Project overviews

Background

Chemical threats have been defined as highly toxic chemicals that could be intentionally used in a terrorist attack or that could be released from transportation and storage facilities after an accident or natural disaster, resulting in mass casualties. Thus, chemical threats include not only traditional Chemical Warfare Agents (CWA) but also some highly toxic industrial compounds (TICs). In fact, in recent years there has been growing concern that many of the most likely threats of chemical terrorism involve TICs, also called “agents of opportunity”, as they are readily available for the perpetrator. Both central and peripheral nervous system are likely targets for chemical terrorism, as neurotoxic syndromes may fully impair their functionality, rendering the individual unable to ‘fight or flight’. Organophosphorus compounds (OPs), acrylamide (ACR) and methyl-mercury (MeHg) are three common TICs with a selective toxic effect at the nervous system level, and no fully effective countermeasures are currently available against their neurotoxic effect. N-acetylcysteine-amide (NAC-amide or AD4) and thioredoxin-mimetic (TXM) peptides are blood-brain barrier (BBB) permeable drugs specifically developed for reducing inflammation, oxidative stress and apoptosis in the central nervous system (CNS). Whereas these drugs have already been successfully used for treating different neurological conditions, there is no information about the therapeutic potential of these drugs for the treatment of acute neurotoxic syndromes.

Objectives

The main objective of this project is to determine the therapeutic value of AD4 and five TXM-peptides in the treatment of the severe acute organophosphorus poisoning (OPP), acute ACR neurotoxicity and acute MeHg poisoning. To achieve this goal, four research objectives will be implemented:

1. To determine the protective effects of the BBB-permeable drugs AD4 and TXM-peptides in an in vitro cell model of ACR neurotoxicity.
2. To determine the therapeutic value of AD4 and TXM-peptides in the treatment of the severe acute OPP, acute ACR neurotoxicity and acute MeHg poisoning by using adult zebrafish models.
3. To determine in adult zebrafish the therapeutic value of different combinations of drugs specifically directed against potential therapeutic targets identified for each neurotoxic syndrome.
4. To evaluate in rodents the therapeutic value of the most promising positive hits identified in objectives (2) and (3).

Specific workplan

Expected Outcomes

1. The development and validation of an in vitro cell model of ACR acute neurotoxicity
2. The evaluation of the protective effects of the BBB-permeable drugs AD4 and TXM-peptides in the developed in vitro cell model of ACR neurotoxicity
3. The development of new models for acute OPP and MeHg poisoning developed in adult zebrafish
4. The evaluation of the therapeutic value of AD4 and TXM-peptides in the treatment of the severe acute OPP, acute ACR neurotoxicity and acute MeHg poisoning by using adult zebrafish models
5. The evaluation in adult zebrafish of the therapeutic value of different combinations of drugs, specifically directed against potential therapeutic targets identified for each neurotoxic syndrome
6. The evaluation in rodents of the therapeutic value of the most promising positive hits identified in objectives (4) and (5).