Investigation of mechanism of non-cholinergic toxicity at acute sarine poisoning

有多种有毒化学物质会导致细胞死亡。然而。在某些情况下，有害物质在细胞死亡之前引起各种细胞反应。确定引起这种细胞反应的细胞机制是很重要的，但迄今为止还没有对这个问题给予足够的重视。在这项研究中，我们展示了我们为研究有机磷神经毒剂而合成的有机磷（OP）剂，双（蒎酰甲基）膦酸酯（BPMP）对培养的大鼠星形胶质细胞的特征性作用。在形态学上，BPMP诱导大鼠星形胶质细胞胞浆空泡化和星形。细胞质空泡化是一种观察到的细胞病理变化，例如，在空泡变性中，星形细胞对各种刺激的反应中有报道。用蛋白质合成抑制剂环己亚胺预处理后，星状被抑制，但液泡形成不被抑制。用线粒体选择性染料染色的细胞表明，空泡化可能发生在中央肿胀和空泡化的线粒体中。有趣的是。细胞外信号调节激酶（ERK）级联抑制剂抑制液泡形成，并在一定程度上抑制星形。这些结果表明，ERK信号级联对于诱导线粒体空泡化是重要的。我们期望对这些星形细胞反应的详细研究将为我们提供关于细胞形态变化的变化和病理意义的新视角，例如空泡变性，以及各种神经系统疾病的机制。

There are various toxic chemicals that cause cell death. However. in certain cases deleterious agents elicit various cellular responses prior to cell death. To determine the cellular mechanisms by which such cellular responses arc induced is important, but sufficient attention has not been paid to this issue to date. In this study, we showed the characteristic effects of an organophosphorus (OP) agent, bis (pinacolyl methyl) phosphonate (BPMP), which we synthesized for the study of OP nerve agents, on cultured rat astrocytes. Morphologically, BPMP induced cytoplasmic vacuolation and stellation in the rat astrocytes. Cytoplasmic vacuolation is a cell pathological change observed, for example, in vacuolar degeneration, and stellation has been reported in astrocytic reactions against various stimuli. By pretreatment with cycloheximide, a protein synthesis inhibitor, stellation was inhibited, although vacuolation was not. Cell staining with a mitochondrion-selective dye indicated that the vacuolation probably occurs in the mitochondria that are swollen and vacuolatred in the center. Interestingly. the extracellular signal-regulated kinase (ERK) cascade inhibitor inhibited vacuolation and, to some extent, stellation. These results suggest that the ERK signaling cascade is important for the induction of mitochondrial vacuolation. We expect that a detailed study of these astrocytic reactions will provide us new perspectives regarding the variation and pathological significance of cell morphological changes, such as vacuolar degeneration, and also the mechanisms underlying various neurological disorders.