Fullerenes Counteracting Organophosphorus Threats

描述(由申请人提供)： 被用作恐怖毒剂的神经毒剂包括有机磷(OP)化合物，即抑制乙酰胆碱酯酶(AChE)活性的神经毒性物质。当神经递质乙酰胆碱没有被破坏时，就会导致胆碱能中毒。当代的治疗依赖于阻断胆碱能受体，去除疼痛中的OP化合物，并治疗症状。在使用强效和快速起作用的OP神经毒剂中毒时，这通常是不完整的，因此需要采取其他对策。我们的初步数据表明，水溶性羟基C60富勒烯(C60-OH)具有减轻神经细胞AChE抑制的能力。我们的初步数据显示，在静脉注射可溶的C80-OH金属富勒烯三聚物后，小鼠没有明显的毒性。这些数据表明，在体内，可溶性富勒烯具有安全解毒OP毒物的潜力。C60/C80-OH富勒烯和其他可溶性衍生物还具有抗氧化特性，可能有助于对抗与快速和危及生命的AChE耗竭引起的兴奋毒性相关的氧化应激，这种作用可能是长期的和/或延迟的，如果不加以对抗，就会导致神经病变。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，也可以抵消氧化作用。我们预测，可溶性C60/C80衍生物可以安全地作为OP解毒剂使用，可以单独使用，也可以与目前接受的治疗(静脉注射阿托品、普拉定、安定)联合使用。我们建议检测可溶性C60/C80衍生物与OP神经毒剂替代品(DFP，对氧磷)的相互作用能力。将通过评估非细胞毒性的可溶性C60/C80衍生物在神经组织和神经细胞中减少OP诱导的效应(包括AChE抑制)的能力来进行体外初步筛选。使用体外研究中表现最好的化合物，用小鼠进行的实验将验证体外结果，测试单独或与传统治疗联合服用时，可溶性C60/C80衍生物作为OP诱导的行为、AChE抑制以及脑神经化学和结构影响的改善效果的有效性。成功地鉴定出安全有效的富勒烯，具有AChE保护和抗氧化性，将为保护和治疗神经毒剂中毒的急性和延迟效应提供潜在的可能性。

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.