Chao C F, Subjeck J R, Brody H, Shen J, Johnson R J
Radiat Res. 1984 Jan;97(1):87-96.
The radiation sensitizers misonidazole (MISO) and desmethylmisonidazole (DMM) can produce central and peripheral neuropathy in patients and laboratory animals. Behavioral and pathological investigations have indicated that in the central nervous system this primarily involves the cochlear and vestibular systems. Nitroimidazoles can also interfere with glycolysis in vitro under aerobic and anaerobic conditions. In the present work we have studied the effect of MISO or DMM on lactate production and glucose utilization in mouse brain. It is observed that these compounds result in a 25% inhibition of lactate production in brain slices relative to the control at a 10 mM level. Additionally, MISO (1.0 mg/g/day) or DMM (1.4 mg/g/day) were administered daily (oral) for 1, 4, 7, or 14 days to examine the effect of these two drugs on the regional glucose utilization in C3Hf mouse brain. Five microcuries of 2-deoxy[14C]glucose was given following the last drug dose and autoradiographs of serial brain sections were made and analyzed by a densitometer. Following a single dose of either MISO or DMM, no significant differences in glucose uptake were observed when compared with controls. However, following 4, 7, and 14 doses the rate of glucose utilization was significantly reduced in the intoxicated animals. Larger reductions were measured in specific regions including the posterior colliculus, cochlear nuclei, vestibular nuclei, and pons with increasing effects observed at later stages. These results share a degree of correspondence with the regional brain pathology produced by these nitroimidazoles.
放射增敏剂米索硝唑（MISO）和去甲基米索硝唑（DMM）可在患者和实验动物中引发中枢和外周神经病变。行为学和病理学研究表明，在中枢神经系统中，这主要涉及耳蜗和前庭系统。硝基咪唑类药物在有氧和无氧条件下还能在体外干扰糖酵解过程。在本研究中，我们探讨了MISO或DMM对小鼠脑内乳酸生成和葡萄糖利用的影响。结果发现，在10 mM浓度下，相对于对照组，这些化合物可使脑切片中的乳酸生成受到25%的抑制。此外，每天（口服）给予MISO（1.0 mg/g/天）或DMM（1.4 mg/g/天），持续1、4、7或14天，以研究这两种药物对C3Hf小鼠脑内区域葡萄糖利用的影响。在最后一次给药后给予5微居里的2-脱氧[14C]葡萄糖，制作连续脑切片的放射自显影片，并通过密度计进行分析。与对照组相比，单次给予MISO或DMM后，葡萄糖摄取未观察到显著差异。然而，在给予4、7和14次剂量后，中毒动物的葡萄糖利用率显著降低。在包括后丘、耳蜗核、前庭核和脑桥等特定区域测量到更大程度的降低，且在后期观察到的影响不断增加。这些结果与这些硝基咪唑类药物所导致的脑局部病理学表现存在一定程度的对应关系。
