New generic approach to the treatment of organophosphate poisoning: Adenosine receptor mediated inhibition of ACh-release

Current treatment of acute organophosphate (OP) poisoning includes a combin ed administration of a cholinesterase reactivator (oxime), a muscarinic rec eptor antagonist (atropine) and an anticonvulsant (diazepam). This treatmen t is not adequate since it does not prevent neuronal brain damage and incap acitation. Here, as in a recent review(1) it is stated that other therapeut ic approaches may improve protection. Former studies on the "direct effects" of oximes led to the conclusion that drug-induced inhibition of acetylcholine (ACh)-release shortly (1 min) aft er the acute OF-intoxication, could prevent and counteract convulsions and improve survival(1). In general, the accumulation of ACh in the synaptic cl eft is considered to be responsible for the symptoms that ultimately lead t o death. Therefore, prevention or suppression of this excessive accumulatio n of ACh could be a generic approach to antagonize OF-poisoning. Preliminar y evidence for this concept has been put forward(1,2). Evaluation of drugs that would be able to prevent and counteract ACh accumu lation, led to the conclusion that adenosine receptor agonists could be pro mising candidates. Pilot experiments demonstrated that intramuscular administration of the ade nosine receptor agonists NECA (5'-N-ethylcarboxamido-adenosine) or CPA (N-6 -cyclopentyl adenosine) 1 min following a subcutaneous soman poisoning (1.5 - 2LD50) in rats, resulted in (1) prevention or postponement of chewing, s alivation, convulsive activity, and respiratory distress (cholinergic sympt oms), (2) improvement of survival rate (24 h), (3) a low level of extracell ular brain ACh, as opposed to high levels of extracellular brain ACh in unt reated animals. It is concluded that (1) adenosine agonists protect acutely soman-poisoned rats without the need of additional treatment with atropine, oxime or diaze pam, (2) prevention of ACh accumulation in this way may be a new generic ap proach in the treatment of OP-poisoning.