Axonal and neuronal pathology in multiple sclerosis: What have we learnt from animal models

Lassmann, Hans

doi:10.1016/j.expneurol.2009.10.009

Cited by 153 publications

(107 citation statements)

References 67 publications

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“…It arises from a break in tolerance toward self-antigens and is characterized by the development of myelin-reactive Th1 and Th17 lymphocytes, macrophages and several bystander cells, which in susceptible strains of animals infiltrate the brain and develop the typical remitting relapsing course of the disease [21,22,23,24]. The outcome, however, depends on the interplay between the pathogenic and regulatory T cell populations, as well as on several local and systemic inflammatory and anti-inflammatory mechanisms that affect the development of immunogenic and tolerogenic lymphatic subsets and regulate the susceptibility of target organs or target tissue structures to the autoimmune attack.…”

Section: Discussionmentioning

confidence: 99%

Metallothioneins I/II Expression in Rat Strains with Genetically Different Susceptibility to Experimental Autoimmune Encephalomyelitis

Grubić-Kezele

Jakovac²,

Tota³

et al. 2013

Neuroimmunomodulation

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Objectives: Compared to the Dark Agouti (DA), the Albino Oxford (AO) rat strain exhibits lower susceptibility to the induction of experimental autoimmune encephalomyelitis (EAE). Here, we investigated the potential contribution of the heavy metal-binding proteins metallothioneins (MTs) I/II to these effects. Methods: Rats were immunized with bovine brain homogenate emulsified in complete Freund's adjuvant or only with complete Freund's adjuvant. The expression patterns of MTs mRNA and proteins and tissue concentrations of Zn²⁺ and Cu²⁺ were estimated in the brain and in the liver on days 7 and 12 after immunization, by real-time PCR, immunohistochemistry and inductively coupled plasma spectrometry, respectively. Additionally, the hepatic transforming growth factor beta and nuclear factor kappa B immunoreactivities were tested. Results: Clinical signs of EAE were not induced in AO rats, but they upregulated the expression of MT I/II proteins in the brain (hippocampus and cerebellum) and in the liver, similarly as DA rats. The transcriptional activation of MT-I occurred, however, only in DA rats, which accumulated also more zinc in the brain and in the liver. In contrast, intact AO rats had greater hepatic MT-I mRNA immunoreactivity and more Cu²⁺ in the hippocampus. Besides, in immunized AO rats a high upregulation of transforming growth factor beta and nuclear factor kappa B immunoreactivities was found in several hepatic structures (vascular endothelium, Kupffer cells and hepatocytes). Conclusions: Our data show that AO and DA rats differ in constitutive and inductive MT-I gene expression in the brain and in the liver, as well as in the hepatic cytokine profile, suggesting that these mechanisms may contribute to the discrepancy in the susceptibility to EAE.

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Section: Discussionmentioning

confidence: 99%

Metallothioneins I/II Expression in Rat Strains with Genetically Different Susceptibility to Experimental Autoimmune Encephalomyelitis

Grubić-Kezele

Jakovac²,

Tota³

et al. 2013

Neuroimmunomodulation

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“…For instance, and of pivotal clinical importance, these tools help to study the involvement of CNS pathways in MS pathogenesis. MS is a condition associated with substantial neuronal and axonal damage, and this neurodegeneration probably drives long-term neurological disability 12 . Hence, pathways that are related to neuronal death and axonal damage may be of particular interest for the development of neuroprotective therapies, an approach pursued for decades without success to date.…”

Section: New Roles In Ms Of Components In Known Pathwaysmentioning

confidence: 99%

Signaling networks in MS: A systems-based approach to developing new pharmacological therapies

et al. 2014

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The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies. Systems biology approaches that study pathway dysregulation should offer benefits by integrating molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NF-Kb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis/cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress, although which pathways contribute to the cascade of damage and can be modulated remains an open question. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. These data serve as a scaffold on which computational modeling can be performed to identify disease subgroups based on the contribution of different processes. Such an analysis, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies. AbstractThe pathogenesis of MS involves alterations to multiple pathways and processes, which represent a significant challenge for developing more effective therapies. Systems biology approaches that study pathway dysregulation will offer benefits by integrating in molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NFKb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis / cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. This data serves as a scaffold upon which computational modeling can be performed to identify disease subgroups based in the contribution of different processes. Such an analysis, targeting these relevant MS signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies.

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“…Experimental autoimmune encephalomyelitis (EAE) is a well recognized animal model for multiple sclerosis (MS), which is characterized by lymphocyte infiltration, macrophages/microglia activation, demyelination, oligodendrocyte (OL) loss and axonal injury (Bjartmar et al, 2003;Furlan et al, 2009;Lassmann, 2010;Steinman and Zamvil, 2006). Although a number of pharmacological agents have shown promise in the treatment of EAE, the pathogenic mechanisms of MS/EAE and the therapeutic targets of the drugs' action are still not well understood.…”

Section: Introductionmentioning

confidence: 99%

Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter

Vana

Ribeiro

et al. 2011

Experimental Neurology

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Inhibition of phospholipase A 2 (PLA 2 ) has recently been found to attenuate the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of multiple sclerosis (MS). However, the protective mechanisms that underlie PLA 2 inhibition are still not well understood. In this study, we found that cytosolic PLA 2 (cPLA 2 ) was highly expressed in infiltrating lymphocytes and macrophages/microglia in mouse spinal cord white matter. Although cPLA 2 is also expressed in spinal cord neurons and oligodendrocytes, there were no differences observed in these cell types between EAE and control animals. Arachidonyl trifluoromethyl ketone (AACOCF3), a cPLA 2 inhibitor, significantly reduced the clinical symptoms and inhibited the body weight loss typically found in EAE mice. AACOCF3 also attenuated the loss of mature, myelin producing, oligodendrocytes, and axonal damage in the spinal cord white matter. Nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was dramatically increased in EAE mice and attenuated by treatment with AACOCF3. These protective effects were not evident when AA861, an inhibitor of lipoxygenase, was used. In primary cultures of microglia, lipopolysaccharide (LPS) induced an upregulation of cPLA 2 , inducible nitric oxide synthase (iNOS) and components of the NADPH oxidase complex, p47phox and p67phox. AACOCF3 significantly attenuated iNOS induction, nitric oxide production and the generation of reactive oxygen species in reactive microglia. Similar to the decomposition catalyst of peroxynitrite, AACOCF3 also blocked oligodendrocyte toxicity induced by reactive microglia. These results suggest that AACOCF3 may prevent oligodendrocyte loss in EAE by attenuating peroxynitrite formation in the spinal cord white matter.Published by Elsevier Inc.

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Axonal and neuronal pathology in multiple sclerosis: What have we learnt from animal models

Cited by 153 publications

References 67 publications

Metallothioneins I/II Expression in Rat Strains with Genetically Different Susceptibility to Experimental Autoimmune Encephalomyelitis

Metallothioneins I/II Expression in Rat Strains with Genetically Different Susceptibility to Experimental Autoimmune Encephalomyelitis

Signaling networks in MS: A systems-based approach to developing new pharmacological therapies

Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter

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