Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Localized permeability of blood brain barrier for antibody-conjugates in the cuprizone model of demyelination

Tatiana Abakumova
* ORCID logo ,
Anastasia Kuzkina
,
Philipp Koshkin
,
Daria Pozdeeva
,
Maxim Abakumov
ORCID logo ,
Pavel Melnikov
,
Klavdia Ionova
,
Ilia Gubskii
,
Olga Gurina
,
Natalia Nukolova
,
Vladimir P. Chekhonin
Version 1 : Received: 28 June 2023 / Approved: 29 June 2023 / Online: 29 June 2023 (13:19:21 CEST)

A peer-reviewed article of this Preprint also exists.

Abakumova, T.; Kuzkina, A.; Koshkin, P.; Pozdeeva, D.; Abakumov, M.; Melnikov, P.; Ionova, K.; Gubskii, I.; Gurina, O.; Nukolova, N.; Chekhonin, V. Localized Increased Permeability of Blood–Brain Barrier for Antibody Conjugates in the Cuprizone Model of Demyelination. Int. J. Mol. Sci. 2023, 24, 12688. Abakumova, T.; Kuzkina, A.; Koshkin, P.; Pozdeeva, D.; Abakumov, M.; Melnikov, P.; Ionova, K.; Gubskii, I.; Gurina, O.; Nukolova, N.; Chekhonin, V. Localized Increased Permeability of Blood–Brain Barrier for Antibody Conjugates in the Cuprizone Model of Demyelination. Int. J. Mol. Sci. 2023, 24, 12688.

Abstract

Development of new neurotherapeutics is strongly depending on appropriate animal model chosen in preclinical studies. A cuprizone model is an effective tool for studying demyelination and re-myelination processes in the brain, but BBB integrity in cuprizone model is still a topic for debate. Several publications claim that BBB remains intact during cuprizone-induced demyelination; others demonstrate results that could be explained by the increased BBB permeability. In our work we aim to analyze permeability of BBB for different macromolecules, particularly, antibody-conjugates in cuprizone-intoxicated mice. We compared the traditional approach using Evans blue injection with following dye extraction and detection of antibody-conjugates using magnetic resonance imaging (MRI) and confocal microscopy to analyze BBB permeability in cuprizone model. First, we validated our model of demyelination by detecting changes in gene expression of myelin basic protein and proteolipid protein, and by performing MRI and histological analysis. Our results suggest that the methods with better sensitivity were able to detect the accumulation of macromolecules (such as fluorescent-labeled or gadolinium-labeled antibody conjugates) in the brain, suggesting a local BBB disruption in the demyelinating area. These findings support previous investigations that ques-tioned BBB integrity in cuprizone model and demonstrate possibility for delivery of anti-body-conjugates to demyelinated corpus callosum

Keywords

cuprizone, BBB permeability, demyelination, antibody conjugates, Gd-DTPA, MRI, Evans Blue

Subject

Biology and Life Sciences, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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