Multiple Sclerosis Research: Studying MS-like Disease in Mice
Several types of animals, including cats, dogs, monkeys, mice and rats, have been used in research laboratories to study demyelinating diseases such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), amyotrophic lateral sclerosis (ALS), or Guillain-Barré syndrome (GBS). Multiple sclerosis is a demyelinating disease for which the exact cause(s) is unknown. It is believed that a combination of factors are involved: genetics, environment, and autoimmunity. Science is still unraveling the pathophysiology of MS.
To investigate potential causes and treatments for demyelinating diseases such as MS, researchers use various methods to cause a condition or symptoms similar to MS in laboratory animals. Mice do not naturally develop MS, but mice are especially suited to studying MS-like disease because of their similarity to humans in anatomy, physiology, and genetics. Researchers are able to create various genetic modifications in mice to mimic human disease. Mice are small, inexpensive, and can reproduce quickly.
There are three major types of animal models used to study demyelinating disease: 1) genetic models, where genes important for CNS myelination, myelin maintenance or glial function have been altered; 2) immune-mediated models of induced pathogenesis towards myelin; and 3) toxin-mediated models using toxic substances that preferentially affect myelin (Pohl, 2011).
In genetic mouse models, genes that affect myelination or oligodendroglial function are altered. These mouse models provide researchers with insight into the process of myelination and myelin maintenance. Transgenic or knock-out mice are especially useful in studying inherited demyelinating diseases, such as Charcot-Marie-Tooth disease.
Inflammatory immune-mediated models
In addition to genetic and environmental factors, it is believed that viruses may play a role in the etiology (cause) of MS. In immune-mediated mouse models, mice may be injected in the central nervous system with viruses that trigger inflammatory demyelinating disease, such as Theiler’s murine encephalomyelitis virus (TMEV), neurotropic mouse hepatitis virus (MHV), or Semliki Forest virus (SFV). Inflammatory demyelinating models can also be caused by injections of lipopolysaccharide (LPS) or peroxynitrite scavengers such as uric acid. Scientists associated with the Myelin Repair Foundation have developed a technique using diphtheria toxin subunit A (DTA) as a demyelinating agent.
The most prominent inflammatory model used in MS research is experimental autoimmune encephalomyelitis (EAE) which is caused by immunizing the animal with CNS-derived antigens such as proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) or myelin associated glycoprotein (MAG). Depending upon the specific antigen used for immunization, the resulting disease pattern varies and can mimic either relapsing-remitting or chronic progressive disease. There are many different EAE models that have been developed to affect certain areas of the central nervous system, each mimicking a particular facet of MS (Croxford, 2011; Linker, 2009). More recently novel models of EAE have been developed to induce specific symptoms such as optic neuritis (Lidster, 2013).
Following immunization for EAE, encephalitogenic T helper cells are activated in the peripheral lymph nodes and migrate to the CNS where they induce activation of microglia, macrophages, and dendritic cells. The resultant inflammation causes demyelination of neurons, prompting the presentation of myelin basic protein (MBP) to additional T cells in the cervical lymph nodes by migratory dendritic cells. The spontaneous recovery that occurs following autoimmune episodes is associated with a major reduction in the T cell infiltration in the CNS.
The similarly named experimental autoimmune neuritis (EAN) is an animal model for chronic inflammatory demyelinating polyradiculoneuropathy, a disease of the peripheral nervous system known as Guillain-Barré syndrome (GBS) (Gold, 2000). A variation of the Theiler’s murine encephalitis virus (TMEV) MS model has been used to study acute hemorrhagic leukoencephalomyelitis (AHLE), a rare neurological condition characterized by the development of acute hemorrhagic demyelination and rapidly deteriorating neurological symptoms often leading to death within 2-14 days (Pirko, 2009).
A number of toxin-mediated demyelination models have been developed. The most familiar is the cuprizone model in which mice are fed with chronic low doses of the copper-chelator cuprizone which damages oligodendrocytes, especially within the corpus callosum, and leads to oligodendroglial apoptosis (cell death) and demyelination. Remyelination occurs after the neurotoxin is removed from the diet. In a similar model, mice who are fed irradiated food develop an MS-like condition with wide-spread demyelination. Other toxin-mediated models involve focal injections of lysolecithin or ethidium bromide that result in locally-restricted demyelination and fast subsequent remyelination within white matter tracts.
In vivo, In vitro, and In silico models
In vivo (Latin for “within the living”) refers to experimentation using a whole, living organism as opposed to a partial or dead organism. Animal studies using disease models described above and clinical trials with human subjects are two forms of in vivo research. In vitro (Latin for “within the glass”) refers to the technique of performing a given procedure in a controlled environment outside of a living organism. In vitro modeling allows researchers to dissect certain aspects of myelination/demyelination and create screening assays in the search for new drugs (Zhang, 2011; Merrill, 2009), but it does not fully mimic the complex pathology and factorial interplay in CNS myelin damage and disease (Pohl, 2011). In silico is an expression used to characterize biological experiments “performed on computer or via computer simulation.”
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