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O1‐11‐04: Targeting leukocyte integrins has therapeutic effect in Alzheimer's‐like disease
Author(s) -
Constantin Gabriela,
Pietronigro Enrica Caterina,
Zenaro Elena,
Piacentino Gennj,
Della Bianca Vittorina,
Rossi Maria Giovanna,
Laudanna Carlo
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.07.090
Subject(s) - extravasation , parenchyma , pathology , monoclonal antibody , integrin , inflammation , leukocyte extravasation , blood–brain barrier , immunology , amyloid (mycology) , microglia , lymphocyte , medicine , antibody , biology , neuroscience , central nervous system , receptor
demonstrated that the classic TSPO ligands, Ro5-4864 and PK11195, increase brain steroid levels, reduce Ab accumulation, and improve cognition in a mouse model of AD. Here we evaluated the steroidogenic efficacy and acute behavioral effects of three TSPO imidazopyridine ligands, CLINDE, PBR175, and PBR162, which we have previously shown to be non-toxic in vitro. CLINDE, which exhibited the most favorable behavioral and pharmacokinetic profile, was investigated further for its specificity and binding affinity in human brain. Methods: The acute behavioural effects of the three novel TSPO ligands were compared with Ro5-4864, in 3 month old castrated C57BL/6J mice. Two hours after ligand injection (3 mg/kg i.p.), anxiety-, depression-, and memory-related behaviors were assessed in the elevated-plus maze, open field maze, tail-suspension test, and object recognition tests respectively. Brain steroids levels were measured by LC-MS/MS. To determine if the behavioral effects of TSPO ligands were mediated via increased neurosteroidogenesis, mice were pretreated with a steroidogenesis inhibitor, aminogluthetimide (10mg/ kg). The pharmacokinetic properties of the novel ligands were assessed by competitive PET imaging [11C]PK-11195. The specificity of action of CLINDE was determined in TSPO knockout mice, and the affinity for TSPO (Ki value) in human brain homogenate was investigated in vitro by [11C] PK-11195 binding assay. Results: CLINDE and PBR175 improved learning and memory performance equally well as Ro5-4864. These improvements were completely ablated by aminogluthetimide, confirming that the beneficial effects were mediated through an increase in neurosteroidogenesis. Anxietyand depression-related behaviors were unaffected by the TSPO ligands. Competitive PET studies indicated that CLINDE showed the most long lasting binding to TSPO. The specificity of behavioral effects of CLINDE was confirmed. The affinity of CLINDE in high-affinity binder (HAB) and low-affinity binder (LAB) subjects were 5.5 and 29.7 respectively. Conclusions:These findings indicate that CLINDE and PBR175 rapidly promote neurosteroidogenesis, thereby enhancing learning and memory in vivo. These second generation TSPO ligands are promising therapeutic candidates with improved pharmacokinetic properties compared to classic TSPO ligands.