Autoimmune-induced damage of the midbrain dopaminergic system in lupus-prone mice

Ballok, David A.; Earls, Aoife M.; Krasnik, Catherine; Hoffman, Steven A.; Šakić, Boris

doi:10.1016/j.jneuroim.2004.04.003

Cited by 46 publications

(54 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…21 We observed earlier that tyrosine-hydroxylase (TH, a critical enzyme in dopamine synthesis) is less abundant in SN and ventral tegmentum of many diseased, pharmacologically unchallenged MRL-lpr mice. 24 Increased staining with Fluoro Jade B suggested a neurodegenerative process in these dopamine-rich regions. If the damage occurs at an early stage of brain development indeed (either in utero or after birth), one may expect major perturbations in behavioral profile when lupus-prone mice reach adulthood.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, we detected earlier a significant accumulation of dopamine in the median eminence and the paraventricular nucleus, 18 as well as reduced number of TH þ cells in SN and ventral tegmentum. 24 Other factors, such as metalloproteinases 59 and prostaglandins, 60 have been also considered in neurodegeneration of inflammatory type. Our recent study excluded COX-dependent mechanisms 54 and steered future research towards the role of brain-reactive autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

“…25 The possibility that dopaminergic system is affected was further supported by B35% reduction in tyrosine hydroxylase-positive cells in the substantia nigra (SN), and increased number of degenerating neurons in the SN and ventral tegmentum. 24 In summary, several lines of evidence suggested that deficits in dopaminergic transmission underlie certain aspects of AABS including proclivity to SIB.…”

Section: Introductionmentioning

confidence: 99%

“…18 Functional damage of the nigrostriatal pathway was inferred from excessive rotational behavior after a single injection of a D1/D2-receptor agonist apomorphine. 24 Similarly, acute amphetamine injection (known to enhance responsiveness to sucrose) was ineffective in diseased MRL-lpr mice and correlated with dying neurons in the nucleus accumbens. 25 The possibility that dopaminergic system is affected was further supported by B35% reduction in tyrosine hydroxylase-positive cells in the substantia nigra (SN), and increased number of degenerating neurons in the SN and ventral tegmentum.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

et al. 2007

View full text Add to dashboard Cite

Systemic lupus erythematosus is frequently accompanied by psychiatric manifestations of unknown origin. Although damage of central neurons had been documented, little is known about neurotransmitter systems affected by the autoimmune/inflammatory process. Recent studies on lupus-prone MRL-lpr mice point to imbalanced dopamine function and neurodegeneration in dopamine-rich brain regions. We follow up on anecdotal observations of singly housed mice developing chest wounds. Compulsive grooming and/or skin biting accounted for open lesions, lending itself to the operational term 'self-injurious behavior' (SIB). Low incidence of spontaneous SIB increased significantly after repeated injections of dopamine-2/ 3 receptor (D2/D3R) agonist quinpirole (QNP). To further probe the dopaminergic circuitry and examine whether SIB is associated with development of lupus-like disease, we compared behavioral responses among cohorts that differed in the immune status. Two-week treatment with QNP (intraperitoneal, 0.5 mg kg À1 body weight per day) induced SIB in 60% of diseased MRL-lpr mice, and exacerbated their splenomegaly. Although increased grooming and stereotypy were observed in less symptomatic MRL þ / þ controls, only one mouse (10%) developed SIB. Similarly, SIB was not seen in young, asymptomatic groups despite dissimilar ambulatory responses to QNP. In situ hybridization revealed treatment-independent upregulation of D2R mRNA in substantia nigra of diseased MRL-lpr mice. The above results suggest that development of systemic autoimmunity alters sensitivity of the dopaminergic system and renders MRL-lpr mice prone to SIB. Although pathogenic factors were not examined, we hypothesize that immune and endocrine mechanisms jointly contribute to early neuronal damage, which underlies behavioral deficiency in the adulthood.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

et al. 2007

View full text Add to dashboard Cite

show abstract

“…To examine whether CSF toxicity is associated with neuronal degeneration in situ (Schmued and Hopkins, 2000), brain sections were stained with the FJB dye (Histo-Chem Inc., Jefferson, AR), using the previously published protocol (Ballok et al, 2004a). Four brains from mice that largely differed in the extent of CSF toxicity were stored in 30% sucrose for at least 24 h before a frozen coronal section (cut at Bregma ~−1.0 mm) was processed (1 section/brain).…”

