engleski

Evaluation of primary DNA damage in brain cells of rats administered K048 oxime to relieve symptoms of tabun-poisoning

Aim: Tabun is a highly toxic chemical warfare agent which causes fatal intoxication due to inhibition of acetylcholinesterase (AChE). Recent knowledge confirms the use of pyridinium oximes as causal antidotes for the protection/reactivation of AChE inhibited by organophosphorus compounds. K048 oxime showed an acceptable genotoxic profile both in vitro and in vivo models. Here we studied its potential neuroprotective effects in vivo using the alkaline comet assay in brain cells of rats which were given K048 oxime to relieve symptoms of tabun-poisoning. Methods: Altogether sixty male adult Wistar rats were used in the experiment. They were divided in five groups according to the treatment: (1) tabun-poisoned (75% LD50, s.c.), (2) K048-treated (25% LD50 i.p.), (3) atropine-treated (10 mg kg-1, i.p.) after tabun poisoning (75% LD50, s.c.), (4) concomitant treatment with K048 (25% LD50, i.p.) and atropine (10 mg kg-1, i.p.) after tabun poisoning (75% LD50, s.c.), and (5) negative controls given saline only (2 mL kg-1, i.p.). Rats were sacrificed 1, 6 and 24 h after the treatment, and comet assay on brain cells was performed. Results: We found that tabun itself caused a most notable increase of primary DNA damage in rat brain cells 24 h after its administration. K048 oxime had an acceptable genotoxicity profile at each time- point studied. Minor differences in the genotoxicity observed between three time-points could be explained by the metabolism of the compound. Concomitant administration of K048 with atropine changed its genotoxicity profile in the brain cells, especially 6 h and 24 after treatment, which has to be further studied. Conclusions: Taken together, K048 effectively counteracted the poisoning of rats by tabun, both alone and in combination with atropine. Observed neuroprotective ability speaks in favour of K048 as a promising molecule for therapeutic treatment against intoxication with organophosphorus compounds.

Tabun; neurotoxicity; genotoxicity; oximes; rats

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