3. INTRODUCTION
Multiple sclerosis is one of the neuro degenerative disorder in central nervous system
that include brain, spinal cord and nerves.
Including problem with vision ,arm or leg movement, sensation or balance.
SYMPTOMS OF MS
The symptoms of MS vary widely from person to person and can affect any part of the body.
The main symptoms include:
• fatigue
• difficulty walking
• vision problems, such as blurred vision
• problems controlling the bladder
• numbness or tingling in different parts of the body
• muscle stiffness and spasms
• problems with balance and co-ordination
• problems with thinking, learning and planning
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4. TYPES OF MS
1. Relapsing-remitting
2. Primary progressive
3. Progressive relapsing
4. Secondary progressive relapsing
PATHOPHYSIOLOGY OF MS
• MS is an autoimmune condition, which means your immune system mistakes
part of your body for a foreign substance and attacks it.
• The immune system attacks axon, leads to destruction of myelin sheath in brain and
Spinal cord resulting in Conduction block which leads to permanent loss of function.
• The attacks cause the myelin sheath to become inflamed in small patches (plaques or lesions),
which can be seen on an MRI scan
• These patches of inflammation can disrupt the messages travelling along the nerves.
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6. CAUSES OF MS
• It's not clear what causes the immune system to attack the myelin sheath.
• It seems likely that it's partly caused by genes you inherit from your parents and
partly by outside factors that may trigger the condition.
• Some of the factors that have been suggested as possible causes of MS include:
I. Genes
II. Lack of sunlight and vitamin D
III. Smoking
IV. Teenage obesity
V. Viral infections(Epstein-Barr virus ,responsible for glandular fever)
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9. INVITRO TESTS
1. Microglia activation is observed in actively demyelinating MS lesions, pre-active
lesions, areas of remyelination as well as the normal-appearing white matter.
2. primary microglia cultures are derived from embryonic or
early post-natal animals.
1.MICROGLIA
PROCEDURE
This method is simple and allows for relatively high yields of cells.
Microglia can also be separated from confluent primary mixed glial cultures by agitation
on a rotary shaker, producing a highly enriched (> 95%) cell culture.
Given that microglia in the brain , The initial trigger of microglia activation.
microglia phenotype supportive of regeneration is observed at the earliest stages of
demyelination
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10. INVIVO TEST
1.EXPERIMENTAL AUTO IMMUNE ENCEPHALOMYLTIS
I. EAE is a spectrum of neurological disorders induced in laboratory animals
following immunisation with CNS.
II. Antigens emulsified in an adjuvant to augment the immune response
III. These models generally use purified myelin, recombinant proteins or
encephalitogenic peptides of myelinproteins.
IV. EAE studies used myelin basic protein (MBP) since it is a major protein component
of the myelin sheath and highly soluble, and can therefore be purified relatively
easily.
PROCEDURE
Active EAE relies on CNS-reactive T cells that are induced following immunisation
by an autoantigen
Emulsified in an adjuvant, while passive or adoptive transfer EAE is induced by
transferring the autoreactive T cells to native recipient animals.
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11. Adjuvants used for EAE induction frequently contain killed mycobacteria that elicit T cell
responses as well as antibody production due to innate immune activation via
Toll-like receptor triggering
The first adjuvant for EAE studies was an oil-in-water emulsion called Incomplete
Freund’s Adjuvant (IFA). Addition of inactivated dried mycobacteria such as M. butyricum,
M. tuberculosis or Bordetella pertussis.
This has led to the development of secondary progressive EAE , models of
cortical demyelination and experimental inflammatory neurodegenerative and
spastic diseases.
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12. 2.VIRAL
several mechanisms have been proposed to explain how viruses can induce demyelination,
and may thus be involved in MS. Damage may result either from a direct effect on neurons,
in which case myelin damage occurs as a secondary event (the so-called ‘insideout’model )or
from a direct attack on myelin, in which case neurons die due to the lack of trophic support by
myelin (the so-called ‘outside-in’ model).
PROCEDURE
Some of the viruses are used to induce the disorder, virus infection could additionally induce
or augment autoimmunity to myelin and neurons via several pathways.
1.Semliki Forest Virus
2.Japanese Macaque Encephalomyelitis
3. Theiler’s Murine Encephalomyelitis Virus
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13. 1.SEMLIKI FOREST VIRUS
Semliki Forest virus (SFV) does not cause demyelination in humans.SFV is an enveloped
Togavirus, first isolated from mosquitoes in 1942.The common strains used to induce
myelin damage in mice are the mutant M9 and avirulent A7. SFV is neuroinvasive.
once inoculated peripherally and after crossing the BBB, the virus infects neurons and
oligodendrocytes. While the M9 strain is highly virulent, causing death in 10-20% of adult mice
or paralysis as a result of neuronal damage
2. JAPANESE MACAQUE ENCEPHALOMYELITIS
A spontaneous inflammatory demyelinating disease was reported in a colony of
Japanese macaques in Oregon from which a gamma-herpes virus was isolated.
3. THEILER’S MURINE ENCEPHALOMYELITIS VIRUS
Theiler’s Murine Encephalomyelitis Virus, first identified by Max Theiler, is a natural pathogen
of mice,causing paralysis and encephalomyelitis.
Theiler’s Murine Encephalomyelitis Virus infection induces clinical neurological disease in
immunocompetent mice, along with atrophy of the brain and spinal cord.
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14. 3.TOXIN MODELS
In these models, demyelination is induced after focal application or systemic administration of
the toxin.
Agents for focal demyelination used so far are
• Lysolecithin, also called LPC
• Ethidium bromide (EB)
• Antibodies to oligodendrocyte-related proteins
• Bacterial endotoxins
• 6-aminonicotinamide
• Electrolytes or cocktails containing complement and antibodies
• against galactocerebroside
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15. REFERENCES
•Baukje J. van der Star etal., In Vitro and In Vivo Models of Multiple Sclerosis
CNS & Neurological Disorders - Drug Targets, 2012, 11, 570-588.
•Text book of pharmacology by lippincott illustrated reviews 6th edition.
•www.nhs.uk
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