Cationic pyridinium oximes are used as reactivators of inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the treatment of poisoning with organophosphorus (OP) nerve agents and pesticides. However, they are ineffective in reactivating synaptic AChE in the brain due to the difficulty of cation passage through the blood-brain barrier, which can induce neuroinflammation and permanently damage brain functions. The goal of this research was determining the neuroprotective potential of three newly synthesized oxime groups with regard to improved physicochemical characteristics compared to pyridinium oximes. Out of the eight cationic imidazolium oximes, 1,3-dibenzyl-2-((hydroxyimino)methyl)imidazolium bromide proved to be an effective ex vivo reactivator of phosphorylated BChE and as a pseudocatalytic pair it restored 60 % of the enzyme activity with a 10-fold excess cyclosarin, which makes it an excellent candidate for the degradation of OP compounds in the circulation before they reach the target tissues. Three zwitterionic acetamide bis-oximes showed a better protective index and less acute toxicity than standard oximes in a mouse model. Therapy with one of the bis- oximes restored about 70 % of the inhibited AChE in the brain and significantly reduced the expression of neuroinflammatory markers of astrogliosis and microgliosis. The analyzed bis- oximes have the capacity to prevent the activation of neuroinflammation and show promising physicochemical properties for the improvement of therapy in case of OP poisoning.