Memory, Learning Ability, and Neuropathologic Status of Mice with Systemic Lupus Erythematosus<sup>a</sup>

Walker, Sara E.; Wright, Dennis C.; O’Sullivan, Frank X.; Johnson, Gayle C.; Besch‐Williford, Cynthia; Vogelweid, Catherine M.

doi:10.1111/j.1749-6632.1997.tb48383.x

Cited by 12 publications

(9 citation statements)

References 22 publications

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“…Using the MRL/lpr strain as an established animal model to explore NPSLE [17-19, 27], we report for the first time that the TWEAK/Fn14 pathway is important in the pathogenesis of this major organ manifestation. Specifically, we found that Fn14 is upregulated in brains of MRL/lpr mice, and that the severe depression-like behavior observed in MRL/lpr Fn14WT mice is significantly ameliorated in Fn14 deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Wen

Xia

Stock

et al. 2013

Journal of Autoimmunity

104

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Given the early onset of neuropsychiatric disease and the potential response to immunosuppressive therapy, neuropsychiatric disease is considered a primary disease manifestation in SLE. However, the pathogenesis is not fully understood and optimal treatment has yet to be determined. TWEAK is a TNF family ligand that mediates pleotropic effects through its receptor Fn14, including the stimulation of inflammatory cytokines by astrocytes, endothelial cells, and other non-hematopeotic cell types, and induction of neuronal death. Furthermore, TWEAK-inducible mediators are implicated in neuropsychiatric lupus. Thus, we hypothesized that the TWEAK/Fn14 pathway may be involved in the pathogenesis of neuropsychiatric SLE. We generated MRL-lpr/lpr (MRL/lpr) mice deficient for Fn14, the sole known signaling receptor for TWEAK. Neuropsychiatric disease was compared in age- and gender-matched MRL/lpr Fn14 wild type (WT) and knockout (KO) mice, using a comprehensive battery of neurobehavioral tests. We found that MRL/lpr Fn14WT mice displayed profound depression-like behavior as seen by increased immobility in a forced swim test and loss of preference for sweetened fluids, which were significantly ameliorated in Fn14KO mice. Similarly, MRL/lpr Fn14WT mice had impaired cognition, and this was significantly improved in Fn14KO mice. To determine the mechanism by which Fn14 deficiency ameliorates neuropsychiatric disease, we assessed the serum levels of autoantibodies and local expression of cytokines in the cortex and hippocampus of lupus mice. No significant differences were found in the serum levels of antibodies to nuclear antigens, or autoantibodies specifically associated with neuropsychiatric disease, between MRL/lpr Fn14WT and KO mice. However, MRL/lpr Fn14KO mice had significantly decreased brain expression of RANTES, C3, and other proinflammatory mediators. Furthermore, MRL/lpr Fn14KO mice displayed improved blood brain barrier integrity. In conclusion, several central manifestations of neuropsychiatric lupus, including depression-like behavior and altered cognition, are normalized in MRL/lpr mice lacking Fn14. Our results are the first to indicate a role for the TWEAK/Fn14 pathway in the pathogenesis of neuropsychiatric lupus, and suggest this ligand-receptor pair as a potential therapeutic target for a common and dangerous disease manifestation.

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Section: Discussionmentioning

confidence: 99%

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Wen

Xia

Stock

et al. 2013

Journal of Autoimmunity

104

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“…The “spontaneous” MRL model has been used for more than two decades (11-14) and proven instrumental in documenting bona fide neurodegeneration of central neurons and cytotoxicity of cerebrospinal fluid (CSF) in SLE-like disease (15;16). In particular, MRL/MpJ-Fas lpr /J (MRL/lpr) and MRL/MpJ (MRL +/+) mice spontaneously develop lupus-like manifestations (e.g., high serum levels of autoantibodies, skin lesions, lymph node and spleen enlargement, renal inflammation), but differ in their onset.…”

Section: Introductionmentioning

confidence: 99%

Effects of prolonged treatment with memantine in the MRL model of central nervous system lupus

