticitythan they did prior to starting CBD oil treatment, the exact method through which CBD interacts with the mechanisms that are thought to cause MS remains unclear.
New research from the Department of Pathology in the University of South Carolina School of Medicine, Columbia, published last week inFrontiers in Immunologystudied the treatment of murine EAE with CBD oil in order to characterize the previously unknown biochemical mechanisms through which CBD inhibits MS-like symptoms.
The effect of CBD on clinical symptoms
The research team induced EAE in groups of female mice using the peptide MOG35-55 as an antigen. These mice were then treated with either CBD or a control vehicle once the first EAE symptoms were observed. The progression of disease was tracked using clinical scores associated with different symptom expressions. The scores were measured on a scale of 0 to 6, representing the full range of observable symptoms from no clinical signs all the way to death. The mean score for each group of mice was calculated daily and the scores for CBD treated mice (EAE-CBD) and the control group treated with the vehicle (EAE-VEH) were compared to assess the objective effectiveness of CBD treatment.
EAE-VEH老鼠以稳定的速度开发的实验性自身免疫性脑脊髓炎,with a maximum mean clinical score of 4.1 over the course of the study. A clinical score of 4 in this study corresponds to a state of tetraparalysis. The EAE-CBD mice experienced a slower onset of symptoms, and at their peak the mean clinical score of symptoms was 2.2, which indicates only partial paralysis of the hind limbs.
With confirmation that CBD treatment does have a clear effect on EAE, the researchers carried out a number of in vivo and ex vivo tests to try to pinpoint exactly what biochemical mechanisms were responsible for the effectiveness of the treatment.
The effect of CBD on cytokines and transcription factors
It is already known thatEAE in mice is triggered by Th1 and TH17 cells, so the researchers first chose to examine the effect of CBD on the cytokines that affect these cells, as well as some additional cytokines and transcription factors that are closely related.
It was found that EAE-VEH mice had considerably higher levels of the transcription factors T-bet and RORγT compared to mice who did not have EAE. These levels were not seen in EAE-CBD mice, indicating that treatment with CBD may affect these transcription factors.
Analysis of the cytokine levels in EAE-VEH mice re-stimulated with MOG showed heightened levels of IFNγ, IL-17, TNFα, and IL-10 cytokines. By comparison, the EAE-CBD mice displayed far lower levels of IFNγ and IL-17, but had a similar TNFα reading, and production of IL-10 in the mice had increased.
Taking into account both the differences in cytokine and transcription factors, the data indicates that CBD treatment leads to the suppression of cytokines and transcription factors that are known to display pro-inflammatory effects, while also promoting the production of IL10, a cytokine which is known to havestrong anti-inflammatory properties.
The importance of MDSCs
MDSCs, or myeloid-derived suppressor cells, are another suspected factor in the onset of MS and MS-like symptoms as they are known to take part in thesuppression of neuroinflammation. It is thought that MDSCs also play a role in autoimmune diseases byaffecting T cell functionand so the effect of CBD on MDSCs was also studied as an alternate route by which CBD might be suppressing MS symptoms.
EAE-CBD老鼠被发现显示显著的家庭r counts of CD11b+Gr-1+ MDSCs than the EAE-VEH mice in the peritoneal cavity where the CBD was injected, but that these levels were not heightened in the central nervous system, spinal cord, or brain. Levels in the central nervous system were actually slightly reduced in comparison to EAE-VEH mice. It is theorized that this difference is due to the MDSCs in the periphery being unable to migrate to the central nervous system, but by inhibiting T cell induction in secondary lymphoid organs it was possible for the CBD-induced MDSCs to prevent the T cells from proliferating and causing the clinical disease. This was supported by the total viable cell number of the T cells, which showed that the MDSCs were not killing the T cells after they were triggered by the autoimmune disease, but that they were being suppressed and inhibited from proliferating.
Importantly, MDSCs areknown to produce IL-10. Researchers noted a dose-dependent response from CBD treatment on MDSC levels in this study, indicating that CBD’s ability to mediate EAE symptoms could be a result of both its direct IL-10 induction, and by an indirect effect through raising the MDSC levels which in turn produces more of the anti-inflammatory IL-10.
