Localized Increased Permeability of Blood–Brain Barrier for Antibody Conjugates in the Cuprizone Model of Demyelination

Author:

Abakumova Tatiana1ORCID,Kuzkina Anastasia23,Koshkin Philipp4,Pozdeeva Daria23,Abakumov Maxim45ORCID,Melnikov Pavel3,Ionova Klavdia3,Gubskii Ilia4,Gurina Olga3,Nukolova Natalia36,Chekhonin Vladimir34

Affiliation:

1. Department of Synthetic Neurotechnology, Pirogov Russian National Research Medical University, Moscow 117997, Russia

2. Faculty of Medicine, Sechenov First Medical University, Moscow 119991, Russia

3. Department of Immunochemistry, V. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia

4. Department of Medicine and Biology, Chair of Medical Nanotechnology, Pirogov Russian National Research Medical University, Moscow 117997, Russia

5. Laboratory of Biomedical Nanomaterials, National University of Science and Technology MISIS, Moscow 119049, Russia

6. Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA

Abstract

The development of new neurotherapeutics depends on appropriate animal models being chosen in preclinical studies. The cuprizone model is an effective tool for studying demyelination and remyelination processes in the brain, but blood–brain barrier (BBB) integrity in the cuprizone model is still a topic for debate. Several publications claim that the BBB remains intact during cuprizone-induced demyelination; others demonstrate results that could explain the increased BBB permeability. In this study, we aim to analyze the permeability of the BBB for different macromolecules, particularly antibody conjugates, in a cuprizone-induced model of demyelination. We compared the traditional approach using Evans blue injection with subsequent dye extraction and detection of antibody conjugates using magnetic resonance imaging (MRI) and confocal microscopy to analyze BBB permeability in the cuprizone model. First, we validated our model of demyelination by performing T2-weighted MRI, diffusion tensor imaging, quantitative rt-PCR to detect changes in mRNA expression of myelin basic protein and proteolipid protein, and Luxol fast blue histological staining of myelin. Intraperitoneal injection of Evans blue did not result in any differences between the fluorescent signal in the brain of healthy and cuprizone-treated mice (IVIS analysis with subsequent dye extraction). In contrast, intravenous injection of antibody conjugates (anti-GFAP or non-specific IgG) after 4 weeks of a cuprizone diet demonstrated accumulation in the corpus callosum of cuprizone-treated mice both by contrast-enhanced MRI (for gadolinium-labeled antibodies) and by fluorescence microscopy (for Alexa488-labeled antibodies). Our results suggest that the methods with better sensitivity could 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 questioned BBB integrity in the cuprizone model and demonstrate the possibility of delivering antibody conjugates to the corpus callosum of cuprizone-treated mice.

Funder

RSF

RFBR

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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