Challenges in Batch-to-Bed Translation Involving Inflammation-Targeting Compounds in Chronic Epilepsy: The Case of Cathepsin Activity-Based Probes.

Abstract

Our goal was to test the feasibility of a new theranostic strategy in chronic epilepsy by targeting cathepsin function using novel cathepsin activity-based probes (ABPs). We assessed the biodistribution of fluorescent cathepsin ABPs in vivo, in vitro, and ex vivo, in rodents with pilocarpine-induced chronic epilepsy and naïve controls, in human epileptic tissue, and in the myeloid cell lines RAW 264.7 (monocytes) and BV2 (microglia). Distribution and localization of ABPs were studied by fluorescence scanning, immunoblotting, microscopy, and cross-section staining in anesthetized animals, in their harvested organs, in brain tissue slices, and in vitro. Blood-brain-barrier (BBB) efflux transport was evaluated in transporter-overexpressing MDCK cells and using an ATPase activation assay. Although the in vivo biodistribution of ABPs to both naïve and epileptic hippocampi was negligible, ex vivo ABPs bound cathepsins preferentially within epileptogenic brain tissue and colocalized with neuronal but not myeloid cell markers. Thus, our cathepsin ABPs are less likely to be of major clinical value in the diagnosis of chronic epilepsy, but they may prove to be of value in intraoperative settings and in CNS conditions with leakier BBB or higher cathepsin activity, such as status epilepticus.

• Authors: Roa'a Hamed, Emmanuelle Merquiol, Ivan Zlotver, Galia Blum, Sara Eyal, Dana Ekstein
• Journal: ACS omega (ACS Omega) Vol. 9 Issue 6 Pg. 6965-6975 (Feb 13 2024) ISSN: 2470-1343 [Electronic] United States
• PMID: 38371846 (Publication Type: Journal Article)
• Copyright: © 2024 The Authors. Published by American Chemical Society.