scholarly journals Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katharina Robichon ◽  
Sven Sondhauss ◽  
T. William Jordan ◽  
Robert A. Keyzers ◽  
Bronwen Connor ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mass Spectrometry ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Brain Regions ◽  
Receptor Expression ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

AbstractMultiple sclerosis is a disease characterised by axonal demyelination in the central nervous system (CNS). The atypical antipsychotic drug clozapine attenuates experimental autoimmune encephalomyelitis (EAE), a mouse model used to study multiple sclerosis, but the precise mechanism is unknown and could include both peripheral and CNS–mediated effects. To better understand where clozapine exerts its protective effects, we investigated the tissue distribution and localisation of clozapine using matrix-assisted laser desorption ionization imaging mass spectrometry and liquid chromatography-mass spectrometry. We found that clozapine was detectable in the brain and enriched in specific brain regions (cortex, thalamus and olfactory bulb), but the distribution was not altered by EAE. Furthermore, although not altered in other organs, clozapine levels were significantly elevated in serum during EAE. Because clozapine antagonises dopamine receptors, we analysed dopamine levels in serum and brain as well as dopamine receptor expression on brain-resident and infiltrating immune cells. While neither clozapine nor EAE significantly affected dopamine levels, we observed a significant downregulation of dopamine receptors 1 and 5 and up-regulation of dopamine receptor 2 on microglia and CD4+-infiltrating T cells during EAE. Together these findings provide insight into how neuroinflammation, as modelled by EAE, alters the distribution and downstream effects of clozapine.

scholarly journals Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

2005 ◽  
Vol 185 (2) ◽  
pp. 243-252 ◽  
Author(s):  
M Merle Elloso ◽  
Kristen Phiel ◽  
Ruth A Henderson ◽  
Heather A Harris ◽  
Steven J Adelman
Keyword(s):  
Multiple Sclerosis ◽  
Estrogen Receptor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Responses ◽  
Clinical Symptoms ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Selective Agonist ◽  
Selective Ligands ◽  
Experimental Autoimmune

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERα and ERβ. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17β-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERα-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERβ-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139–151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERβ agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERα-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

A novel connection of autophagy related gene 7 to multiple sclerosis and experimental autoimmune encephalomyelitis

2014 ◽  
Vol 275 (1-2) ◽  
pp. 136-137
Author(s):  
Rasmus Berglund ◽  
Melanie Thessen Hedreul ◽  
Roham Parsa ◽  
Petra Bergman ◽  
Maja Jagodic ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Related Gene ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

2021 ◽  
Author(s):  
William E. Barclay ◽  
M. Elizabeth Deerhake ◽  
Makoto Inoue ◽  
Toshiaki Nonaka ◽  
Kengo Nozaki ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Animal Model ◽  
Cell Death ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

ABSTRACTInflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.

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