Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis

Espejo, Carmen; Carrasco, Javier; Hidalgo, Juan; Penkowa, Milena; Garcı́a, Agustina; Sáez-Torres, Irene; Martı́nez-Cáceres, Eva

doi:10.1016/s0306-4522(01)00252-4

Cited by 46 publications

(23 citation statements)

References 57 publications

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“…A general correlation between the appearance of clinical signs of EAE and BBB permeability changes has been noted in conventional EAE models (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). The loss of BBB integrity is likely to contribute to the pathogenesis of a neuroinflammatory disease by providing circulating cells and factors access to normally privileged CNS tissues and soluble CNS products access to the circulation.…”

Section: Discussionmentioning

confidence: 95%

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Fabis¹,

Scott²,

Kean³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the CNS that is used to model certain parameters of multiple sclerosis. To establish the relative contributions of T cell reactivity, the loss of blood-brain barrier (BBB) integrity, CNS inflammation, and lesion formation toward the pathogenesis of EAE, we assessed the incidence of EAE and these parameters in mice lacking NF-B, TNF-␣, IFN-␣␤ receptors, IFN-␥ receptors, and inducible nitric oxide synthase. Although increased myelin oligodendrocyte glycoprotein-specific T cell reactivity was generally associated with a more rapid onset or increased disease severity, the loss of BBB integrity and cell accumulation in spinal cord tissues was invariably associated with the development of neurological disease signs. Histological and real-time RT-PCR analyses revealed differences in the nature of immune/inflammatory cell accumulation in the spinal cord tissues of the different mouse strains. On the other hand, disease severity during the acute phase of EAE directly correlated with the extent of BBB permeability. Thus, the loss of BBB integrity seems to be a requisite event in the development of EAE and can occur in the absence of important inflammatory mediators.gene knockout mice ͉ multiple sclerosis

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Section: Discussionmentioning

confidence: 95%

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Fabis¹,

Scott²,

Kean³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Further, immune response genes may be linked to other heritable factors mediating toxin-induced CNS damage, such as systems regulating antioxidant 45 or DNA methylation 46 status, apoptosis pathways, 47 glutamatergic transmission or excitotoxicity, 48 metallothionein isoforms, 49 or proinflammatory cytokine responses. 50 As a central role is implicated for the Th1-type cytokine, interferon-g (IFN-g), in mercuryinduced autoimmunity 51 and general autoimmune disease susceptibility, 52 we included C57 mice in our strain comparison; similar to SJL mice, C57 mice show a Th1-type cytokine predominance, including increased levels of IFN-g gene expression at baseline, 53 yet are less sensitive than SJL mice to autoimmune sequelae following mercury or other Th1-dependent, autoimmunity-provoking challenges.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

2004

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The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/ 6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.

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“…Zinc metallothioneins have been suggested to have a role in preventing demyelination and neurodegeneration as well as decreasing inflammation during EAE and MS. Increased expression of metallothioneins I and II has been detected in microglia, macrophages and astrocytes in both MS and EAE (Espejo et al, 2001;Lock et al, 2002;Penkowa and Hidalgo, 2000). Treatment of rats with zinc metallothionein II prior to or during EAE significantly decreased the amount of demyelination and axonal loss compared to controls (Penkowa and Hidalgo, 2003).…”

Section: Do Other Factors Cause Inflammation And/or Neurodegenerationmentioning

confidence: 98%

Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis

Peterson¹,

Fujinami²

2007

Journal of Neuroimmunology

167

104

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Although axonal loss has been observed in demyelinated multiple sclerosis (MS) lesions, there has been a major focus on understanding mechanisms of demyelination. However, identification of markers for axonal damage and development of new imaging techniques has enabled detection of subtle changes in axonal pathology and revived interest in the neurodegenerative component of MS. Axonal loss is generally accepted as the main determinant of permanent clinical disability. However, the role of axonal loss early in disease or during relapsing-remitting disease is still under investigation, as are the interactions and interdependency between inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of MS.

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Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis

Cited by 46 publications

References 57 publications

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Loss of blood–brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models

Neurotoxic effects of postnatal thimerosal are mouse strain dependent

Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis

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