The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. I. Accelerated clinical neuropathy is accompanied by more proximal axonal swellings.
The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. I. Accelerated clinical neuropathy is accompanied by more proximal axonal swellings.
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DOI：
10.1016/0041-008x(83)90023-6
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发表时间：
1983-12
影响因子：
3.8
通讯作者：
D. Anthony;Kim Boekelheide;C.William Anderson;Doyle G. Graham
中科院分区：
文献类型：
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作者：
D. Anthony;Kim Boekelheide;C.William Anderson;Doyle G. Graham
在大鼠身上研究了γ-二酮3,4-二甲基-2,5-己二酮的神经毒性，并与母体化合物2,5-己二酮的已知神经毒性进行了比较。测试化合物被发现在摩尔基础上比己二酮强20到30倍。此外，与与己二酮相关的远端轴突变化不同，暴露于二甲基类似物后的神经丝状肿胀更近端发生在轴突，主要发生在脊髓前角和外侧束以及前根。由于烷基取代导致支链化合物比非支链类似物更迅速地环化，二甲基化合物更大的神经毒性暗示了吡咯在正己烷神经病发病机制中的形成。此外，3,4-二甲基2,5-己二酮引起的轴突肿胀的位置表明，在所有类型的神经丝神经病变中存在共同的损伤机制，在β，β ' -亚氨基二丙腈（IDPN）的椎内肿胀与2,5-己二酮、二硫碳和丙烯酰胺的远端轴突病变之间提供了一个连续体。此外，较长时间低剂量的3,4-二甲基-2,5-己二酮导致轴突肿胀的位置转移，包括更多的远端部位。这些观察结果支持了一种假设，即稳定的神经丝的共价交联是这些毒性神经病分子发病机制的主要事件，神经丝的交联率决定了轴突肿胀的近端和远端位置。
The neurotoxicity of the γ-diketone, 3,4-dimethyl-2,5-hexanedione, was studied in rats and compared to the known neurotoxicity of the parent compound, 2,5-hexanedione. The test compound was found to be 20 to 30 times more potent on a molar basis than hexanedione. In addition, unlike the distal axonal changes associated with hexanedione, the neurofilamentous swellings following exposure to the dimethyl analog occurred more proximally in the axon, with a preponderance in the anterior horn and lateral tracts of the spinal cord, and in the anterior roots. Since alkyl substitution causes branched-chain compounds to cyclize more rapidly than unbranched analogs, the greater neurotoxicity of the dimethyl compound implicates pyrrole formation in the pathogenesis of n-hexane neuropathy. Furthermore, the location of the axonal swellings induced with 3,4-dimethyl 2,5-hexanedione suggests that there is a common mechanism of injury for the entire class of neurofilament neuropathies, providing a continuum between the intraspinal swellings of β,β′-iminodipropionitrile (IDPN) and the distal axonopathies of 2,5-hexanedione, carbon disulfide, and acrylamide. In addition, lower doses of 3,4-dimethyl-2,5-hexanedione for longer periods of time led to a shift in the location of the axonal swellings to include more distal sites. These observations support the hypothesis that covalent crosslinking of the stable neurofilament is the primary event in the molecular pathogenesis of these toxic neuropathies, and that the rate of crosslinking of neurofilaments determines the proximodistal location of the axonal swelling.