Osuchowski Marcin F, Edwards Gaylen L, Sharma Raghubir P
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.
Neurotoxicology. 2005 Mar;26(2):211-21. doi: 10.1016/j.neuro.2004.10.001.
Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides, causes equine leukoencephalomalacia, a condition not reproduced in any other species. We hypothesized that direct exposure of murine brain to FB1 will result in neurotoxicity, characterized by biochemical and pathological alterations. The present study compared the toxicity of FB1 in mouse brain after an intracerebroventricular (icv) or subcutaneous (sc) infusion. Female BALB/c mice (5/group) were infused (0.5 microl/h) with total doses of 0, 10 or 100 microg FB1 in saline over 7 days via osmotic pumps implanted either via icv cannulation of the ventricle or via the sc route. One day after the last day of treatment, brains were dissected either fresh or after intracardiac paraformaldehyde fixation. In mice given 100 microg of FB1 icv, FluoroJade B staining revealed neurodegeneration in the cortex, and anti-glial fibrillary acidic protein staining detected activated astrocytes in the hippocampus. High performance liquid chromatography indicated accumulation of free sphinganine in animals given FB1 icv in all brain regions and increased free sphingosine after the 100 microg FB1 in the cortex. The concentration of cortical sphingomyelin and complex sphingolipids remained unchanged. The icv administration of FB1 induced expression of tumor necrosis factor alpha, interleukin-1beta, interleukin-6 and interferon gamma after both doses, assayed by the real-time polymerase chain reaction. The sc administration of 100 microg FB1 caused slight sphinganine accumulation and increased IL-1beta expression in cortex only. Results indicated that icv injection of FB1 caused neurodegeneration with simultaneous inhibition of de novo ceramide synthesis, stimulation of astrocytes, and upregulation of pro-inflammatory cytokines in the murine brain. A relative lack of FB1 availability into the brain could be responsible for the absence of its neurotoxicity in mouse.
伏马菌素B1（FB1）是由轮枝镰孢菌产生的一种霉菌毒素，可导致马脑白质软化症，这是一种在其他任何物种中都不会出现的病症。我们推测，将小鼠脑直接暴露于FB1会导致神经毒性，其特征为生化和病理改变。本研究比较了经脑室内（icv）或皮下（sc）注射后FB1对小鼠脑的毒性。通过植入的渗透泵，经脑室icv插管或sc途径，以0.5微升/小时的速度，在7天内给雌性BALB/c小鼠（每组5只）输注总剂量为0、10或100微克的FB1生理盐水溶液。在治疗的最后一天后的一天，将脑新鲜解剖或在心脏内注入多聚甲醛固定后解剖。在经icv给予100微克FB1的小鼠中，FluoroJade B染色显示皮质中有神经变性，抗胶质纤维酸性蛋白染色检测到海马中有活化的星形胶质细胞。高效液相色谱法表明，经icv给予FB1的动物所有脑区中游离鞘氨醇均有蓄积，在皮质给予100微克FB1后游离鞘氨醇增加。皮质鞘磷脂和复合鞘脂的浓度保持不变。通过实时聚合酶链反应检测，两种剂量的FB1经icv给药后均诱导肿瘤坏死因子α、白细胞介素-1β、白细胞介素-6和干扰素γ的表达。皮下给予100微克FB1仅导致皮质中鞘氨醇略有蓄积和白细胞介素-1β表达增加。结果表明，icv注射FB1会导致神经变性，同时抑制神经酰胺的从头合成，刺激星形胶质细胞，并上调小鼠脑中促炎细胞因子的表达。FB1进入脑内的相对缺乏可能导致其在小鼠中无神经毒性。
