Abou-Donia M B, Ibrahim S M, Corcoran J J, Lack L, Friedman M A, Lapadula D M
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
J Toxicol Environ Health. 1993 Aug;39(4):447-64. doi: 10.1080/15287399309531764.
Acrylamide (2-propenamide) monomer produces central-peripheral distal axonopathy in humans and some animal species. Its neurotoxicity is characterized by abnormal sensation, decreased motor strength, and ataxia. Acrylamide forms adducts with glutathione, proteins, and DNA. Recent studies demonstrated that acrylamide is metabolized to its epoxide, glycidamide (2,3-epoxy-1-propanamide). We studied the neurotoxicity potential of glycidamide in male Sprague-Dawley rats. Animals (groups of 6) were injected ip daily with either aqueous acrylamide or glycidamide at an acrylamide-equivalent dose of 50 mg/kg (0.70 mmol/kg). Both treatments resulted initially in the rats circling, which was followed by the onset of ataxia at 7-9 d and hindlimb paralysis at 12-14 d. Treated animals showed muscle wasting. At termination, acrylamide- and glycidamide-treated rats weighed 105% and 86% of initial weight, respectively, compared to 145% for controls. Animals were anesthetized and perfused with 10% neutral phosphate-buffered formalin 12 or 14 d after beginning of treatment. Both treatment groups exhibited similar neuropathologic changes in the central and peripheral nervous systems. More severe lesions were produced by glycidamide. A marked increase in the number of affected Purkinje cells in the cerebellum, which exhibited changes ranging from pyknosis to cell death, were present. The brainstem exhibited axonal degeneration with chromatolytic necrosis in midbrain medial and lateral reticular nuclei. The spinal cord was characterized by spongy form changes with vacuoles of different sizes in various levels. These results suggest that glycidamide is an active neurotoxic metabolite of acrylamide.
丙烯酰胺（2-丙烯酰胺）单体可导致人类和某些动物物种出现中枢-外周远端轴索性神经病。其神经毒性表现为感觉异常、运动强度下降和共济失调。丙烯酰胺会与谷胱甘肽、蛋白质和DNA形成加合物。最近的研究表明，丙烯酰胺可代谢为其环氧化物——缩水甘油酰胺（2,3-环氧-1-丙酰胺）。我们研究了缩水甘油酰胺对雄性斯普拉格-道利大鼠的神经毒性潜力。将动物（每组6只）每天腹腔注射丙烯酰胺水溶液或缩水甘油酰胺，剂量相当于50 mg/kg（0.70 mmol/kg）的丙烯酰胺。两种处理最初都会导致大鼠转圈，随后在7 - 9天出现共济失调，在12 - 14天出现后肢麻痹。接受处理的动物出现肌肉萎缩。处死时，与对照组体重增加145%相比，丙烯酰胺和缩水甘油酰胺处理的大鼠体重分别为初始体重的105%和86%。在开始处理12或14天后，将动物麻醉并用10%中性磷酸盐缓冲福尔马林灌注。两个处理组在中枢和外周神经系统均表现出相似的神经病理变化。缩水甘油酰胺产生的损伤更严重。小脑浦肯野细胞受影响数量显著增加，表现出从核固缩到细胞死亡的一系列变化。脑干在中脑内侧和外侧网状核出现轴突变性伴染色质溶解坏死。脊髓的特征是在不同节段出现大小各异的空泡形成的海绵状改变。这些结果表明，缩水甘油酰胺是丙烯酰胺的一种活性神经毒性代谢产物。
