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Open Access 01-12-2022 | Multiple Sclerosis | Research

Cladribine treatment improves cortical network functionality in a mouse model of autoimmune encephalomyelitis

Authors: Christina B. Schroeter, Leoni Rolfes, K. S. Sophie Gothan, Joel Gruchot, Alexander M. Herrmann, Stefanie Bock, Luca Fazio, Antonia Henes, Venu Narayanan, Steffen Pfeuffer, Christopher Nelke, Saskia Räuber, Niklas Huntemann, Eduardo Duarte-Silva, Vera Dobelmann, Petra Hundehege, Heinz Wiendl, Katharina Raba, Patrick Küry, David Kremer, Tobias Ruck, Thomas Müntefering, Thomas Budde, Manuela Cerina, Sven G. Meuth

Published in: Journal of Neuroinflammation | Issue 1/2022

Abstract

Background

Cladribine is a synthetic purine analogue that interferes with DNA synthesis and repair next to disrupting cellular proliferation in actively dividing lymphocytes. The compound is approved for the treatment of multiple sclerosis (MS). Cladribine can cross the blood–brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. Here, we explored compartment-specific immunosuppressive as well as potential direct neuroprotective effects of oral cladribine treatment in experimental autoimmune encephalomyelitis (EAE) mice.

Methods

In the current study, we compare immune cell frequencies and phenotypes in the periphery and CNS of EAE mice with distinct grey and white matter lesions (combined active and focal EAE) either orally treated with cladribine or vehicle, using flow cytometry. To evaluate potential direct neuroprotective effects, we assessed the integrity of the primary auditory cortex neuronal network by studying neuronal activity and spontaneous synaptic activity with electrophysiological techniques ex vivo.

Results

Oral cladribine treatment significantly attenuated clinical deficits in EAE mice. Ex vivo flow cytometry showed that cladribine administration led to peripheral immune cell depletion in a compartment-specific manner and reduced immune cell infiltration into the CNS. Histological evaluations revealed no significant differences for inflammatory lesion load following cladribine treatment compared to vehicle control. Single cell electrophysiology in acute brain slices was performed and showed an impact of cladribine treatment on intrinsic cellular firing patterns and spontaneous synaptic transmission in neurons of the primary auditory cortex. Here, cladribine administration in vivo partially restored cortical neuronal network function, reducing action potential firing. Both, the effect on immune cells and neuronal activity were transient.

Conclusions

Our results indicate that cladribine exerts a neuroprotective effect after crossing the blood–brain barrier independently of its peripheral immunosuppressant action.

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Title: Cladribine treatment improves cortical network functionality in a mouse model of autoimmune encephalomyelitis
Authors: Christina B. Schroeter
Leoni Rolfes
K. S. Sophie Gothan
Joel Gruchot
Alexander M. Herrmann
Stefanie Bock
Luca Fazio
Antonia Henes
Venu Narayanan
Steffen Pfeuffer
Christopher Nelke
Saskia Räuber
Niklas Huntemann
Eduardo Duarte-Silva
Vera Dobelmann
Petra Hundehege
Heinz Wiendl
Katharina Raba
Patrick Küry
David Kremer
Tobias Ruck
Thomas Müntefering
Thomas Budde
Manuela Cerina
Sven G. Meuth
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Multiple Sclerosis
Cladribine
Published in: Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-022-02588-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Cladribine treatment improves cortical network functionality in a mouse model of autoimmune encephalomyelitis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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