Possible Multiple Sclerosis Treatment Approach

From several years ago, this paper suggests that (abstract):

Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2+APC+ oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.

We will be on the lookout out for any further advances in such approaches to report them here.

Nervous System Immune Cells

There are distinct populations of central nervous system immune cells comparing states of health, aging, and disease Alzheimer's disease and multiple sclerosis). This may assist in devising new therapeutic strategies against those diseases as well as giving insights into the human aging process. Abstract:

Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer's disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease. 

Microbial Metabolites Against Multiple Sclerosis?

More possible benefits for modulating the microbiome; abstract:

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1-3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.

New Inroads Against Multiple Sclerosis

Read this.  Excerpts:

Medical progress against multiple sclerosis (MS) took a major leap forward in 2017 with the approval by the US Food and Drug Administration (FDA) of ocrelizumab, a drug that has shown success against 2 different forms of the disease. The year also brought further signs that it may be possible to biochemically reverse damage wrought by MS.

So, there’s a potentially effective monoclonal antibody drug, and there are possibilities of reversing the damage.  Stem cells are always useful for repair.

One of the key epidemiologic points about MS is that it has increased in frequency, and although there are now 203 genes that influence MS risk, all of these influences are very small effects, and the majority of susceptibility is not genetic and is almost certainly environmental. What in the environment is responsible for triggering MS is one of the great questions in MS research. It's unanswered but is likely to be a virus or bacterium. 

Dr Cohen:I would add that the microbe may not only be external to the person, but something in their own microbiome. It probably is not one single culprit, but many potential culprits. Or the distribution, the presence of some or absence of other microbial agents, may be what leads to susceptibility.

Once again, the microbiome.  Remember that your microbiome is influenced by diet.

Dr Hauser:It's likely that the microbiome has a substantial effect on MS in 2 ways. The first is the molecular mimicry, where some cell component of a bacterium or virus resembles a protein or substance in the brain. The second is that our microbiota influence the regulatory tone of our immune system, and that could lead to differences in the trajectory of disease after it begins. 

We don't yet know what the likely microbial culprit or culprits are. The strongest epidemiologic link to multiple sclerosis remains a late onset infection with the Epstein-Barr virus (EBV), [perhaps] the occurrence of infectious mononucleosis, but we really don’t know if EBV is causally linked or is a surrogate for some other infectious agent.

That’s also useful to know, and another avenue to explore for prevention of therapy, mostly the former.

Wnt Signaling And Multiple Sclerosis

By Quasar Jarosz at English Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7616130

The paper linked here asserts that downregulation of Wnt signaling (also involved in many types of cancer) is essential for proper neuronal differentiation, and that activated Wnt signaling can impair remyelination of neurons. Since demyelination – loss of the myelin sheath of neurons that is important for nerve signal conduction – leads to multiple sclerosis, this finding points the way for possible therapeutic interventions against that disease.  Abstract:

Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.

Stress, Dopamine, Wnt signaling, And Myelin Loss

Dopamine is related to major aspects of behavior, and abnormal regulation of the dopamine system is linked to depression and other mental disorders. Mice with knocked out dopamine receptors display increased anxiety and depression when confronted with chronic stress. Loss of myelin occurs with multiple sclerosis, and this study shows that chronic stress causes myelin loss in wild-type mice, while the dopamine receptor mutant mice have lower baseline (starting) levels of myelin, but in these mutant mice, myelin levels are not further decreased by stress.  Wnt signaling, which is abnormally regulated in different forms of cancer, is downregulated in the brains of stressed mice; this effect is reversed by lithium treatment (lithium can upregulate Wnt signaling), which normalizes myelin and behavior in stressed wild-type mice.  However, this effect of lithium did not occur in dopamine receptor-mutant mice.  This links the dopamine system with Wnt signaling affecting myelin levels and behavior in mice; the possibility exists that the same association occurs in humans. Stress has previously been linked to multiple sclerosis – with inflammation being one possible mechanism – but the dopamine pathway is another possibility, one that requires further consideration and study. Abstract:

Dopaminergic systems play a major role in reward-related behavior and dysregulation of dopamine (DA) systems can cause several mental disorders, including depression. We previously reported that dopamine D2 receptor knockout (D2R-/-) mice display increased anxiety and depression-like behaviors upon chronic stress. Here, we observed that chronic stress caused myelin loss in wild-type (WT) mice, while the myelin level in D2R-/- mice, which was already lower than that in WT mice, was not affected upon stress. Fewer mature oligodendrocytes (OLs) were observed in the corpus callosum of stressed WT mice, while in D2R-/- mice, both the control and stressed group displayed a decrease in the number of mature OLs. We observed a decrease in the number of active β-catenin (ABC)-expressing and TCF4-expressing cells among OL lineage cells in the corpus callosum of stressed WT mice, while such regulation was not found in D2R-/- mice. Administration of lithium normalized the behavioral impairments and myelin damage induced by chronic stress in WT mice, and restored the number of ABC-positive and TCF4-positive OLs, while such effect was not found in D2R-/- mice. Together, our findings indicate that chronic stress induces myelin loss through the Wnt/β-catenin signaling pathway in association with DA signaling through D2R.