Shibutani M, Okeda R
Department of Pathology, Tokyo Medical and Dental University, Japan.
Acta Neuropathol. 1989;78(3):291-300. doi: 10.1007/BF00687759.
An experimental study on the pathogenesis of methotrexate (MTX)-related neurotoxicity including disseminated necrotizing leukoencephalopathy (DNL) was conducted in cats. MTX was administered to the cerebrospinal fluid (CSF) of adult cats using either an intracisternal intermittent instillation (ICI) model or an intraventricular continuous instillation (IVC) model. Furthermore, the synergistic effects of CSF-flow disturbance with kaolin-induced hydrocephalus, and 60Co irradiation were morphologically examined in these models. None of the animals from either the ICI and IVC groups showed DNL, but all animals showed segmental axonal degeneration, suggesting that MTX had a direct toxic effect on the axon. In the ICI groups, no apparent synergistic effect of CSF-flow disturbance and radiation was noted on this axonal change. In the IVC groups, CSF-flow disturbance augmented the degree of the axonal injury. Axonal degeneration and fibrin exudation in the walls of small blood vessels occurred in one animal of the IVC groups with CSF-flow disturbance, suggesting that a toxic effect of MTX on blood vessels is another mechanism of MTX-induced neurotoxicity.
在猫身上进行了一项关于甲氨蝶呤（MTX）相关神经毒性发病机制的实验研究，包括播散性坏死性白质脑病（DNL）。使用脑池内间歇性滴注（ICI）模型或脑室内连续滴注（IVC）模型，将MTX注入成年猫的脑脊液（CSF）中。此外，在这些模型中从形态学上研究了脑脊液流动紊乱与高岭土诱导的脑积水以及60Co照射的协同作用。ICI组和IVC组的动物均未出现DNL，但所有动物均出现节段性轴索变性，提示MTX对轴突有直接毒性作用。在ICI组中，未观察到脑脊液流动紊乱和辐射对这种轴突变化有明显的协同作用。在IVC组中，脑脊液流动紊乱加剧了轴突损伤的程度。在伴有脑脊液流动紊乱的IVC组的一只动物中，出现了轴索变性和小血管壁的纤维蛋白渗出，提示MTX对血管的毒性作用是MTX诱导神经毒性的另一种机制。
