CE39 - Sécurité globale, résilience et gestion de crise, cybersécurité

Diagnostic and therapeutic strategies targeting the Neurovascular-unit after Organophosphate exposure – NeuroTarget

Submission summary

Organophosphorus (OP) compounds are highly toxic chemicals widely used as pesticides, but also as chemical warfare agents (sarin, VX). The incidence of passive, active or accidental poisoning with OP pesticides is associated with nearly 100,000 annual deaths worldwide for nearly 2 million reported cases of intoxication. More alarming, the resurgent of neurotoxic weapons containing OP use during Syrian conflict, assassinations, and the emergence of new compounds (Novichok, used for Alexei Navalany and Sergei Skripal targeted attack) highlight the present threat. Pathophysiologically, exposure to OP leads to the irreversible inhibition of cholinesterases, increasing the concentration of acetylcholine throughout the body and at the central nervous system (CNS) level. In the CNS, if the cholinergic hyperactivity is not quickly stopped, it will lead to seizure and epileptic activity inducing brain damages, neuronal degeneration, blood-brain barrier (BBB) dysfunction, cerebral oedema and significant brain inflammation. Emergency treatment includes muscarinic receptor blockade, cholinesterases reactivation, and stabilization of epileptic seizures, but the action of this therapy is limited in the CNS. In addition, knowledge of the effects of OPs on the neurovascular system remains sparse. Based on the synergy between a laboratory specialized in the field of neurovascular diseases (INSERM U1237) and the department of Toxicology and Chemical Risks of French Armed Forces Biomedical Research Institute, the proposed project aim to study the neurovascular system following exposure to OP in order to 1/ identify molecular and cellular targets for the development of new tools to detect cerebral damages and 2 / test and validate a new therapeutic strategy on neurovascular dysfunctions induced by OP exposure.

Project coordination

Cyrille Orset (Physiopathologie et imagerie des maladies neurologiques)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IRBA Ministère de la défense
PHIND Physiopathologie et imagerie des maladies neurologiques

Help of the ANR 427,140 euros
Beginning and duration of the scientific project: September 2022 - 42 Months

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