Paraoxon-Induced BBB Dysfunction: A Triple Arm Mechanism Investigation
Abstract
Organophosphorus compounds (OPs) are highly toxic chemicals widely used as pesticides (e.g. paraoxon) and as chemical warfare nerve agents. Blood-brain barrier (BBB) leakage has been shown in rodents exposed to paraoxon, which is an organophosphate oxon. In this proposal, we investigate the cellular mechanisms involved in BBB reaction after exposure to paraoxon. We focus our investigation in three directions: 1) Barrier disruption at the paracellular (between cells) route i.e. alterations in tight junction proteins expression and patterns- thus enabling paracellular permeation of paraoxon and other native blood circulating compounds which might disrupt brain chemical homeostasis. 2) Barrier disruption at the intracellular (through cells) route i.e. changes in the efflux pump P-glycoprotein activity after exposure to paraoxon, which can alter brain homeostasis by changing the brain concentrations of its multitude substrates and 3) Paraoxon-induced inflammation-like phenotype at the BBB surroundings which will suggest an indirect mechanism that can lead to both para and intracellular disruption pathways. We anticipate that these three ways are interrelated, thus blocking one of them might attenuate the others. Therefore, in the second part of this proposal we intend to investigate the possibility of reversing the paraoxon-induced effects targeting tight junctions and P-glycoprotein trafficking mechanisms. An established in-vitro BBB system made of porcine brain endothelial cells together with astrocytes that closely mimic the in-vivo BBB is being used as the key methodological platform. In order to initiate translation to human we also started using a human BBB model to validate the conclusions obtained.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 26, 2016
- Source ID
- HDTRA11510055
Entities
People
- Itzik Cooper
Organizations
- Defense Threat Reduction Agency