PROTECTION AGAINST ORGANOPHOSPHATE NEUROTOXINS BY TOBACCO CEMBRANOIDSThe long term objective of this project is to develop a novel antidote against the organophosphate nervetoxins like soman and sarin. The increased awareness of terrorist threats prompted the development ofstrategies for protection against nerve toxin attacks. The most likely nerve toxins to be used are theorganophosphate (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 thatis fatal if untreated. The classic antidotes now in use protect against a wide spectrum of neural injury anddramatically decrease mortality. They fail, however, to target neuronal apoptosis initiated by the toxic OPallowing for long term neurological impairment. Here we propose to test a novel neuroprotective compoundthe (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R). 4R neuroprotection is mediated by a nicotinicantiapoptotic mechanism found effective in in vitro and in vivo models. 4R is not toxic and has a favorablepharmacological profile with antiapoptotic and antiinflammatory properties. Since the use of war neurotoxinsis impractical in the early stages of antidotes development the neuroprotective efficacy of 4R will be testedagainst two less toxic analogues, paraoxon (POX) and diisopropylfluorophosphate (DFP). The first objectiveproposed here is to test 4R in an in vitro model against POX and DFP. The in vitro neuroprotective activity of4R will be tested alone and in combination with the classical antidotes. The model to be used for the in vitrostudies is the hippocampal slice. The damage inflicted by the toxins will be determined byelectrophysiological and histological methods.
The second aim will address the efficacy of 4R against bothtoxins in vivo using a rat model. 4R in several combinations with classical antidotes will be tested againstvarious doses of POX and DFP. Behavioral, physiological, and histological determinations will be used todetermine the efficacy of 4R. In the third aim the window of therapeutical opportunity for 4R neuroprotectionwill be investigated in various combinations with the classical antidotes. The variables to asses the toxiceffect 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 civilianpopulation would be of great value in human suffering and costs involved. The risk of OPs exposure is notrestricted to war scenario or terrorist attacks but includes industrial leaks of insecticides, accidentalpoisonings and chronic occupational exposure.
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