Lopachin Richard M, Jortner Bernard S, Reid Maria L, Monir Alim
Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, Moses Research Tower-7, 111 E. 2210th St., Bronx, NY 10467-2490, USA.
Neurotoxicology. 2005 Dec;26(6):1021-30. doi: 10.1016/j.neuro.2005.04.008. Epub 2005 Jun 17.
Loss of axon caliber is a primary component of gamma-diketone neuropathy [LoPachin RM, DeCaprio AP. gamma-Diketone central neuropathy: axon atrophy and the role of cytoskeletal protein adduction. Toxicol Appl Pharmacol 2004;199:20-34]. It is possible that this effect is mediated by changes in the density of cytoskeletal components and corresponding spatial relationships. To examine this possibility, morphometric methods were used to quantify the effects of 2,5-hexanedione (HD) intoxication on neurofilament-microtubule densities and nearest neighbor distances in myelinated rubrospinal axons. Rats were exposed to HD at one of two daily dose-rates (175 or 400 mg/kg per day, gavage) until a moderate level of neurotoxicity was achieved (99 or 21 days of intoxication, respectively) as determined by gait analysis and measurements of hindlimb grip strength. Results indicate that, regardless of dose-rate, HD intoxication did not cause changes in axonal neurofilament (NF) density, but did significantly increase microtubule (MT) density. No consistent alterations in interneurofilament or NF-MT distances were detected by ultrastructural morphometric analyses. These data suggest that the axon atrophy induced by HD was not mediated by major disruptions of stationary cytoskeletal organization. Recent biochemical studies of spinal cord from HD intoxicated rats showed that, although the NF protein content in the stationary cytoskeleton (polymer fraction) was not affected, the mobile subunit pool was depleted substantially [LoPachin RM, He D, Reid ML, Opanashuk LA. 2,5-Hexanedione-induced changes in the monomeric neurofilament protein content of rat spinal cord fractions. Toxicol Appl Pharmacol 2004;198:61-73]. The stability of the polymer fraction during HD intoxication is consistent with the absence of significant ultrastructural modifications noted in the present study. Together, these findings implicate loss of mobile NF proteins as the primary mechanism of axon atrophy.
轴突管径减小是γ-二酮神经病的主要组成部分[洛帕钦RM，德卡普里奥AP。γ-二酮中枢神经病：轴突萎缩及细胞骨架蛋白内收的作用。毒理学应用药理学2004；199：20 - 34]。这种效应可能是由细胞骨架成分密度的变化及相应的空间关系介导的。为了检验这种可能性，采用形态计量学方法来量化2,5 -己二酮（HD）中毒对有髓红核脊髓轴突中神经丝 - 微管密度及最近邻距离的影响。大鼠以两种每日剂量率之一（每天175或400毫克/千克，灌胃）暴露于HD，直至达到中度神经毒性水平（分别为中毒99天或21天），这是通过步态分析和后肢握力测量确定的。结果表明，无论剂量率如何，HD中毒均未引起轴突神经丝（NF）密度的变化，但确实显著增加了微管（MT）密度。超微结构形态计量分析未检测到神经丝间或NF - MT距离的一致改变。这些数据表明，HD诱导的轴突萎缩不是由固定细胞骨架组织的重大破坏介导的。最近对HD中毒大鼠脊髓的生化研究表明，虽然固定细胞骨架（聚合物部分）中的NF蛋白含量未受影响，但可移动亚基池大量减少[洛帕钦RM，何D，里德ML，奥帕纳什克LA。2,5 -己二酮诱导大鼠脊髓组分中单体神经丝蛋白含量的变化。毒理学应用药理学2004；198：61 - 73]。HD中毒期间聚合物部分的稳定性与本研究中未观察到明显超微结构改变一致。总之，这些发现表明可移动NF蛋白的丧失是轴突萎缩的主要机制。
