MODIFICATION OF ORGANOPHOSPHORUS NEUROPATHY

长期目标是提供一种手段， 暴露于某些有机磷酸盐的人和动物的神经病。 作为 有机磷化合物目前广泛用于农业， 工业，意外和职业风险相对较高 exposure. 虽然有急性毒性的解毒剂，但没有 对于不可逆的神经病变已经开发出了特定的治疗方法， 在暴露于这些化合物中的一些后数周至数月发生。 正如我们实验室和其他实验室最近所证实的那样， 激素似乎很有希望作为提供一些适度的药物， 有机磷化合物的迟发性神经毒性作用。 使用 三邻甲苯基磷酸（TOTP）诱导鸡迟发性神经病， 将检查天然皮质激素的广泛饮食浓度， 皮质酮，用于对这种迟发性神经病的指数的影响，例如 临床体征、组织病理学、电生理学和神经毒性酯酶 活动 我们将观察皮质酮本身对 通过监测嗜异性细胞/淋巴细胞比率、肝脏 功能和饲料效率。 此外，作为拟议工作的一部分， 皮质激素的性质可能与调节 将检查有机磷诱导的迟发性神经病。 这些将 包括皮质激素类型，通过使用盐皮质激素 （脱氧皮质酮）、糖皮质激素（曲安西龙），和 皮质酮，具有这两种性质，以修改TOTP诱导的延迟 神经病变 皮质激素可能改变 有机磷，从而提供保护，将审查 比较由原氧化剂（TOTP）诱导的迟发性神经病与 诱导其活性代谢产物（磷酸苯基水杨苷）在 皮质酮的存在。 内源性类固醇可能是 替代外源性类固醇，如有机磷酸酯抑制 类固醇生成，将通过尝试使用ACTH而不是 皮质酮，以保护鸟类免受TOTP诱导的迟发性神经病变。 这些研究应加强我们对基本发病机制的理解 有机磷诱导的迟发性神经毒性机制，以及， 希望能带来理性治疗

The long term objective is to provide a means for reducing delayed neuropathy in man and animals exposed to certain organophosphates. As organophosphorus compounds are widely used today in agriculture and industry, risk is relatively high for accidental and occupational exposure. Although antidotes for acute toxicities are available, no specific treatment has been developed for the irreversible neuropathy that occurs weeks to months after exposure to some of these compounds. As recently demonstrated in our laboratory and others, adrenocorticoid hormones appear promising as agents to provide some moderation of the delayed neurotoxic effects of organophosphorus compounds. Using triorthotolyl phosphate (TOTP) to induce delayed neuropathy in chickens, we will examine a wide range of dietary concentrations of a natural corticoid, corticosterone, for effects on indices of this delayed neuropathy, such as clinical signs, histopathology, electrophysiology and neurotoxic esterase activity. We will observe effects of the corticosterone per se on the health of the birds by monitoring the heterophil/lymphocyte ratio, liver function, and feed efficiency. Also, as part of the work proposed, some properties of corticoids that may be relevant in moderation of organophosphate induced delayed neuropathy will be examined. These will include type of corticoid, by using a mineralocorticoid (deoxycorticosterone), a glucocorticoid (triamcinolone), and corticosterone, which has both properties, to modify TOTP-induced delayed neuropathy. The possibility that corticoids may alter metabolism of organophosphates, thereby providing protection, will be examined by comparing delayed neuropathy induced by a protoxicant (TOTP) with that induced by its active metabolite (phenyl saligenin phosphate) in the presence of corticosterone. The possibility that endogenous steroid may be substituting for exogenous steroid, as organophosphates inhibit steroidgenesis, will be examined by attempting to use ACTH rather than corticosterone to protect the birds from TOTP-induced delayed neuropathy. These studies should enhance our understanding of the basic pathogenetic mechanisms in organophosphate-induced delayed neurotoxicity, and, hopefully, lead to rational therapy.