Blood-brain barrier crossing of conventional and new antidotes to treat organophosphate poisoning. – BHE-OP-Antidotes

Organophosphates (OPs) constitute a class of synthetic molecules still widely used as an insecticide but also as chemical weapons. This class has been the subject of numerous investigations by the chemical industry in search of pesticides that are more effective and potentially less harmful to the environment. In addition, the military authorities are interested in these molecules to counteract their effects. Indeed, a number of OPs pose serious environmental toxicity problems as well as the civilian or military populations targeted by attacks perpetrated with such compounds. Globally, there are around 250,000 fatal cases of OP poisoning per year.
OPs interfere with the esterase activity essential for the degradation of certain active molecules in organisms. The most studied is acetylcholinesterase (AChE) which hydrolyzes acetylcholine. This neurotransmitter is essential in the cholinergic transmission of nerve impulses in the central (CNS) and peripheral (PNS) nervous systems, the failure of which leads to a major cholinergic syndrome which combines peripheral manifestations and epileptic seizures. In the event of accidental poisoning by an OP or during terrorist attacks, conventional emergency medical treatment consists of the injection of antidotes composed of pyridinium oxime for the reactivation of AChE and substances countering the effects of excess acetylcholine. However, pyridinium oxime remains ineffective in reactivating CNS AChE due to its poor passage through the blood brain barrier (BBB).
The BHE-OP-Antidotes project aims to discover transient opening treatments for BBB or vector drug delivery systems to be used to facilitate the passage of BBB through the AChE reactivating molecules of the CNS. The project uses two complementary and validated in vivo models for this type of work, the zebrafish larva and the mouse. These two models are predictive for applications in humans given the very high evolutionary conservation of the biological processes studied. The zebrafish opens up the possibility of carrying out many combinations of experiments that will make it possible to amend the mouse model and whose results will be validated with the mammalian model. These models will be used to test the conditions for opening the BBB according to a genetic or pharmacological approach in association with a decrease in neurotoxicity induced by conventional pyridinium oximes following intoxication by OPs. The ability of vectorized biomimetic nanoparticles (NPs) loaded with conventional pyridinium oximes or new antidotes to prevent and treat the effects on the CNS of poisoning by OPs will be evaluated. For the two animal models used, the combination of biochemical, molecular and cellular studies, functional imaging, electroencephalographic studies and locomotor tests will be implemented to assess the restoration of the functional integrity of the CNS.
The project mobilizes is carried out in collaboration between four teams which have internationally recognized expertise in chemistry, biochemistry, molecular biology, neurosciences, toxicology, pharmacology and the use of zebrafish and mouse animal models including the effects of OPs on the CNS and PNS, study of AChE reactivators, and study of BBB permeability: Pr. P. Babin, project coordinat or (Partner n ° 1, University of Bordeaux, INSERM U1211) (zebrafish model, OPs and antidotes, cholinergic and neuropathic effects), Dr. N. Soussi-Yanicostas (Partner n ° 2, NeuroDiderot INSERM U1141, Hôpital Robert Debré) (OPs and models of epilepsy in zebrafish), Dr. A.-G . Calas (Partner n ° 3, Toxicology & Chemical Risks Department, IRBA, Brétigny) (mouse model, OPs and antidotes, effects on the CNS and SNP) and Dr. C. Chapouly (Partner n ° 4, INSERM U1034, University de Bordeaux) (mouse model, in vitro and in vivo studies of BBB and its permeability).