The long term objective of this project is to develop a novel antidote against the organophosphate nerve toxins like soman and sarin. The increased awareness of terrorist threats prompted the development of strategies for protection against nerve toxin attacks. The most likely nerve toxins to be used are the organophosphate (OP) neurotoxins that have been used before against military and civilian populations. OPs inhibit the acetylcholinesterase (AChE) in brain and peripheral nerves, causing a cholinergic crisis that is fatal if untreated. The classic antidotes now in use protect against a wide spectrum of neural injury and dramatically decrease mortality. They fail, however, to target neuronal apoptosis initiated by the toxic OP allowing for long term neurological impairment. Here we propose to test a novel neuroprotective compound the (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R). 4R neuroprotection is mediated by a nicotinic antiapoptotic mechanism found effective in in vitro and in vivo models. 4R is not toxic and has a favorable pharmacological profile with antiapoptotic and antiinflammatory properties. Since the use of war neurotoxins is impractical in the early stages of antidotes development the neuroprotective efficacy of 4R will be tested against two less toxic analogues, paraoxon (POX) and diisopropylfluorophosphate (DFP). The first objective proposed here is to test 4R in an in vitro model against POX and DFP. The in vitro neuroprotective activity of 4R will be tested alone and in combination with the classical antidotes. The model to be used for the in vitro studies is the hippocampal slice. The damage inflicted by the toxins will be determined by electrophysiological and histological methods.
The second aim will address the efficacy of 4R against both toxins in vivo using a rat model. 4R in several combinations with classical antidotes will be tested against various doses of POX and DFP. Behavioral, physiological, and histological determinations will be used to determine the efficacy of 4R. In the third aim the window of therapeutical opportunity for 4R neuroprotection will be investigated in various combinations with the classical antidotes. The variables to asses the toxic effect of the organophosphates and of 4R neuroprotection will be as in aim 2. From the public health perspective any improvement in the treatment of OPs poisoning of military or civilian population would be of great value in human suffering and costs involved. The risk of OPs exposure is not restricted to war scenario or terrorist attacks but includes industrial leaks of insecticides, accidental poisonings and chronic occupational exposure.
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