An additional experiment was carried out to investigate the effects of MDSC depletion on clinical symptoms. Lowering MDSC levels by injection of the antibody RB6-8C5 into mice that had been successfully treated with CBD reversed the effects of the treatment. This further supports the theory that indirect manipulation of MDSCs is a significant contributing factor to the effectiveness of CBD treatment.
The new model for CBD’s action on MS symptoms
The research carried out in this study has identified two previously unknown mechanisms through which CBD can act to curb the clinical effects of MS and MS-like conditions - the first being through a direct positive influence on the levels of anti-inflammatory cytokines and a similar negative influence on pro-inflammatory cytokines; the second being via an indirect manipulation of anti-inflammatory MDSCs which inhibit the T cell induction that normally occurs in autoimmune disease. The discovery of these mechanisms provides the field of cannabis science with a better understanding of the action of CBD in the body, which is important in the efforts to discover more effective drugs to combat autoimmune diseases.
The authors of the study conclude their research paper with the recommendation that “CBD may constitute an excellent candidate for the treatment of MS and other autoimmune diseases” as a novel non-psychoactive therapeutic. Further study of MDSC manipulation by cannabinoid-based drugs could lead to the development of novel drugs and other future advances in autoimmune disease treatment.
The disease is most commonly characterized by issues with mobility, ranging anywhere from numbness in one or more limbs, to paralysis. People with MS also report experiencing one, or a combination of, the following symptoms: problems with their vision, pain or muscle spasms, cognitive impairment, and fatigue.
Though it isstill unknownexactly causes MS, studies on animals with experimental autoimmune encephalomyelitis (EAE), the animal model for MS in humans, revealedantigen-specific T cells crossing the blood-brain barrierwhich triggered neuroinflammation. This led to the destruction of myelinated neuronal cells and produced symptoms of paralysis as a result of this demyelination.
A commercial cannabis-based treatment for MS
Cannabidiol (CBD), the main non-psychoactive component of cannabis, is known to exhibit bothanti-inflammatoryandneuroprotectiveeffects against known and suspected autoimmune diseases, such as ulcerative colitis andAlzheimer’s disease. Given what little is known about the etiology of MS, it was theorized that medicinal CBD could also be of benefit to MS patients. Drugs such asSativex, a cannabis oil consisting mainly of CBD and Δ9-tetrahydrocannabinol (THC), can now be prescribed to MS patients living in countries and states with medicinal cannabis programs who feel that their symptoms are not being relieved by traditional pharmaceuticals.
While clinical studies show that patients receiving Sativex doreport a better quality of life and lower spasticitythan they did prior to starting CBD oil treatment, the exact method through which CBD interacts with the mechanisms that are thought to cause MS remains unclear.
New research from the Department of Pathology in the University of South Carolina School of Medicine, Columbia, published last week inFrontiers in Immunologystudied the treatment of murine EAE with CBD oil in order to characterize the previously unknown biochemical mechanisms through which CBD inhibits MS-like symptoms.
The effect of CBD on clinical symptoms
The research team induced EAE in groups of female mice using the peptide MOG35-55 as an antigen. These mice were then treated with either CBD or a control vehicle once the first EAE symptoms were observed. The progression of disease was tracked using clinical scores associated with different symptom expressions. The scores were measured on a scale of 0 to 6, representing the full range of observable symptoms from no clinical signs all the way to death. The mean score for each group of mice was calculated daily and the scores for CBD treated mice (EAE-CBD) and the control group treated with the vehicle (EAE-VEH) were compared to assess the objective effectiveness of CBD treatment.
EAE-VEH老鼠以稳定的速度开发的实验性自身免疫性脑脊髓炎,with a maximum mean clinical score of 4.1 over the course of the study. A clinical score of 4 in this study corresponds to a state of tetraparalysis. The EAE-CBD mice experienced a slower onset of symptoms, and at their peak the mean clinical score of symptoms was 2.2, which indicates only partial paralysis of the hind limbs.
