Zinc’s Role in Multiple Sclerosis Development

Past research has shown that it is a pathological disruption of zinc homeostasis that causes multiple sclerosis-induced motor deficits and spinal cord white matter damage. It is known that an abnormal vesicular release of zinc and accumulation of intracellular zinc may help to mediate several of the steps in the pathophysiological processes of multiple sclerosis (MS). Some of the affected steps include the subsequent immune cell infiltration from peripheral systems, the blood-brain barrier (BBB) disruptions, and the matrix metallopeptidase 9 (MMP-9) activation.

Decreasing disruption related to MS

Researchers have found that an oral dose of a zinc chelator can decrease spinal white matter myelin destruction, immune cell infiltration, and BBB disruption.

In order to confirm previous research results, researchers have employed zinc transporter 3 (ZnT3) mouse models to determine whether or not vesicular zinc depletion can produce protective effect on MS-induced motor deficits and white matter damage. The deletion of ZnT3 genes dramatically reduced demyelination in the spinal cords and the daily clinical score of experimental autoimmune encephalomyelitis (EAE) through the suppression of demyelination and inflammation in the spinal cord. Through the process of ZnT3 deletion, researchers were also able to inhibit the BBB disruption, MMP-9 activation, and MS-associated aberrant synaptic zinc patches. These two research studies support the hypothesis that MS pathogenesis may be extremely mediate by the release of zinc from presynaptic terminals. Further research is needed to add detail to the process and to clarify how past research may lead to the development of new therapeutic approaches for the treatment of MS.

MS and the myelin sheath

MS is characterized by several abnormal or maladaptive responses of the immune system, which often result in the progressive and erroneous destruction of structures in the central nervous system (CNS), including the spinal cord and brain. As an autoimmune disease, MS is also characterized by damage to the myelin sheath that covers and protects nerve fibers and allows efficient transmission of neural impulses. The demyelination process occurs when T-cells become sensitized to myelin proteins and gradually begin to attack the myelinated structures in the CNS and the peripheral nervous system. Damage to myelin can result in a slowing of the velocity of conduction of the nerve and impair communication between the brain and other parts of the body. The majority of patients with MS experience difficulties with coordination that can result in irreparable neurological problems and muscle weakness or disability.

While there is no effective treatment for MS yet, there are a number of therapies that reduce inflammation available. Unfortunately, there is very little confirmation of the efficacy of such therapeutic agents and researchers believe that through the definition of the full mechanism of MS, they can one day design an effective treatment. Furthermore, a large majority of available MS treatments have been shown to produce adverse side effects.

The exact cause of MS remains unknown, although it is currently believed by researchers that it is the interaction of several different elements, including environmental, immunologic, infectious, and genetic factors that may be responsible for MS. Therefore, the pathogenesis of MS may be the result of an interaction between the several factors. One study reported that genetic factors cannot be the sole cause of MS through research on monozygotic twins.

Research into risk factors

There have been several studies that have investigated the risk factors of the pathogenesis of MS. Some researchers have suggested that viral infection may play a significant role in the development of MS through the modulation of the immune system, which can result in a person's susceptibility to MS. Several other studies reported that patients with MS have immunoglobulin G (IgG) antibodies that work against viruses, such as the varicella zoster virus (VZV) and the Epstein-Barr virus (EBV). The human herpesvirus 6 (HHV 6) may also have a link with MS although the cytomegalovirus (CMV) does not. There have been other studies that have suggested that a specific infection of parasites may provide protection against MS. For example, MS patients in a study in Turkey who were found to be positive for Toxoplasma gondii had more positive clinical outcomes than MS patients who did not have Toxoplasma gondii. Furthermore, MS patients who had Trichuris suis seemed to experience a decrease in disease severity in EAE. All of these findings support the hypothesis that parasite infection may offer protective qualities to patients with MS, although the exact mechanism in which the infections work is still widely unknown.

The International Advisory Committee on Clinical Trials of MS has classified MS into 4 subtypes that are based on the clinical patterns presented by patients. The 4 subtypes are clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and a primary progressive MS (PPMS). CIS is a subtype that involved only a single episode of MS, without a secondary attack, RRMS is characterized by relapsing MS symptoms of MS followed by a period without progression of the disease and is the most common subtype of MS, SPMS is the subtype where a stage of disease progression follows a period of RRMS, and PPMS is subtype that is characterized by progression without any symptoms of relapse. The classification was devised because each subtype responds differently to different treatments. As the disease progresses, each subtype can transform into another subtype.

The differences between EAE and MS

EAE, a common disease model of MS, has often been used in the exploration of neuroinflammatory pathology. However, there are some key differences between EAE and MS. For example, MS does not have a known etiology while EAE does. Scientists can induce EAE in animal models through the immunization of tissue or molecules which originate in the CNS, as with myelin oligodendrocyte glycoprotein (MOG) proteolipid protein (PLP), and myelin basic protein (MBP). EAE can also be induced by transferring MOG, PLP, or MBP-specific T lymphocytes as forms of direct induction. Depending on the type of antigen used and the genetic design of the animal model, EAE can be induced in either a relapsing-remitting form or chronic form. The typical animal model will present clinical symptoms in between 10 or 15 days after which paralysis begins in the tail and back legs with eventual progression to the front legs and weight loss.

Zinc: What’s the connection?

In previous studies, researchers have demonstrated that spinal cord white matter damage that is induced by EAE, as well as motor deficits, are mediated by the pathological disruption of zinc homeostasis. The abnormal release of vesicular zinc and the accumulation of intracellular zinc may actually play a role in the mediation of several of the steps of the pathophysiological process of EAE.

However, there is no research as of this time that address whether or how zinc may cause the damage of myelin. Although several studies have suggested that zinc alone may induce NADPH oxidase activation in neurons and may result in the production of reactive oxygen. Labs have shown that the translocation of the p67 phox and the p47phox subunits occurs during glucose deprivation or glucose reperfusion.

Because zinc has been found to exist in high concentrations in the CNS and is involved in brain physiology, researchers believe that zinc may play a major role in the pathogenesis of MS. Zinc has become a primary target of treatment due to its role in zinc homeostasis in acute brain injury and neurodegenerative diseases. Several groups of researchers have suggested that one of the main mediators of zinc neurotoxicity and gliotoxicity is oxidative stress. Oxidative stress is thought to be a main cause of MS, therefore the role of zinc in MS pathology should be evaluated.

Reference

Choi, B., Jung, J., and Suh, S. (2017, September 28). The Emerging Role of Zinc in the Pathogenesis of Multiple Sclerosis. Department of Physiology. Retrieved from: http://www.mdpi.com/1422-0067/18/10/2070/htm