Multiple sclerosis: can myelin be restored?
: 27.04.2015
Multiple sclerosis is another evidence of the imperfection of our immune system, which sometimes “goes crazy” and begins to attack not the external “enemy”, but the tissues of our own body. In this disease, cells of the immune system destroy the myelin sheath of nerve fibers, which is formed during the development of the body from a certain type of glial cells - “service” cells of the nervous system. The myelin sheath covers the axons, the long extensions of the neuron that act as the “wires” along which the nerve impulse travels. The sheath itself serves for electrical insulation, and as a result of its destruction, the passage of an impulse along the nerve fiber slows down 5-10 times.
In the photo, clusters of macrophages (brown color) are visible along the periphery of the plaques. Macrophages are attracted to the lesion and activated by other cells of the immune system - T-lymphocytes. Activated macrophages phagocytose (“eat”) dying myelin, and, in addition, themselves contribute to its damage by producing proteases, proinflammatory molecules, and reactive oxygen species. (Immunohistochemistry, macrophage marker – CD68).
Normally, cells of the immune system, like other blood cells, are not able to penetrate directly into the nervous tissue - they are not allowed in by the so-called blood-brain barrier. But in multiple sclerosis, this barrier becomes passable: “crazy” lymphocytes gain access to neurons and their axons, where they begin to attack the molecules of myelin, which is a complex multilayered protein-lipid structure. This sets off a cascade of molecular events leading to the destruction of myelin, and sometimes the axons themselves.
The destruction of myelin is accompanied by the development of inflammation and sclerosis of the affected area, i.e. the formation of a connective tissue scar in the form of a plaque, replacing the myelin sheath. Accordingly, in this area the conducting function of the axon is disrupted. Plaques are located diffusely, scattered throughout the nervous system. It is with this arrangement of lesions that the very name of the disease is associated - “multiple” sclerosis, which has nothing to do with ordinary absent-mindedness (the one that we sometimes talk about in everyday life - “I have complete sclerosis, I forgot everything again”).
The symptoms of multiple sclerosis vary depending on which nerves are affected. Among them are paralysis, problems with balance, cognitive impairment, changes in the functioning of the sensory organs (in a quarter of patients, the development of the disease begins with visual impairment due to optic neuritis).
Current treatment for multiple sclerosis leaves much to be desired. There is no effective treatment yet, especially since the causes of this disease are still unknown; there is only evidence of the possible influence of the environment and genetic predisposition. For treatment, in addition to symptomatic therapy to relieve pain and reduce muscle spasms, glucocorticoid drugs are used to reduce inflammation, as well as immunomodulators and immunosuppressants aimed at suppressing the “bad” activity of the immune system. All these remedies can slow down the development of the disease and reduce the frequency of exacerbations, but do not cure the patient completely. There are no drugs that can restore already damaged myelin.
However, such a medicine, aimed specifically at restoring myelin, and not just at slowing down the pathological process, may soon appear. The development, under the working title Anti-LINGO-1, from the Swiss company, the largest manufacturer of drugs for the treatment of multiple sclerosis, is now undergoing phase 2 clinical trials. The drug is a monoclonal antibody that can specifically bind to the LINGO-1 protein, which interferes with the process of myelination and the formation of new axons. Accordingly, if this protein is “turned off,” myelin begins to recover.
In animal experiments, the use of the new drug led to 90 percent remyelination. Patients with multiple sclerosis taking Anti-LINGO-1 are currently experiencing improvements in optic nerve conduction. However, full results of clinical trials on patients will not be available until 2016.
By: RScleros.Ru, HCP Live
Prepared by Maria Perepechaeva
: 27.04.2015
What is multiple sclerosis
Multiple sclerosis has nothing to do with absent-mindedness or old-age forgetfulness.
This is a serious autoimmune disease that affects the myelin in the white matter of the spinal cord and brain. In foci of sclerosis scattered throughout the central nervous system, plaques form - places where nerve fibers are replaced by connective tissue. Such pathological changes provoke neurological manifestations in patients, which can only be dealt with with the help of qualified specialists. The disease occurs both in children and young people, most often from 15 to 30 years old, and in older people - the largest number of cases of primary progression of the disease was recorded in 50-year-olds.
Sex hormone may stop multiple sclerosis
1 minute
The hormone prolactin, produced in the female body during pregnancy, can stop the development of multiple sclerosis, American scientists believe. In their opinion, the disappearance of the symptoms of this serious disease in pregnant women is associated with the protective effect of prolactin.
Multiple sclerosis is an incurable disease of the central nervous system caused by the gradual destruction of the protective myelin sheath of nerve fibers. Damaged nerves lose conductivity, which leads to a variety of disorders - from increased fatigue and muscle weakness to complete loss of mobility and decreased intelligence.
