MS pathogenesis is a complex process involving a vast array of cell types, that all vary in their phenotype and function, which can can switch from pro- to anti-inflammatory and vice versa, and thus their pathogenic contribution, depends on the stage of disease, and other factors, including initial attack, damage extent, age, gut microbiome, environmental influences, genes, etc., and so on.
That is still the best quote I have seen, so I had to repeat it. There’s just so much going on in normal CNS physiology that there’s no real way to explain the pathophysiology occurring in MS accurately, especially considering the heterogeneity of the disease. I’ve been telling my neurologist that when I look down I lose most of my strength and I have to look up to use my arms, and even my legs back when I could limp around. I always figured it stretched out the lesions in my cervical spine, but they would never give me an answer and always talked about different muscles in the neck et cetera and so on. I used Google AI about no strength to lift arms or legs arms in MS when flexing the neck downward. After rewording it around 8 times I found an article on McArdle sign in MS that explained it, similarly to what I thought. When I use my arms looking upward or straight ahead I get zingers in my triceps and have to flex the neck downward to stop. Just like the opening quote implies, it’s a pretty unique disease. I figure it ectopic firing through a demyelinated axonal segment, but maybe not.
Anyhow, the hallmark of SPMS is activated microglia, which is also the main cause for reactive astrogliosis. They produce and release the combination of IL-1a, TNFa, and compliment protein C1q to trigger it. These two cell types are key to the innate immune system in the CNS. In SPMS, they cause most of the neurodegenerative damage as opposed to peripheral immune system infiltrating T and B cells. Peripheral immune cells see something called endotoxin tolerance where an immune challenge is met by the full strength of the immune system, but a secondary assault causes a reduced response. This isn’t seen inside the CNS by innate immune cells.
Activated microglia and reactive astrocytes cause neurodegeneration mostly by increasing oxidative and nitrosative stress. They highly express and continuously activate NADPH oxidase, myeloperoxidase, cyclooxygenase, and inducible nitric oxide synthase that produce large amounts of ROS/RNS, that also include free radicals. These are highly reactive with unpaired electrons in their outer orbits that take electrons from other biomolecules and use them to create new free radicals. This starts a chain reaction that causes extensive cellular damage, especially in OLs and the myelin sheath due to their lower antioxidant defenses and high metabolic activity.
The mitochondrial electron transport chain consumes molecular oxygen as the final electron acceptor to create water, but a small percent of electrons leak out and react with O2 to form superoxide and hydrogen peroxide . These are used as signaling molecules in regular physiological functions, but if created in excess they lead to oxidative stress. Mitochondrial dysfunction, NOX activity, and toxins are leading causes of excess production. Nitrosative stress is caused by excess production of nitric oxide and super oxide reacting to form the peroxynitrite anion. It can cause protein, lipid, or DNA nitration that creates 3-Nitrotyrosine that induces cell death. Oxidative stress and nitrosative stress are closely linked together. ROS, like superoxide anion , singlet oxygen, hydroxyl radical, hydrogen peroxide, peroxynitrite anion, and RNS like nitric oxide overlap in scavenging pathways that regulate each other reciprocally. They react with each other directly like in forming peroxynitrite and indirectly by modulating cellular processes that control their own production and signaling. To make a long story short, these oxidant species increase above antioxidant defenses in these cells causing a redox imbalance. The main antioxidants in context of MS are glutathione, glutathione peroxidase, superoxide dismutase, and catalase. Natural plant products can increase them, that’s why I like to make my potions, but that’s another someday post.
Another way to go about this is through the use of a bile acid metabolite that has anti inflammatory properties whose receptor expresses throughout the body. I’ve taken this in the past, but upon further review, I wasn’t taking enough for a long enough period of time. TUDCA is a secondary bile acid with hydrophilicity that can cross the BBB, whose receptor is seen in MS CNS lesions. A study found that those with MS have lower levels of circulating bile acid metabolites compared to healthy controls, especially in progressive forms. It also finds bile acid receptors are on immune and glial cells in MS white matter brain lesions. They use 1000mg in the morning and evening to block microglia activation and reactive astrogliosis that needs continual use for effective results. In the EAE model of MS, TUDCA blocks microglia and astrocyte polarization to pro-inflammatory phenotypes, reduces immune cell infiltration into the CNS, and lowers disease severity. TUDCA binds to the bile salt receptor, GPBAR 1 (TGR 5) that increases intracellular cAMP levels in microglia that induces anti-inflammatory markers while reducing pro-inflammatory markers. Other studies show TUDCA transcriptionally inhibits inducible nitric oxide synthase, inhibits in NF-kB activation in glial cells, and activates the transforming growth factor B pathway. The most common adverse effect seems to be mild GI distress in some people.
On another note, fibrinogen is converted into fibrin in the CNS where it potently activates microglia. Even though there are numerous ways to activate microglia, it would seem that increased BBB permeability in SPMS would allow fibrinogen and other blood components to leak into the CNS. Nattokinase is a very strong fibrinolytic enzyme derived from fermented soybeans. Thrombus Are blood clots made of fibrin, platelets and red and white blood cells that get trapped in them. Fibrin forms a type of mesh the clot uses as a scaffold. When endothelial cells lining the blood vessel or blood flow slows , the clotting mechanism gets activated. As MS lesions usually form around small blood vessels in the cerebrospinal fluid peravascular spaces, it seems reduced CSF flow and leaking blood components are key causes. CSF flow slows during inflammation and by reactive astrogliosis that disrupts the glymphatic system. The body produces plasmin to break down and dissolve blood clots and nattokinase is very similar to plasmin and can dissolve fibrin directly. Most blood clot dissolving drugs have to be taken by IV, but can’t be used in overhardened arteries. Nattokinase can be used orally, is natural, prevents fibrin and its formation, enhances the body’s endogenous fibrinolytic activity, and degrades fibrin and clots. It also acts for 8-12 hours, where the IV drugs wear off shortly after infusion. However, It can’t cross the BBB, but if it can reduce fibrinogen near the barrier, it seems that would help. Lumbrokinase is another potent fibrin dissolving enzyme that is derived from earthworms. It’s actually a group of 6 proteolytic enzymes that is only active in the presence of fibrin. It only dissolves fibrinogen and fibrin without hydrolyzing other blood proteins like plasminogen. Therefore, there’s little chance of causing hemorrhage by excessive fibrinolysis.