A cembranoid protects acute hippocampal slices against paraoxon neurotoxicity

Many neurotoxic organophosphates (OPs) inhibit acetylcholinesterase (AChE) and as a result can cause a life threatening cholinergic crisis. Current medical countermeasures, which typically include atropine and oximes target the cholinergic crisis and are effective in decreasing mortality but do not sufficiently protect against delayed neurological deficits. There is, therefore, a need to develop neuroprotective drugs to prevent long-term neurological deficits. We used acute hippocampal slices to test the hypothesis that 4R,6R-cembratrienediol (4R) protects against functional damage caused by the OP paraoxon (POX). To assess hippocampal function, we measured synaptically evoked population spikes (PSs). Application of 4R reversed POX inhibition of PSs and the EC₅₀ of this effect was 0.8 μM. Atropine alone did not protect against POX neurotoxicity, but it did enhance protection by 4R. Pralidoxime partially regenerated AChE activity and protected against POX inhibition of PSs. 4R did not regenerate AChE suggesting that under our experimental conditions, the deleterious effect of POX on hippocampal function is not directly related to AChE inhibition. In conclusion, 4R is a promising neuroprotective compound against OP neurotoxins.