Blood-Brain Barrier Group, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA.
J Mol Neurosci. 2013 Oct;51(2):364-70. doi: 10.1007/s12031-013-9993-8. Epub 2013 Mar 16.
We have shown that mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, have upregulated leptin receptor expression in reactive astrocytes of the hippocampus, a region involved in sickness behavior. Leptin can exacerbate EAE when its serum concentration is high. Although leptin receptors in astrocytes modulate leptin transport across cultured endothelial cell monolayers, it is not known how leptin transport in EAE mice is regulated. Here, we determined brain and cervical spinal cord uptake of leptin in early and recovery stages of EAE, after either intravenous delivery or in situ brain perfusion of (125)I-leptin and the vascular marker (131)I-albumin. While increased vascular space and general blood-brain barrier (BBB) permeability after EAE were expected, the specific saturable transport system for leptin crossing the BBB also persisted. Moreover, there was upregulation of leptin transport in hippocampus and cervical spinal cord in the early stage of EAE, shown by higher leptin uptake in these regions and by competitive inhibition with coadministered excess unlabeled leptin. We conclude that EAE induced a time- and region-specific increase of leptin transport. The results provide a link between circulating leptin and enhanced leptin signaling that may play a crucial role in disease progression.
我们已经表明，患有实验性自身免疫性脑脊髓炎（EAE）的小鼠，即多发性硬化症的模型，其海马体反应性星形胶质细胞中的瘦素受体表达上调，而海马体是与疾病行为相关的区域。当血清瘦素浓度升高时，瘦素可以使 EAE 恶化。尽管星形胶质细胞中的瘦素受体可以调节培养的内皮细胞单层中的瘦素转运，但尚不清楚 EAE 小鼠中的瘦素转运是如何调节的。在这里，我们通过静脉内给药或原位脑灌注（125）I-瘦素和血管标记物（131）I-白蛋白，确定了 EAE 早期和恢复期的脑和颈脊髓中瘦素的摄取。虽然 EAE 后预计会增加血管空间和一般血脑屏障（BBB）通透性，但 BBB 穿越的瘦素特异性可饱和转运系统也持续存在。此外，在 EAE 的早期阶段，海马体和颈脊髓中的瘦素转运上调，这些区域的瘦素摄取增加，并且与同时给予的过量未标记瘦素的竞争抑制作用证明了这一点。我们得出结论，EAE 诱导了瘦素转运的时间和区域特异性增加。这些结果提供了循环瘦素与增强的瘦素信号之间的联系，这可能在疾病进展中起着至关重要的作用。
