Insulin insufficiency and increased glucose levels are the major features of diabetes type 1 leading to cognitive dysfunctions and neurodegeneration. A reason why different brain structures are characterized by diverse response to increased glucose level is not known. Our previous study showed increased ceramide levels in the brains of rats with diabetes induced by streptozotocin (STZ) injection, which was abolished by myriocin, the inhibitor of serine palmitylotransferase. Ceramides may be important mediators of neuropathological changes and its elevation was found in many brain disorders. The main goal of our present study was to verify if hippocampus, prefrontal cortex and cerebellum response differently to hyperglycemia/hypoinsulinemia in terms of changes in sphingolipids concentrations. We attempted to identify potential source of ceramides by measuring the sphingomyelinase concentrations and by blocking the ceramide de novo synthesis pathway. We found that in cerebellum and hippocampus of hyperglycemic animals sphingolipids concentrations underwent subtle modifications while prefrontal cortex exhibited massive changes in ceramides and SMs content. Total ceramide levels was significantly elevated in prefrontal cortex of diabetic rats, which was reduced by myriocin, while rats exposed to STZ showed only small increase of total SM in this brain structure. The increased content of ceramides containing SAFAs (saturated fatty acids) in prefrontal cortex was diminished by myriocin. SAFA-contained SMs did not present changes. Elevation of MUFA- (monounsaturated fatty acids), and PUFA-ceramides (polyunsaturated fatty acids) in prefrontal cortex of STZ-treated rats was reduced by myriocin, similarly as MUFA-SMs augmentation. PUFA-ceramides and PUFA-SMs experienced only slight modifications. Both – ceramides and omega-6 – SMs increased dramatically and were downregulated by myriocin. We conclude that the prefrontal cortex may be particularly sensitive to hyperglycemic conditions and hypoinsulinemia. Moreover, the novo synthesis seems to be an important pathway of ceramide generation since usage of myriocin strongly reduced ceramide levels enhanced by STZ injection. Augmentation in ceramide content was correlated with enhancement of SMs production. These unexpected results may be explained by the incorporation of redundant ceramides into SMs, a mechanism by which the toxic level of ceramides is reduced in the brain. Supported by grant 123-27575 P from the State Committee for Scientific Research, Warsaw, Poland
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