With confirmation that CBD treatment does have a clear effect on EAE, the researchers carried out a number of in vivo and ex vivo tests to try to pinpoint exactly what biochemical mechanisms were responsible for the effectiveness of the treatment.
The effect of CBD on cytokines and transcription factors
It is already known thatEAE in mice is triggered by Th1 and TH17 cells, so the researchers first chose to examine the effect of CBD on the cytokines that affect these cells, as well as some additional cytokines and transcription factors that are closely related.
It was found that EAE-VEH mice had considerably higher levels of the transcription factors T-bet and RORγT compared to mice who did not have EAE. These levels were not seen in EAE-CBD mice, indicating that treatment with CBD may affect these transcription factors.
Analysis of the cytokine levels in EAE-VEH mice re-stimulated with MOG showed heightened levels of IFNγ, IL-17, TNFα, and IL-10 cytokines. By comparison, the EAE-CBD mice displayed far lower levels of IFNγ and IL-17, but had a similar TNFα reading, and production of IL-10 in the mice had increased.
Taking into account both the differences in cytokine and transcription factors, the data indicates that CBD treatment leads to the suppression of cytokines and transcription factors that are known to display pro-inflammatory effects, while also promoting the production of IL10, a cytokine which is known to havestrong anti-inflammatory properties.
The importance of MDSCs
MDSCs, or myeloid-derived suppressor cells, are another suspected factor in the onset of MS and MS-like symptoms as they are known to take part in thesuppression of neuroinflammation. It is thought that MDSCs also play a role in autoimmune diseases byaffecting T cell functionand so the effect of CBD on MDSCs was also studied as an alternate route by which CBD might be suppressing MS symptoms.
EAE-CBD老鼠被发现显示显著的家庭r counts of CD11b+Gr-1+ MDSCs than the EAE-VEH mice in the peritoneal cavity where the CBD was injected, but that these levels were not heightened in the central nervous system, spinal cord, or brain. Levels in the central nervous system were actually slightly reduced in comparison to EAE-VEH mice. It is theorized that this difference is due to the MDSCs in the periphery being unable to migrate to the central nervous system, but by inhibiting T cell induction in secondary lymphoid organs it was possible for the CBD-induced MDSCs to prevent the T cells from proliferating and causing the clinical disease. This was supported by the total viable cell number of the T cells, which showed that the MDSCs were not killing the T cells after they were triggered by the autoimmune disease, but that they were being suppressed and inhibited from proliferating.
Importantly, MDSCs areknown to produce IL-10. Researchers noted a dose-dependent response from CBD treatment on MDSC levels in this study, indicating that CBD’s ability to mediate EAE symptoms could be a result of both its direct IL-10 induction, and by an indirect effect through raising the MDSC levels which in turn produces more of the anti-inflammatory IL-10.
An additional experiment was carried out to investigate the effects of MDSC depletion on clinical symptoms. Lowering MDSC levels by injection of the antibody RB6-8C5 into mice that had been successfully treated with CBD reversed the effects of the treatment. This further supports the theory that indirect manipulation of MDSCs is a significant contributing factor to the effectiveness of CBD treatment.
The new model for CBD’s action on MS symptoms
The research carried out in this study has identified two previously unknown mechanisms through which CBD can act to curb the clinical effects of MS and MS-like conditions - the first being through a direct positive influence on the levels of anti-inflammatory cytokines and a similar negative influence on pro-inflammatory cytokines; the second being via an indirect manipulation of anti-inflammatory MDSCs which inhibit the T cell induction that normally occurs in autoimmune disease. The discovery of these mechanisms provides the field of cannabis science with a better understanding of the action of CBD in the body, which is important in the efforts to discover more effective drugs to combat autoimmune diseases.
The authors of the study conclude their research paper with the recommendation that “CBD may constitute an excellent candidate for the treatment of MS and other autoimmune diseases” as a novel non-psychoactive therapeutic. Further study of MDSC manipulation by cannabinoid-based drugs could lead to the development of novel drugs and other future advances in autoimmune disease treatment.
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