Bicyclic phosphorus esters increase the cyclic GMP level in rat cerebellum

Abstract

4-ALKYLDERIVATIVES of 1-phospha-2,6,7-trioxabicyclo[2.2.2] octane-1-oxide (PTBO derivatives) are highly toxic organophosphates. On intraperitoneal injection to mammals they produce tonic–clonic convulsions and death within a few minutes^1,2. Their mechanism of action is unknown, but it is different from that of other toxic phosphorus esters which act as inhibitors of cholinesterase¹. The symptoms of poisoning by PTBO derivatives indicate an activation of the central nervous system². There is evidence suggesting that the cyclic nucleotides AMP and GMP act as second messengers in central and peripheral synapses and so we have investigated the effects of PTBO compounds on the level of these nucleotides in the brain. The ethyl (EPTBO) and isopropyl (IPTBO) compounds, two of the most toxic PTBO derivatives, were used. The results show that following intraperitoneal injection of these compounds into rats, the cyclic GMP concentration is increased in cerebellum by both convulsive and subconvulsive doses, whereas the levels of the nucleotide are unchanged in cerebral cortex and subcortical tissues. The increase in cyclic GMP level in the cerebellum is thus not due to the convulsive state.