Fullerenes Counteracting Organophosphorus Threats

富勒烯对抗有机磷威胁。神经毒剂，用作 恐怖包括有机磷化合物、抑制乙酰胆碱酯酶神经毒性物质 （AChE）活性。当神经递质乙酰胆碱不被破坏时，可导致胆碱能中毒。 现代治疗依赖于阻断胆碱能受体，从AChE中去除OP化合物， 治疗症状。在使用强效和快速作用的OP神经毒剂中毒时，这通常是不完全的， 因此需要额外的对策。我们的初步数据表明，水溶性羟基化C60 富勒烯（C60-OH）具有降低神经细胞中AChE抑制的能力。初步数据显示 小鼠静脉注射可溶性C80-OH金属富勒烯Trimetasphere？后出现明显毒性。这些数据 表明可溶性富勒烯在体内安全地使OP毒物解毒潜力。C60/C80-OH富勒烯和 其它可溶性衍生物也具有抗氧化性能 与快速和危及生命的乙酰胆碱酯酶耗竭引起的兴奋性毒性有关， 持久和/或延迟的，并且当无对抗时，导致神经病。因此，根据我们的 初步数据，假设是可溶性C60/C80-OH和其他衍生物可以降低的能力， OP化合物抑制乙酰胆碱酯酶，也抵消氧化作用。我们预测可溶性C60/C80 衍生物可以作为OP解毒剂安全地施用，无论是单独施用还是与目前的药物组合施用。 接受治疗（IV阿托品、解磷定、地西泮）。我们建议检查可溶性 C60/C80衍生物与OP神经毒剂替代物（DFP，对氧磷）相互作用。初步筛选将是 通过评价非细胞毒性可溶性C60/C80衍生物降低OP诱导的细胞凋亡的能力， 影响，包括乙酰胆碱酯酶抑制，在神经组织和神经元细胞。使用性能最好的化合物 从体外研究中，使用小鼠的实验将验证体外研究结果，检查 可溶性C60/C80衍生物作为OP诱导的行为、AChE抑制和脑效应的改善剂 当单独给予或与传统治疗组合时，神经化学和结构。成功 具有乙酰胆碱酯酶保护和抗氧化特性安全有效富勒烯的鉴定将 提供保护和治疗神经毒剂中毒的急性和延迟效应的潜力。

FULLERENES COUNTERACTING ORGANOPHOSPHORUS THREATS. Nerve agents used as agents of terror 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, and treating 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 C60 fullerenes (C60-OH) have ability to decrease AChE inhibition in neuronal cells. Our preliminary data show no overt toxicity in mice after IV injection of a soluble C80-OH metallofullerene Trimetasphere¿. These data suggest in vivo potential of soluble fullerenes to safely detoxify OP toxicants. C60/C80-OH fullerenes and other soluble derivatives also have antioxidant properties likely to be useful against the oxidative stress associated with excitotoxicity resulting from rapid and life-threatening AChE depletion, effects that can be long-lasting and/or delayed and, when unopposed, contribute to neuropathy. Therefore, based on our preliminary data, the hypothesis is that soluble C60/C80-OH and other derivatives can decrease capability of OP compounds to inhibit AChE and also counteract oxidative effects. We predict that soluble C60/C80 derivatives can be safely administered as OP antidotes, either alone or in combination with currently accepted treatments (IV atropine, pralidoxime, diazepam). We propose to examine the ability of soluble C60/C80 derivatives to interact with OP nerve agent surrogates (DFP, paraoxon). Initial screening will be done in vitro by evaluating non-cytotoxic soluble C60/C80 derivatives for their ability to decrease OP-induced effects, including AChE inhibition, in neural tissue and neuronal cells. Using the best-performing compounds from the in vitro studies, experiments using mice will validate in vitro findings, examining the effectiveness of soluble C60/C80 derivatives as ameliorators of OP-induced effects on behavior, AChE inhibition, and brain neurochemistry and structure when given alone or in combination with traditional treatments. Successful identification of safe and effective fullerenes which have both AChE-protection and antioxidant properties will provide potential to protect and treat acute and delayed effects of nerve agent poisoning.