LoPachin R M, Ross J F, Reid M L, Das S, Mansukhani S, Lehning E J
Neurotoxicology. 2002 May;23(1):95-110. doi: 10.1016/s0161-813x(02)00003-7.
This research was conducted to determine which neurological test or combination of tests can provide sufficient functional information to compliment biochemical or morphological endpoints in mechanistic studies of toxic axonopathies. Using several neurological indices, we evaluated the effects of two prototypical neurotoxicants that cause distal axonopathy: acrylamide monomer (ACR) and 2,5-hexanedione (HD). For each toxicant, rats were exposed to two daily dosing rates (ACR, 50 mg/kg per day i.p. or 21 mg/kg per day, p.o.; HD, 175 or 400 mg/kg per day, p.o.) and neurological endpoints were determined two to three times per week. Specific tests included observations of spontaneous locomotion in an open field, and measurements of hindlimb landingfoot splay, forelimb and hindlimb grip strength and the hindlimb extensor thrust response. For all neurological parameters, the magnitude of defect induced by either neurotoxicant was not related to daily dose-rate, e.g. both the lower and higher ACR dose-rates produced the same degree of neurological dysfunction. Instead, dose-rate determined onset and progression of neurotoxicity, e.g. the higher ACR dose-rate produced moderate neurotoxicity after approximately 8 days of intoxication, whereas the lower dose-rate caused moderate neurotoxicity after 26 days. Regardless of dose-rate, ACR-exposed rats exhibited gait abnormalities (ataxia, splayed hindlimbs), in conjunction with increased landing hindfoot spread and decreased hindlimb grip strength and extensor thrust HD intoxicated rats exhibited hindlimb muscle weakness as indicated by a gait abnormality (dropped hocks) and decreases in grip strength and the extensor thrust response. However, hindlimb landingfoot spread was not affected by HD exposure. For both neurotoxicants, gait changes preceded or coincided with alterations in other neurologic indices. These results suggest that observations of spontaneous behavior in an open field represent a practical approach to assessing temporal development and extent of neurological dysfunction induced by axonopathic toxicants such as ACR and HD.
本研究旨在确定哪种神经学测试或测试组合能够提供足够的功能信息，以补充毒性轴突病机制研究中的生化或形态学终点指标。我们使用多种神经学指标，评估了两种导致远端轴突病的典型神经毒物的作用：丙烯酰胺单体（ACR）和2,5 -己二酮（HD）。对于每种毒物，将大鼠暴露于两种每日给药剂量（ACR，腹腔注射50 mg/kg/天或口服21 mg/kg/天；HD，口服175或400 mg/kg/天），每周测定神经学终点指标两到三次。具体测试包括在旷场中观察自发运动，以及测量后肢着地时的足展、前肢和后肢握力以及后肢伸肌推力反应。对于所有神经学参数，两种神经毒物所诱导的缺陷程度与每日剂量率无关，例如，ACR的较低和较高剂量率均产生相同程度的神经功能障碍。相反，剂量率决定了神经毒性的发作和进展，例如，较高的ACR剂量率在中毒约8天后产生中度神经毒性，而较低剂量率在26天后导致中度神经毒性。无论剂量率如何，暴露于ACR的大鼠均表现出步态异常（共济失调、后肢外展），同时后肢着地时足展增加、后肢握力和伸肌推力降低；暴露于HD的大鼠表现出后肢肌肉无力，表现为步态异常（跗关节下垂）以及握力和伸肌推力反应降低。然而，后肢着地时的足展不受HD暴露的影响。对于两种神经毒物，步态变化先于或与其他神经学指标的改变同时出现。这些结果表明，在旷场中观察自发行为是评估由ACR和HD等轴突病毒物诱导的神经功能障碍的时间发展和程度的一种实用方法。
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