Leptin receptor deficiency induces early, transient and hyperglycaemia-independent blood-brain barrier dysfunction
Leptin receptor deficiency induces early, transient and hyperglycaemia-independent blood-brain barrier dysfunction
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DOI：
10.1038/s41598-019-39230-1
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发表时间：
2019-02-27
影响因子：
4.6
通讯作者：
Ben-Zvi, Ayal
中科院分区：
文献类型：
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作者：
Corem, Noa;Anzi, Shira;Ben-Zvi, Ayal
糖尿病（DM）显著增加了对中枢神经系统（CNS）病变（包括中风、血管性痴呆、认知缺陷和阿尔茨海默病）的易感性。以前的研究（主要使用链脲佐菌素模型）表明，血脑屏障（BBB）破坏参与这些条件。在这里，我们研究了Lepr（db/db）肥胖相关糖尿病小鼠脑毛细血管和血脑屏障通透性的完整性。令人惊讶的是，仅在高血糖前期的年轻小鼠中观察到显著的BBB渗漏。在糖尿病后期对屏障通透性的彻底检查表明，在高血糖状态下没有证据表明存在显著的血脑屏障渗漏。短期高血压小鼠的电子显微镜成像支持正常的血脑屏障通透性，但表明毛细血管超微结构的其他应激相关变化，如线粒体变性。基于我们对肥胖相关DM小鼠遗传模型的研究，我们认为先前报道的高血压诱导的BBB渗漏很可能不是DM相关CNS病理的潜在机制。最后，我们提出血脑屏障通透性过高可能是一个早期和短暂的现象，而应激相关的内皮病理与短期糖尿病状态。
Diabetes mellitus (DM) significantly increases susceptibility to central nervous system (CNS) pathologies, including stroke, vascular dementia, cognitive deficits and Alzheimer's disease. Previous studies (mostly using the streptozotocin model) suggested that blood-brain barrier (BBB) disruption is involved in these conditions. Here, we examined the integrity of brain capillaries and BBB permeability in Lepr(db/db) obesity-related diabetic mice. Surprisingly, significant BBB leakage was observed only in young mice at the pre-hyperglycemic stage. Thorough examination of barrier permeability at later diabetic stages showed no evidence for significant BBB leakage during the hyperglycemic state. Electron microscopy imaging of mice with short-term hyperglycaemia supported normal BBB permeability but indicated other stress-related changes in capillary ultrastructure, such as mitochondrial degeneration. Based on our study with this mouse genetic model of obesity-related DM, we suggest that previously reported hyperglycaemia-induced BBB leakage is most likely not the underlying mechanism of DM-related CNS pathologies. Finally we propose that BBB hyper-permeability might be an early and transient phenomenon while stress-related endothelial pathologies do correlate with a short-term diabetic state.