Fullerenes Counteracting Organophosphorus Threats

富勒烯对抗有机磷的威胁。用作毒剂的神经毒剂 恐怖包括有机磷化合物(OP)，一种抑制乙酰胆碱酯酶的神经毒性物质 (AChE)活动。当神经递质乙酰胆碱没有被破坏时，就会导致胆碱能中毒。 现代治疗依赖于阻断胆碱能受体，去除AChE中的OP化合物，以及 治疗症状。在使用有效且快速起作用的OP神经毒剂中毒时，这通常是不完整的， 因此，需要采取更多的对策。我们的初步数据显示水溶性羟基化的C60 富勒烯(C60-OH)具有减轻神经细胞AChE抑制的作用。我们的初步数据显示没有 小鼠静脉注射可溶的C80-OH金属富勒烯三偏碳层后的明显毒性。这些数据 提示可溶富勒烯在体内安全解毒OP毒物的潜力。C60/C80-OH富勒烯和 其他可溶的衍生物也有可能有助于对抗氧化应激的抗氧化特性。 与快速和危及生命的AChE耗竭引起的兴奋性毒性相关，其影响可能是 长期的和/或延迟的，如果没有对抗，会导致神经病变。因此，基于我们的 初步数据，假设可溶性C60/C80-OH和其他衍生物可以降低 OP化合物可以抑制AChE，也可以抵消氧化作用。我们预测可溶性C60/C80 衍生品可以安全地作为OP解毒剂使用，无论是单独使用还是与当前 接受治疗(静脉注射阿托品、解磷定、安定)。我们建议检查溶解的能力 C60/C80衍生物与OP神经毒剂替代品(DFP、对氧磷)相互作用。初步筛选将是 通过评估非细胞毒性的可溶性C60/C80衍生物降低OP诱导的能力来进行体外实验 对神经组织和神经细胞的影响，包括抑制AChE。使用性能最好的化合物 从体外研究来看，用小鼠进行的实验将验证体外研究结果，检验 可溶性C60/C80衍生物作为OP诱导的行为、AChE抑制和大脑影响的改良剂 单独给药或与传统疗法结合使用时的神经化学和结构。成功 同时具有AChE保护和抗氧化性能的安全有效的富勒烯的鉴定 为保护和治疗神经毒剂中毒的急性和延迟性影响提供潜力。

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.