In their study, researchers at the University of Calgary in Alberta used female mice whose spinal cords were injected with a toxin that destroys myelin, as well as a marker substance that interacts with the DNA of newly formed cells. The animals were divided into two groups, one of which was allowed to mate and become pregnant.
When studying the spinal cord of pregnant mice, it was found that the myelin sheath was absent in only a tenth of the nerve fibers. In non-pregnant mice that received the same toxin injection, about a third of the fibers were damaged. In addition, an increased number of new oligodendrocytes, cells that produce myelin, were found in the spinal cord of pregnant mice. Prolactin receptors were found on the surface of these cells.
After prolactin was administered to non-pregnant mice, the number of nerve fibers with normal myelin sheaths in their spinal cords doubled.
According to study leader Dr. Samuel Weiss, the results of the study prove that prolactin can not only protect the myelin sheath, but also stimulate its restoration in already damaged nerve cells. Thus, theoretically, this hormone could be used to treat multiple sclerosis.
Previous research has shown that some sex hormones, particularly estrogen, can stop the breakdown of the myelin sheath. However, Weiss notes, the importance of prolactin is that it not only prevents breakdown, but also helps restore the protective sheath in already damaged fibers.
However, using prolactin to treat multiple sclerosis may cause unwanted side effects because this hormone regulates breast growth and lactation during and after pregnancy. In addition, prolactin is known to stimulate the immune system, and this is especially dangerous for patients with multiple sclerosis, since this disease is believed to be a consequence of autoimmune reactions.
Chloroindazole restored visual pathways in mice with multiple sclerosis
Sekyi et.
al. / Brain Pathology, 2021 Chloroindazole promoted the restoration of optic tract axon sheaths in mouse models of the acute phase of multiple sclerosis, says a study published in the journal Brain Pathology
. In some structures of the visual system pathways, chloroindazole also promoted cell survival and reduced damage to the axons themselves. The drug also partially restored the spread of visual potential in the cortex, but did not cope with this in the retina.
Multiple sclerosis is an autoimmune disease that affects the central nervous system. Immune cells from patients with this disease attack the axon sheaths of neurons and destroy them, forming cavities called sclera. Axon sheaths are made of myelin, a substance that functions similar to duct tape. The myelin sheath wraps around the axon and insulates it, increasing the speed of nerve impulse transmission. When myelin is destroyed, patients with sclerosis may experience impairments in coordination, speech, vision and cognitive functions.
Most therapeutic methods for multiple sclerosis are effective in the early stages of the disease: they do not restore the myelin sheath, but prevent its destruction. To do this, hormonal drugs are used that suppress the activity of immune T cells that attack axonal myelin. There are also new experimental approaches to the treatment of multiple sclerosis that are capable of restoring the myelin sheath, but they have not yet become widespread.
Researchers from the University of California, led by Maria T. Sekyi, tested the effectiveness of chloroindazole, which restores myelin on axons, to restore visual pathways in multiple sclerosis. To do this, they used a model of this disease - mice with encephalomyelitis. When the mice began to develop the most severe symptoms (complete paralysis of the hind limbs), they were injected with chloroindazole and its effect was monitored in brain slices.
Biologists have tested all the structures through which the visual signal passes at the entrance to the cortex: first, light enters the ganglion cells of the retina, their processes form the optic nerve, which enters the optic tract, then the signal passes through the lateral geniculate body in the brain and finally reaches the optic bark. The researchers took sections of each section of the pathway and then specifically stained them for markers of myelination, cell death and inflammation.
Section of the optic nerve with stains for myelin, inflammation and cell death (in columns). It can be seen that chloroindazole (lower right corner) restores the myelin sheaths and brings them closer to normal (upper right corner).
Sekyi et. al. / Brain Pathology, 2021
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It turned out that the drug helped reduce the destruction of myelin sheaths of axons in all structures of visual signal transmission to the brain, except for the lateral geniculate body (p<0.05). It also promoted the survival of retinal cells and partial restoration of damage to the optic tract axons themselves (p<0.05).
Biologists also tested how the drug affects the propagation of an electrical signal in the nervous system. To do this, they analyzed the potentials that light causes in the retina and cortex in living mice. The signal propagation curves did differ between healthy mice and mouse models of multiple sclerosis. Chloroindazole partially restored signal propagation in the cortex, but not in the retina.
Chloroindazole showed significant restoration of the myelin sheath of axons along the incoming pathways of the visual system. However, after this therapy, mice at the most acute stage of the disease still showed significant axonal pathology, again suggesting that treatments for advanced MS are less effective.
Multiple sclerosis is not the only disease that causes vision problems. For example, retinitis pigmentosa, in which the rods and cones cease to perceive light due to mutations. We recently wrote about how biologists inserted genes for light-sensitive proteins into the retinal cells of mice and restored their vision.
Anna Muravyova