Section: Fluoro Jade B (Fjb) Stainingmentioning

confidence: 99%

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

Šakić

Kirkham

Ballok

et al. 2005

Journal of Neuroimmunology

Self Cite

View full text Add to dashboard Cite

Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented. AbbreviationsACA, anti-cardiolipin antibodiesx; Abbreviations, anti-nuclear antibodies; CSF, cerebrospinal fluid; FJB, Fluoro Jade B stain; NP-SLE, neuropsychiatric systemic lupus erythematosus; PBS, phosphate buffered saline

show abstract

Time course and nature of brain atrophy in the MRL mouse model of central nervous system lupus

Sled¹,

Spring²,

Eede³

et al. 2009

Arthritis & Rheumatism

Self Cite

View full text Add to dashboard Cite

Objective. Similar to patients with systemic lupus erythematosus, autoimmune MRL/lpr mice spontaneously develop behavioral deficits and pathologic changes in the brain. Given that the disease-associated brain atrophy in this model is not well understood, the present study was undertaken to determine the time course of morphometric changes in major brain structures of autoimmune MRL/lpr mice.Methods. Computerized planimetry and highresolution magnetic resonance imaging (MRI) were used to compare the areas and volumes of brain structures in cohorts of mice that differ in severity of lupus-like disease.Results. A thinner cerebral cortex and smaller cerebellum were observed in the MRL/lpr substrain, even before severe autoimmunity developed. With progression of the disease, the brain area of coronal sections became smaller and the growth of the hippocampus was retarded, which likely contributed to the increase in the ventricle area:brain area ratio. MRI revealed reduced volume across different brain regions, with the structures in the vicinity of the ventricular system particularly affected. The superior colliculus, periaqueductal gray matter, pons, and midbrain were among the regions most affected, whereas the volumes of the parietal-temporal lobe, parts of the cerebellum, and lateral ventricles in autoimmune MRL/lpr mice were comparable with values in congenic controls.Conclusion. These results suggest that morphologic alterations in the brains of MRL/lpr mice are a consequence of several factors, including spontaneous development of lupus-like disease. A periventricular pattern of parenchymal damage is consistent with the cerebrospinal fluid neurotoxicity, limbic system pathologic features, and deficits in emotional reactivity previously documented in this model. Neuropsychiatric (NP) manifestations are a common and serious complication of systemic lupus erythematosus (SLE). Contemporary imaging techniques have revealed various abnormalities in patients withSLE, including lesions in the periventricular and subcortical regions (1,2), hypoperfusion (3), and regional metabolic abnormalities (4). Brain atrophy is the most frequent observation (5) and is likely a consequence of widespread neuronal and glial damage (6). Consistent with these reports, recent studies on water diffusivity indicate a genuine loss of brain-tissue integrity in patients with NPSLE/central nervous system (CNS) lupus (7). However, the lack of understanding of CNS damage led to development of animal models of acute and chronic lupus and dissection of complex pathogenic circuits (8).MRL/MpJTnfrsf6 lpr (MRL/lpr) mice and MRL/ MpJϩ/ϩ (MRLϩ/ϩ) congenic control mice share more than 99.9% of their genome but differ in the onset of lupus-like manifestations. The 3-4-month difference in the time to onset allows discrimination of autoimmunityinduced functional and structural brain damage from epiphenomena associated with aging and with damage of vital peripheral organs (9). In addition to accelerated development of serologic signs of inflammation and aut...

show abstract

Autoimmune-induced damage of the midbrain dopaminergic system in lupus-prone mice

Cited by 46 publications

References 116 publications

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

Time course and nature of brain atrophy in the MRL mouse model of central nervous system lupus

Contact Info

Product

Resources

About