Organophosphate (OP) nerve agent (NA) like VX are irreversible acetylcholinesterase (AChE) inhibitors. Acute NA exposure leads to a cholinergic syndrome, due to acetylcholine accumulation in synapses, manifested by fasciculation, tremors, muscle paralysis and a respiratory distress leading to death. Antidote treatment includes a muscarinic cholinergic receptor antagonist (atropine) and an oxime able to reactivate OP-inhibited AChE. In central nervous system, oximes action is limited due to their weak ability to cross the blood brain barrier (BBB). The goal of this study was to test therapeutic potential of a new oxime (RM048) designed to cross the BBB, alone or in association with HI-6, unable to cross the BBB.Nine-week-old male Swiss mice exposed to VX (at sublethal or lethal doses), received an antidote therapy containing atropine with either HI-6, RM048 or both (Mix). Short-term effects of RM048 or the Mix treatments showed their capacity to reactivate central AChE, but not HI-6 alone. Using EEG recording, we showed that RM048 alone and Mix treatments prevent epileptic seizure occurrence and recurrence. Subsequently, we demonstrated the beneficial effects of Mix treatment on mice behaviours at long term, and its ability to attenuate neuroinflammation. Our results showed that RM048 when combined to Hi-6 confers a better neuroprotection after VX-exposure. Finally, the action of RM048 was evaluated with patch-clamp on mice brain slices, deciphering its neuronal activity modulation.HI-6/RM048 association improved mice recovery after VX exposure at short and long term by improving central and peripheral protection.