I2-imidazoline ligand CR4056 improves memory, increases ApoE expression and reduces BBB leakage in 5XFAD mice
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not consequence of reductions in Amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6 months old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.
Date Acceptance
2022-06-28
Citation
International Journal of Molecular Sciences, 23 (13)
ISSN
1422-0067
Publisher
MDPI AG
Journal / Book Title
International Journal of Molecular Sciences
Volume
23
Issue
13
Copyright Statement
© 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
License URL
Sponsor
Rottapharm Biotech Srl
Identifier
https://www.mdpi.com/1422-0067/23/13/7320
Grant Number
MISE prog.486
Subjects
Science & Technology
Life Sciences & Biomedicine
Physical Sciences
Biochemistry & Molecular Biology
Chemistry, Multidisciplinary
Chemistry
imidazoline
astrocyte
Alzheimer's disease
amyloid-beta
blood-brain barrier
aquaporin-4
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
NONADRENERGIC IMIDAZOLINE SITES
ALZHEIMERS-DISEASE
TRANSGENIC MICE
BINDING-SITES
AMYLOID-BETA
BRAIN
RECEPTORS
PROTEIN
TRIAL
Alzheimer’s disease
amyloid-β
aquaporin-4
astrocyte
blood–brain barrier
imidazoline
Alzheimer Disease
Amyloid beta-Peptides
Animals
Apolipoproteins E
Disease Models, Animal
Imidazoles
Imidazolines
Ligands
Mice
Mice, Transgenic
Quinazolines
Blood-Brain Barrier
Animals
Mice, Transgenic
Mice
Alzheimer Disease
Disease Models, Animal
Imidazoles
Imidazolines
Quinazolines
Apolipoproteins E
Ligands
Amyloid beta-Peptides
Chemical Physics
0399 Other Chemical Sciences
0604 Genetics
0699 Other Biological Sciences
Publication Status
Published