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Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE205292 | GEO | 2022/07/15

REPOSITORIES: GEO

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Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [astrocyte]

Project description:Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and non-canonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and inflammation which are highly correlated with the amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking Drd2 in neurons. Together, our findings reveal previously uncharted roles for a DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.

2022-07-15 | GSE205290 | GEO

Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [spinal cord]

2022-07-15 | GSE205291 | GEO

Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis

Project description:Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis

| PRJNA844329 | ENA

Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [astrocyte]

Project description:Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [astrocyte]

| PRJNA844335 | ENA

Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [spinal cord]

Project description:Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis [spinal cord]

| PRJNA844336 | ENA

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis.

Project description:Background and aimsAlemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease severity in the relapsing-remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery of anti-CD52 antibodies reduces disease severity and the neuroinflammatory burden in the experimental autoimmune encephalomyelitis (EAE) model.MethodsAnti-CD52 antibodies were administered intrathecally during the acute and chronic phases of EAE. Flow cytometry and immunohistochemistry were utilized to define immunological and pathological parameters.ResultsWe show that subcutaneously administrated anti-CD52 antibodies completely abolish EAE disease severity. CNS delivery of anti-CD52 antibodies during both the acute and chronic phases of EAE moderately reduces disease severity and the neuroinflammatory burden. Our findings further suggest that CNS delivery of anti-CD52 antibodies impacts both the peripheral and CNS immune cell compartments in the EAE model but not in healthy mice.ConclusionCollectively, our findings highlight the therapeutic potential of CNS delivery of alemtuzumab for the treatment of progressive as well as early MS.

| S-EPMC7443992 | biostudies-literature

CNS inflammation other than multiple sclerosis: how likely is diagnosis?

Project description: Not available

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Calpeptin attenuated inflammation, cell death, and axonal damage in animal model of multiple sclerosis.

Project description:Experimental autoimmune encephalomyelitis (EAE) is an animal model for studying multiple sclerosis (MS). Calpain has been implicated in many inflammatory and neurodegenerative events that lead to disability in EAE and MS. Thus, treating EAE animals with calpain inhibitors may block these events and ameliorate disability. To test this hypothesis, acute EAE Lewis rats were treated dose dependently with the calpain inhibitor calpeptin (50-250 microg/kg). Calpain activity, gliosis, loss of myelin, and axonal damage were attenuated by calpeptin therapy, leading to improved clinical scores. Neuronal and oligodendrocyte death were also decreased, with down-regulation of proapoptotic proteins, suggesting that decreases in cell death were due to decreases in the expression or activity of proapoptotic proteins. These results indicate that calpain inhibition may offer a novel therapeutic avenue for treating EAE and MS.

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Transcriptomic profiling in the animal model of multiple sclerosis

Project description:We have performed transcriptomic analysis in the spinal cord of experimental autoimmune encephalomyelitis (EAE) mice compared to naive mice at different time intervals in order to observe the gene expression changes within the CNS compartment

2017-09-30 | E-MTAB-5225 | biostudies-arrayexpress

Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis.

Project description:Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and a leading cause of neurological disability. The complex immunopathology and variable disease course of multiple sclerosis have limited effective treatment of all patients. Altering the metabolism of immune cells may be an attractive strategy to modify their function during autoimmunity. We examined the effect of inhibiting fatty acid metabolism in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Mice treated with an inhibitor of carnitine palmitoyltransferase 1 (CPT-1), the rate-limiting enzyme in the beta-oxidation of fatty acids, showed a reduction in disease severity as well as less inflammation and demyelination. Inhibition of CPT-1 in encephalitogenic T-cells resulted in increased apoptosis and reduced inflammatory cytokine production. These results suggest that disruption of fatty acid metabolism promotes downregulation of inflammation in the CNS and that this metabolic pathway is a potential therapeutic target for multiple sclerosis.

| S-EPMC3216566 | biostudies-literature

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