NEUROTARGET

NEUROTARGET
Diagnostic and therapeutic strategies targeting the neurovascular-unit after organophosphate nerve agent exposure

ANR AAPG 2022 – Sécurité globale, résilience et gestion de crise, cybersécurité.
Project coordinator:
Pr. Cyrille Orset, INSERM U1237, Blood and Brain Caen Normandie Institute, Caen, France.

Project Partner:
Dr. Gregory Dal Bo, Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, 91220 Bretigny sur Orge, France

Acute OP poisoning causes both peripheral and central cholinergic effects that collectively define the clinical toxidrome known as cholinergic crisis. This toxidrome is characterized by peripheral symptoms, muscle fasciculation followed by flaccid paralysis, centrally-mediated seizures that can quickly progress to status epilepticus, and death by respiratory failure. Cholinergic crisis is frequently fatal unless rapidly treated with atropine to block muscarinic receptors, oxime to reactivate ChE, and benzodiazepines to reduce seizure activity 8,9. Even with treatment, preclinical studies shown that cholinergic crisis often face significant long-term morbidity, including cognitive dysfunction, affective disorders, and spontaneous recurrent seizures (also known as acquired epilepsy) that typically manifest even after ChE activity has recovered to pre-exposure levels.
Clinical and preclinical data suggest that profound ChE inhibition initiates the acute neurotoxic effects of OP. Clinical, epidemiologic, and experimental evidence suggest that other mechanisms than ChE inhibition mediate long-term OP neurotoxicity. In addition, low-level OP exposures, that do not elicit symptoms of cholinergic crisis, are also associated with neurotoxic outcomes in animal model and in Humans, including cognitive deficits and neuropsychiatric conditions such as depression, anxiety, and suicidal tendencies. Interestingly, neuroinflammatory processes induced by OP exposure, are likely to represent the main mechanism that mediate OP long-term neurotoxicity. However, all the OP-induced neuroinflammation studies are focusing on glial and neuronal components, while no attention is given to neurovascular impacts. Indeed, the neurovascular unit (NVU) is deeply affected by NA exposure, oedema occurrence in different brain areas were visualized by IRM early after intoxication, that persists several days. In fact, BBB integrity is clearly affected by ChE inhibitors, but also neurovascular compensatory processes are observed with the angiogenesis establishment in OP exposed victims. Considering that modification of BBB integrity leads to endothelial cell inflammatory responses by secreting pro-inflammatory cytokines (VCAM, ICAM, P-selectine….), evaluation of the NVU implication in neuroinflammation and subsequent brain sequelae becomes a mandatory.
NeuroTarget is an innovative project which aimed to uncover NVU alterations induced by OP exposure using a new method of MRI molecular imaging. Based on this method, it would be possible to diagnose OP exposition even at low dose and to evaluate new therapeutic strategy targeting the neurovascular unit.