A recent study (Rossi et al. Exercise attenuates the clinical, synaptic and dendritic abnormalities of experimental autoimmune encephalomyelitis. Neurobiol Dis 2009 Jul 7) seems to suggest that exercise may be beneficial in slowing progression of multiple sclerosis. 

The investigators induced a multiple sclerosis-like disease in mice by administration of peptides derived from the myelin protein called myelin oligodendrocyte glycoprotein (MOG) and induced the mice to undergo voluntary running in a wheel.

Voluntary exercise decreased progression of disease, and overall severity, as compared to control animals.  Furthermore, the inflammation-associated suppression of GABA synapse stimulation by cannabinoid CB1 receptors, that is associated with the animal model of multiple sclerosis was inhibited as a result of exercise.  Additionally, exercise effectively reduced dendritic spine loss induced by by the multiple sclerosis-like disease in striatal neurons.

Exercise has been demonstrated to induce insulin like growth factor (IGF)-1 expression in certain cell types in response to mechanical motion, as well as growth hormone administration.  It is interesting to note that IGF-1 stimulates production of new myelin, as well protects the animal model of multiple sclerosis from disease (Yao et al. Insulin-like growth factor-I given subcutaneously reduces clinical deficits, decreases lesion severity and upregulates synthesis of myelin proteins in experimental autoimmune encephalomyelitis. Life Sci 1996;58(16):1301-6).  So it would be interesting to see if exercise, along with vitamins and stem cells may be syngergistic in treatment of multiple sclerosis.

When I started my training, if you wanted to know whether one gene goes up or down, it would take at least a week to figure out for every gene.  Now, in one afternoon a scientist in one shot take a look at level of expression of all known genes (about 30,000) of the human body!  This revolution in science has allowed for the discovery of new molecular pathways without having to know what one is looking for.  So in conditions such as multiple sclerosis, many scientists basically “go fishing” to try to find new genes whose expression correlates with disease.  People have even taken it further by being able to assess not only all genes, but also proteins made by the genes (called proteomics), and more recently, like my friend Gabriela Cezar at Stemina does, look for all small molecules (called metabolomics).

These very powerful techniques are beginning to bear their fruits.  A recent paper (Schulze-Topphoff et al.  Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment tothe central nervous system.  Nature Medicine.  June 28, 2009) identified that patients with multiple sclerosis, as well as in animals bearing a disease similar to multiple sclerosis (experimental allergic encephalomyelitis) have increased expression of the kinin receptor B1.  This receptor is activated by components of the kinin-kallikrein system, which are a group of proteins involved in pain, inflammation, and coagulation of blood.

The investigators found that giving mice developing experimental allergic encephalomyelitis (mouse model of multiple sclerosis) activators of the kinin receptor resulted in less disease, whereas administration of inhibitors of this receptor resulted in acceleration of disease onset.  This was demonstrated when the compounds were given before disease onset, but in other experiments even after disease onset. 

Manipulation of receptors using small molecules can be tricky business.  In other words, it may be that the small molecule receptor activator/inhibitors may have been working through other biological pathways to alter disease course.  Therefore, in order to know conclusively whether the kinin receptor B1 is responsible or not for alteration in disease process, the investigators used mice lacking the kinin receptor B1.  These mice suffered from accelerated disease, thus suggesting that the receptor is normally involved in controlling the disease. 

Expression of the receptor had to be on the T cells in order to mediate protection from disease.  It was demonstrated that activation of the kinin receptor B1 selectively suppressed the infiltration of Th17 cells into the central nervous system.  Most interestingly suppression of infiltration was limited to Th17, with Th1 cells still infiltrating.  One intersting question is whether there is selective expression of the kinin receptor B1 associated with various TCR clonotypes that are expanded in multiple sclerosis progression, as seen in this video describing a paper by Eli Sercarz.

These data suggest a brand new molecule that can be targetted in multiple sclerosis.  It also illustrates the power of using “discovery based” approaches.  If indeed selective inhibition of Th17 entry into the CNS can be achieved in humans, this may be useful as a synergistic agent with bone marrow or fat stem cell approaches to multiple sclerosis.

For stem cells to mediate their effects they must either be placed locally at the point of damage, or they must find their way there.  One of the questions that people ask is “how can intravenously administered stem cells home to where they need to go?”  To answer this, lets first think about the stem cell therapy that has been used for more than 4 decades: bone marrow transplantation.

In bone marrow transplantation the stem cells are injected intravenously into the recipient.  So how do they find their way to the bone marrow?  One of the may ways that this occurs is because the bone marrow expresses a protein called stromal derived factor (SDF)-1, which is also known as CXCL-12.  Specifically, bone marrow stromal cells are known to constitutively make this protein, which is what keeps the hematopoietic stem cells in the bone marrow.  So when donor hematopoietic stem cells are injected into a recipient, they selectively home to the bone marrow because of expression of SDF-1.  We know that SDF-1 is important for this process because if you block the interaction of SDF-1 with its receptor on the stem cell, called CXCR4, in a healthy person, then the healthy person’s bone marrow stem cells enter the blood.  The clinically used stem cell mobilizer mozobil works by interrupting this pathway.

We also know that SDF-1 is important for attracting stem cells because after heart attacks, this protein is produced by the injured heart muscle in large quantities, which attracts the patient’s own bone marrow cells to the area of injury.

A recently published study (McCandless et al. IL-1R Signaling within the Central Nervous System Regulates CXCL12 Expression at the Blood-Brain Barrier and Disease Severity during Experimental Autoimmune Encephalomyelitis. J Immunol. 2009 Jun 17) demonstrates that SDF-1 is expressed during the initial phases of disease progression in the mouse model of multiple sclerosis.

This study may provide one important clue as to how stem cells home into the central nervous system of patients with multiple sclerosis.  However this is a controversial area since, although mesenchymal stem cells prevent disease in animal models, some studies suggest that the stem cells do not need to actually home to the area of injury to inhibit multiple sclerosis, but instead may do this through immune modulation.