Fullerenes Counteracting Organophosphorus Threats

描述（由申请人提供）： 用作恐怖剂的神经毒剂包括有机磷化合物、抑制乙酰胆碱酯酶活性的神经毒性物质。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，并治疗症状。这通常是不完全的中毒与强大的和快速作用的OP神经毒剂，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）有能力降低神经细胞中的乙酰胆碱酯酶抑制。我们的初步数据显示，在IV注射可溶性C80-OH金属富勒烯Trimetasphere后，小鼠没有明显的毒性。这些数据表明，在体内的潜力，可溶性富勒烯安全解毒OP毒物。C60/C80-OH富勒烯和其他可溶性衍生物还具有抗氧化性质，可能可用于对抗与由快速和危及生命的AChE消耗引起的兴奋性毒性相关的氧化应激，这种作用可以是持久的和/或延迟的，并且当未被对抗时，有助于神经病。因此，根据我们的初步数据，假设可溶性C60/C80-OH和其他衍生物可以降低OP化合物抑制AChE的能力，并抵消氧化作用。我们预测，可溶性C60/C80衍生物可以安全地作为OP解毒剂，单独或与目前接受的治疗（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）相互作用的能力。通过评价非细胞毒性可溶性C60/C80衍生物降低OP诱导效应（包括神经组织和神经元细胞中的AChE抑制）的能力，在体外进行初步筛选。使用体外研究中表现最好的化合物，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抑制作用的改善剂的有效性，以及单独或与传统治疗组合时的脑神经化学和结构。安全有效的富勒烯，具有乙酰胆碱酯酶保护和抗氧化性能的成功鉴定将提供潜在的保护和治疗神经毒剂中毒的急性和延迟效应。

DESCRIPTION (provided by applicant): 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.