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Author
Goyenechea Cunillera, Júlia
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Abstract
In addition to the neurotoxic chemical warfare, there is a growing concern about the possible use of neurotoxic industrial chemicals (neuroTICs) as “agents of opportunity” by chemical terrorists. NeuroTICs represent a significant military and terrorist threat for NATO countries, since both troops and civilian population can be exposed to high doses of these compounds when used in improvised explosive devices or through contaminated food and water. Despite the risk, no effective medical countermeasures to fight against the effects of NeuroTICs are currently available.
The main goal of this research was to determine the therapeutic value of the new blood-brain barrier (BBB) permeable drugs AD4 and the thioredoxin-mimetic peptides (TXM-peptides) CB3, CB12, CB13 and CB30 in the treatment of severe acute organophosphorus poisoning (OPP) and acute acrylamide (ACR) neurotoxicity. Models of the neurotoxidromes induced by organophosphorus compounds and acrylamide, two relevant neuroTICs, have been recently developed in zebrafish larvae. In order to use these models for assessing the therapeutic value of these BBB permeable drugs, stability studies of these drugs in fish water were carried out, and the potential interactions antidote:toxicant were tested. Ultrahigh-pressure liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer (UHPLC Q-TOF MS) was used, with an Acquity BEH C18 column (2.1 x 100 mm, particle size 1.7 μm) and an Acquity BEH C18 pre-column (2.1 x 5 mm, particle size 1.7 μm). The experimental conditions simulated those of further zebrafish larvae exposures, 28.5 oC and a 12:12 light:dark photoperiod. Once the stability studies were performed, the suitability of an already developed and validated model of severe acute organophosphorus poisoning (OPP) with the contaminant chlorpyrifos-oxon (CPO) in zebrafish larvae was tested for the screening of these antidotes protecting against neurotoxicity, and then readjusted for the use of EtOH instead of DMSO.
For waterborne exposures, 7 dpf zebrafish larvae were used and some selected drugs known to provide protection in other models were tried, such as pralidoxime (2-PAM), the reversible acetylcholine inhibitor pyridostigmine and the NMDA receptor antagonist memantine. While testing these drugs, the therapeutic value of one of the new blood-brain barrier permeable drugs, AD4, was finally tried out.
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