Marcinko

Parsons

Lerch

et al. 2012

Clinical & Exp Neuroim

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Objectives Neuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N-methyl-D-aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we presently examine the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE-like disease. Methods A broad behavioral battery and 7-Tesla MRI were used to examine whether prolonged treatment with MEM (~25 mg/kg b.w. in drinking water) prevents CNS involvement in this spontaneous model of SLE. Results Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain-specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL +/+ mice and had a negative effect on body mass gain. Similarly, MRI revealed comparable increases in the volume of periventricular structures in MEM-treated groups. Conclusions Sustained exposure to MEM affects body growth, brain morphology, and behavior primarily by pharmacological, and not autoimmunity-dependant mechanisms. Substrain-specific improvement in exploratory behavior of MEM-treated MRL/lpr mice may indicate that the NMDA system is merely a constituent of a complex pathogenenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE-like syndrome.

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“…Cerebellar function was assessed using conventional tests of posture, balance, and tremulousness (Wishaw et al, 1983). These tests have been widely used to assess cerebellar function in rodents (Wishaw et al, 1983; Walker et al, 1997). Each component of the neurological examination took approximately 30 sec.…”

Section: Methodsmentioning

confidence: 99%

“…Our understanding of the pathogenesis of cerebellar dysfunction in lupus would be greatly enhanced were an animal model available. In this connection, a report by Walker et al (1997) described disturbances in balance and posture in clinically affected MRL‐ lpr/lpr lupus mice. These mice are genetically programmed to manifest an SLE‐like illness (Theofilopoulos, 1995) and offer the considerable advantage of the ability to study a multifactorial, polygenic disease in a numerically meaningful population under controlled environmental conditions.…”

Section: Introductionmentioning

confidence: 91%

Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus

Tomita

Holman

Williams

et al. 2001

J of Neuroscience Research

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Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology accompanied by central nervous system involvement in up to 60% of patients. The current study chronicles the expression of cerebellar dysfunction in SLE using MRL-lpr/lpr mice as the experimental model. These mice spontaneously develop an illness that has immunological and clinical features of human lupus. We found that MRL-lpr/lpr mice manifest severe and progressive behavioral disturbances indicative of cerebellar dysfunction beginning at 11 weeks of age. Although the lpr gene is known to induce autoimmune features, immunologically normal mice rendered congenic for lpr failed to exhibit disturbances in cerebellar function. Because lupus is a cytokine-driven disease and overexpression of certain proinflammatory cytokines has been associated with neurodegeneration, the relationship between cerebellar dysfunction and cytokine gene expression was examined. Relative to immunologically normal CBA/J mice, the cerebellum of young (11-15 weeks of age) MRL-lpr/lpr mice contained high levels of interleukin (IL)-6 and interferon-gamma (IFNgamma) mRNA, which became even more pronounced in old (22-30 weeks of age) autoimmune mice. mRNA levels for the cytokines IL-1beta and IL-10 were elevated in the cerebellum of old, but not young, MRL-lpr/lpr mice relative to CBA/J. In contrast, the levels of cerebellar transcripts for IL-3 and tumor necrosis factor-alpha were comparable in autoimmune and normal mice, indicating that enhanced gene expression of IL-6, IFNgamma, IL-1beta, and IL-10 was selective. These results suggest a potential role for certain proinflammatory cytokines in the pathogenesis of cerebellar disturbances in SLE.

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Memory, Learning Ability, and Neuropathologic Status of Mice with Systemic Lupus Erythematosus^a

Cited by 12 publications

References 22 publications

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Effects of prolonged treatment with memantine in the MRL model of central nervous system lupus

Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus

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Memory, Learning Ability, and Neuropathologic Status of Mice with Systemic Lupus Erythematosusa

Cited by 12 publications

References 22 publications

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Effects of prolonged treatment with memantine in the MRL model of central nervous system lupus

Cerebellar dysfunction is associated with overexpression of proinflammatory cytokine genes in lupus

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Memory, Learning Ability, and Neuropathologic Status of Mice with Systemic Lupus Erythematosus^a