Fumonisin B 1-Induced Neurodegeneration in Mice after Intracerebroventricular Infusion is Concurrent with Disruption of Sphingolipid Metabolism and Activation of Proinflammatory Signaling

Abstract

Fumonisin B 1 (FB 1), 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 FB 1 will result in neurotoxicity, characterized by biochemical and pathological alterations. The present study compared the toxicity of FB 1 in mouse brain after an intracerebroventricular (icv) or subcutaneous (sc) infusion. Female BALB/c mice (5/group) were infused (0.5 μl/h) with total doses of 0, 10 or 100 μg FB 1 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 μg of FB 1 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 FB 1 icv in all brain regions and increased free sphingosine after the 100 μg FB 1 in the cortex. The concentration of cortical sphingomyelin and complex sphingolipids remained unchanged. The icv administration of FB 1 induced expression of tumor necrosis factor α, interleukin-1β, interleukin-6 and interferon γ after both doses, assayed by the real-time polymerase chain reaction. The sc administration of 100 μg FB 1 caused slight sphinganine accumulation and increased IL-1β expression in cortex only. Results indicated that icv injection of FB 1 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 FB 1 availability into the brain could be responsible for the absence of its neurotoxicity in mouse.