Disease relevance of Demyelinating Diseases

• The major human demyelinating disease affecting the central nervous system is multiple sclerosis (MS) [1].
• The chronic variant of experimental allergic encephalomyelitis (EAE), a T-cell mediated autoimmune disease in rodents, represents a relevant animal model for MS given the chronic relapsing disease course and inflammatory changes of CNS observed in these demyelinating disorders [2].
• Infection with the PLP139-151-encoding TMEV led within 10-14 days to a rapid-onset paralytic demyelinating disease characterized by PLP139-151-specific CD4(+) Th1 responses; insertion of a non-self ovalbumin sequence led to restoration of the normal late-onset disease [3].
• Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role [4].
• BACKGROUND: The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3-5 years once clinical symptoms are detectable [5].

Psychiatry related information on Demyelinating Diseases

• The view that affective disturbance may also result from cerebral demyelination is presented, along with a brief discussion of MS as a prototype "subcortical" dementia [6].
• On the other hand, overproduction of proinflammatory cytokines (CKs) and, in particular, tumor necrosis factor-alpha under HIV or lipopolysaccharide stimulation may cause neural damage in terms of demyelination and subsequent development of acquired immunodeficiency syndrome (AIDS) dementia complex [7].
• These data also provide an alternate means of interpreting various aspects of impaired auditory functioning in MS patients, and aid in generating new hypotheses regarding the possible consequences of demyelination on normal auditory perception [8].
• Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain [9].

High impact information on Demyelinating Diseases

• We now demonstrate that mice devoid of Pmp22 are retarded in the onset of myelination and develop abundant sausage-like hypermyelination structures (tomacula) at a young age followed by severe demyelination, axonal loss and functional impairment [10].
• Absence of MHC class II molecules reduces CNS demyelination, microglial/macrophage infiltration, and twitching in murine globoid cell leukodystrophy [11].
• A deletion of MBP sequences in the genome of shiverer mice was also demonstrated. cDNAs for MBP will allow molecular investigation of the role this gene plays in both dysmyelinating and demyelinating diseases, as well as questions of MBP biosynthesis [12].
• These findings demonstrate that lymphocytic cells reactive to myelin basic protein are present in the spinal fluid during active demyelinating disease; and that these cells may be more reactive than peripheral blood lymphocytes [13].
• Thus, autoimmune responses to sulfatide and other lipids are present in individuals with multiple sclerosis and in EAE, and may contribute to the pathogenesis of autoimmune demyelination [14].

Chemical compound and disease context of Demyelinating Diseases

• Here we report that upon immunization with MOG, mice lacking TNF develop severe neurological impairment with high mortality and extensive inflammation and demyelination [15].
• Thus, glutamate excitotoxicity seems to be an important mechanism in autoimmune demyelination, and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for multiple sclerosis [16].
• Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone [17].
• Activation of microglial poly(ADP-ribose)-polymerase-1 by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage [18].
• Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway [19].

Biological context of Demyelinating Diseases

• Thus, tight regulation of Plp gene expression is necessary for normal oligodendrocyte differentiation and survival, and its overexpression can be the cause of both dys- and demyelination [20].
• Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury [21].
• Two patients-a compound heterozygote for truncating and severely inactivating missense mutations and a homozygote for an aberrant splicing MAT1A mutation-have plasma methionine in the 1,226-1,870 microM range (normal 5-35 microM) and manifest abnormalities of the brain gray matter or signs of brain demyelination [22].
• The data provide a strong link between in vivo and in vitro observations regarding demyelinating disease, further indicate a biochemical mechanism for anti-MOG-induced demyelination, and suggest in vitro tools for determining autoimmune antibody pathogenicity in multiple sclerosis patients [23].
• Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination [24].

Anatomical context of Demyelinating Diseases

• Multiple sclerosis is a demyelinating disease of the human central nervous system, and studies of experimental demyelination indicate that remyelination in vivo requires the local generation, migration or maturation of new oligodendrocytes, or some combination of these [25].
• We now report that in spinal cord sections of adult animals with active demyelination and inflammatory cells, in situ hybridization reveals a dramatic increase in probe binding to MBP-specific mRNA at 2-3 weeks after virus inoculation and before remyelination can be detected by morphological methods [26].
• In particular, myelin oligodendrocyte glycoprotein, a central nervous system (CNS)-specific antigen expressed on the myelin surface, is able to induce a paralytic MS-like disease with extensive CNS inflammation and demyelination in several strains of animals [27].
• These mutations are anticipated to disrupt homophilic MPZ binding and result in CMT1B peripheral nerve demyelination [28].
• Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination [29].

Gene context of Demyelinating Diseases

• However, LT-alpha-/- mice were quite resistant to EAE with low average clinical scores (<1), an average disease index of 61, and the negligible CNS inflammation and demyelination [30].
• Since we demonstrated that demyelination in multiple sclerosis involved specific chemical changes in myelin basic protein (MBP), we investigated the MBP in our transgenic line for similar changes [31].
• To investigate insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression during experimental demyelination and myelin regeneration, young mice were fed cuprizone (( bis(cyclohexanone) oxaldihydrazone )) [29].
• Clinical manifestations are variable and poorly understood, although a number of individuals with homozygous null mutations in MAT1A have neurological problems, including brain demyelination [22].
• X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disease caused by loss of function of the peroxisomal transporter ABCD1 (ALD), which results in accumulation of very long chain fatty acids (VLCFAs) in organs and serum, central demyelination and peripheral axonopathy and Addison's disease [32].

Analytical, diagnostic and therapeutic context of Demyelinating Diseases

• Radioimmunoassay of myelin basic protein in spinal fluid. An index of active demyelination [33].
• The demyelination that is characteristic of experimental allergic encephalomyelitis induced in C. jacchus by immunization against human white matter did not occur after adoptive transfer of the MBP-reactive clones [34].
• The identification of MOG as a major target antigen for autoimmune demyelination in a nonhuman primate should facilitate development of specific immunotherapies for human MS [35].
• This finding appears to support the belief that demyelination may be associated with more severe reactions to iophendylate myelography [36].
• In the cohort study, incident cases of MS, demyelination, and/or ON (MS/D/ON) had to occur at least 1 year after registration with the physician and after the diagnosis of IBD [37].

References