Stone J D, Peterson A P, Eyer J, Sickles D W
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 30912, USA.
Neurotoxicology. 2000 Aug;21(4):447-57.
Acrylamide (ACR) and g-diketones (g-DK) produce distal sensory-motor neuropathy in a variety of species, including humans. The specific molecular site and mechanism of toxicant action leading to specific morphological and behavioral abnormalities requires definition. The relative roles of fast anterograde axonal transport and neurofilaments (NF) are investigated using optic nerves of mice, with and without axonal neurofilaments. Segmental analysis, following pulse labeling with 3H-leucine into the vitreous body, was used to detect changes in fast anterograde transport in the optic nerve and tract. Single injections of ACR significantly reduced the quantity of radiolabeled proteins transported in both transgenic (lacking NF) and non-transgenic (containing NF) mice by 68.4% and 46.2%, respectively. Similarly, single injections of 2,5-hexanedione (2,5-HD) reduced the quantity of radiolabeled transport in transgenic and non-transgenic mice by 55.2% and 47.1%, respectively. Equimolar doses of propionamide and 3,4-hexanedione (non-neurotoxic analogues of ACR and 2,5-HD, respectively) produced no changes in the quantity or apparent rate of optic nerve transport. Additionally, no differences in quantity or apparent rate of transport between transgenic and non-transgenic animals were observed under control or experimental conditions. Therefore, ACR and 2,5-HD reduce the quantity of fast anterograde axonal transport in mouse CNS axons in a comparable amount to previously reported reductions in rat PNS axons. The absence of axonal neurofilaments had no effect on normal fast transport. Furthermore, the presence or absence of neurofilaments did not alter the effect of these toxicants on fast axonal transport. We conclude that toxicant-induced reductions in fast axonal transport are unrelated to ACR and g-diketone effects on NF or their accumulation.
丙烯酰胺（ACR）和γ-二酮（γ-DK）会在包括人类在内的多种物种中引发远端感觉运动神经病变。导致特定形态和行为异常的毒物作用的具体分子位点和机制需要明确。利用有或没有轴突神经丝的小鼠视神经，研究了快速顺向轴突运输和神经丝（NF）的相对作用。在用³H-亮氨酸脉冲标记玻璃体后进行节段分析，以检测视神经和视束中快速顺向运输的变化。单次注射ACR可使转基因（缺乏NF）和非转基因（含有NF）小鼠中运输的放射性标记蛋白量分别显著减少68.4%和46.2%。同样，单次注射2,5-己二酮（2,5-HD）可使转基因和非转基因小鼠中放射性标记运输量分别减少55.2%和47.1%。等摩尔剂量的丙酰胺和3,4-己二酮（分别为ACR和2,5-HD的非神经毒性类似物）对视神经运输的量或表观速率没有影响。此外，在对照或实验条件下，未观察到转基因和非转基因动物在运输量或表观速率上的差异。因此，ACR和2,5-HD使小鼠中枢神经系统轴突中快速顺向轴突运输量减少的程度，与先前报道的大鼠周围神经系统轴突减少程度相当。轴突神经丝的缺失对正常快速运输没有影响。此外，神经丝的存在与否并未改变这些毒物对快速轴突运输的影响。我们得出结论，毒物诱导的快速轴突运输减少与ACR和γ-二酮对NF的影响或它们的积累无关。
