FULLERENES COUNTERACTING ORGANOPHOSPHORUS THREATS. Nerve agents used as agents ofterror include organophosphorus (OP) compounds, neurotoxic substances that inhibit acetylcholinesterase(AChE) activity. When the neurotransmitter acetylcholine is not destroyed cholinergic poisoning can result.Contemporary treatment relies on blocking cholinergic receptors, removing OP compounds from AChE, andtreating symptoms. This is often incomplete in poisoning with the potent and rapidly acting OP nerve agents,so additional countermeasures are desired. Our preliminary data show water soluble hydroxylated C60fullerenes (C60-OH) have ability to decrease AChE inhibition in neuronal cells. Our preliminary data show noovert toxicity in mice after IV injection of a soluble C80-OH metallofullerene Trimetasphere . These datasuggest in vivo potential of soluble fullerenes to safely detoxify OP toxicants. C60/C80-OH fullerenes andother soluble derivatives also have antioxidant properties likely to be useful against the oxidative stressassociated with excitotoxicity resulting from rapid and life-threatening AChE depletion, effects that can belong-lasting and/or delayed and, when unopposed, contribute to neuropathy. Therefore, based on ourpreliminary data, the hypothesis is that soluble C60/C80-OH and other derivatives can decrease capability ofOP compounds to inhibit AChE and also counteract oxidative effects. We predict that soluble C60/C80derivatives can be safely administered as OP antidotes, either alone or in combination with currentlyaccepted treatments (IV atropine, pralidoxime, diazepam). We propose to examine the ability of solubleC60/C80 derivatives to interact with OP nerve agent surrogates (DFP, paraoxon). Initial screening will bedone in vitro by evaluating non-cytotoxic soluble C60/C80 derivatives for their ability to decrease OP-inducedeffects, including AChE inhibition, in neural tissue and neuronal cells. Using the best-performing compoundsfrom the in vitro studies, experiments using mice will validate in vitro findings, examining the effectiveness ofsoluble C60/C80 derivatives as ameliorators of OP-induced effects on behavior, AChE inhibition, and brainneurochemistry and structure when given alone or in combination with traditional treatments. Successfulidentification of safe and effective fullerenes which have both AChE-protection and antioxidant properties willprovide potential to protect and treat acute and delayed effects of nerve agent poisoning.
| Ehrich, Marion; Van Tassell, Roger; Li, Yunbo et al. (2011) Fullerene antioxidants decrease organophosphate-induced acetylcholinesterase inhibition in vitro. Toxicol In Vitro 25:301-7 |
