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

Abstract Multiple 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 unkno...

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Autores principales:	Katharina Robichon, Sven Sondhauss, T. William Jordan, Robert A. Keyzers, Bronwen Connor, Anne C. La Flamme
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1fc8228af1f0439d8a8f71c4d574ac28
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spelling	oai:doaj.org-article:1fc8228af1f0439d8a8f71c4d574ac282021-12-02T14:06:56ZLocalisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors10.1038/s41598-021-82667-62045-2322https://doaj.org/article/1fc8228af1f0439d8a8f71c4d574ac282021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82667-6https://doaj.org/toc/2045-2322Abstract Multiple 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.Katharina RobichonSven SondhaussT. William JordanRobert A. KeyzersBronwen ConnorAnne C. La FlammeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katharina Robichon Sven Sondhauss T. William Jordan Robert A. Keyzers Bronwen Connor Anne C. La Flamme Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors
description	Abstract Multiple 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.
format	article
author	Katharina Robichon Sven Sondhauss T. William Jordan Robert A. Keyzers Bronwen Connor Anne C. La Flamme
author_facet	Katharina Robichon Sven Sondhauss T. William Jordan Robert A. Keyzers Bronwen Connor Anne C. La Flamme
author_sort	Katharina Robichon
title	Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors
title_short	Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors
title_full	Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors
title_fullStr	Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors
title_full_unstemmed	Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors
title_sort	localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1fc8228af1f0439d8a8f71c4d574ac28
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Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

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