NEURONAL PERIKARYAL RESPONSES TO NEUROTOXIC CHEMICALS

区分有毒物质的次要后果的能力 化学物质暴露于直接的毒害作用是一个重要的 毒物学上的问题。此外，在神经元中，它可以延伸 长轴突，可出现继发性形态改变 在细胞的一部分(例如，神经元核周)中被移除很远 从受伤的地方。这导致了对新探测器的搜索 来破译这些形态线索。单克隆抗体 针对磷酸化的神经丝表位提供 研究病理改变的新工具已被应用 几种人类神经纤维性疾病，包括肌营养不良 侧索硬化症(ALS)在这种紊乱中，磷酸化的表位， 它们通常不存在于神经细胞膜中，是 在受影响区域的细胞体中异常表达。这个 这些发现的意义尚不清楚。一直以来 暗示这一变化可能与可能的缺陷有关 在神经丝运输中。或者，它可以表示一个 对轴突损伤的非特异性反应。动物模型采用 有毒化学物质提供了一种方法来区分这些 可能性。先前对慢性丙烯酰胺的研究 导致轴突变性的药物似乎 支持后一种可能性。当前的主要假设是 提议是至少有一些不正常表达 神经元核周区的磷酸化神经丝表位 代表了对轴突损伤的刻板印象。这将是 通过关联任何异常表达的时间进程进行测试 随着1)近端抗原表位的发展 IDPN神经病的肿胀，2)远端肿胀和轴突 慢性2，5-己二酮(HD)神经病的变性 3，4-二甲基HD的近端肿胀和远端变性 (DMHD)神经病，以及4)近端肿胀和变性 联合应用IDPN和神经切断。 此外，使用秋水仙碱的研究将探索可能的 逆行运输的“营养”信号在启动中的作用 这一反应。最后，这之间的关系 下面将对现象和轴突再生进行研究 松果体下注射丙烯酰胺会损害再生。这些 研究可能会建立一个更普遍的标记物 神经元核周的继发性改变，将澄清 这些变化在几种人类疾病中的意义； 肌萎缩侧索硬化。

The ability to differentiate secondary consequences of toxic chemical exposure from direct toxic effects is an important problem in toxicology. Moreover, in neurons, which can extend long axonal processes, secondary morphological changes may arise in a portion of the cell (e.g. the neuronal perikaryon) far removed from the site of injury. This has led to the search for new probes to decipher these morphological clues. Monoclonal antibodies directed against phosphorylated neurofilament epitopes provide new tools to study pathological alterations and have been applied to several human neurofibrillary disorders, including amyotrophic lateral sclerosis (ALS). In this disorder, phosphorylated epitopes, which are not normally present in neuronal perikarya, are abnormally expressed in cell bodies from affected regions. The significance of these findings remains unknown. It has been suggested that this alteration may be related to a possible defect in neurofilament transport. Alternatively, it may represent a nonspecific response to axonal injury. Animal models employing toxic chemicals offer a means to distinguish between these possibilities. Previous studies following chronic acrylamide administration, which produces axonal degeneration, appear to support the latter possibility. The major hypothesis of the present proposal is that abnormal expression of at least some phosphorylated neurofilament epitopes in neuronal perikarya represents a stereotypic response to axonal injury. This will be tested by correlating the time course of any abnormal expression of phosphorylated epitopes with the development of, 1) proximal swellings in IDPN neuropathy, 2) Distal swellings and axonal degeneration in chronic 2,5-hexanedione (HD) neuropathy, 3) proximal swellings and distal degeneration in 3,4-dimethyl HD (DMHD) neuropathy, and 4) Proximal swellings and degeneration following combined IDPN administration and nerve transection. Furthermore, studies using colchicine will explore the possible role of retrogradely transported "trophic" signals in the initiation of this response. Finally, the relationship between this phenomenon and axonal regeneration will be examined following subepineural acrylamide injection to impair regeneration. These studies may establish a more universal marker for the presence of secondary changes in neuronal perikarya and will clarify the significance of these alterations in several human disorders; e.g. ALS.