Neuroprotection Research Laboratory, Massachusetts GeneralHospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Diabetes. 2011 Jun;60(6):1789-96. doi: 10.2337/db10-1371. Epub 2011 May 11.
Diabetes is an independent risk factor for stroke. However, the underlying mechanism of how diabetes confers that this risk is not fully understood. We hypothesize that secretion of neurotrophic factors by the cerebral endothelium, such as brain-derived neurotrophic factor (BDNF), is suppressed in diabetes. Consequently, such accrued neuroprotective deficits make neurons more vulnerable to injury.
We examined BDNF protein levels in a streptozotocin-induced rat model of diabetes by Western blotting and immunohistochemistry. Levels of total and secreted BDNF protein were quantified in human brain microvascular endothelial cells after exposure to advanced glycation end product (AGE)-BSA by enzyme-linked immunosorbent assay and immunocytochemistry. In media transfer experiments, the neuroprotective efficacy of conditioned media from normal healthy endothelial cells was compared with AGE-treated endothelial cells in an in vitro hypoxic injury model.
Cerebrovascular BDNF protein was reduced in the cortical endothelium in 6-month diabetic rats. Immunohistochemical analysis of 6-week diabetic brain sections showed that the reduction of BDNF occurs early after induction of diabetes. Treatment of brain microvascular endothelial cells with AGE caused a similar reduction in BDNF protein and secretion in an extracellular signal-related kinase-dependent manner. In media transfer experiments, conditioned media from AGE-treated endothelial cells were less neuroprotective against hypoxic injury because of a decrease in secreted BDNF.
Taken together, our findings suggest that a progressive depletion of microvascular neuroprotection in diabetes elevates the risk of neuronal injury for a variety of central nervous system diseases, including stroke and neurodegeneration.
糖尿病是中风的一个独立危险因素。然而，糖尿病如何增加这种风险的潜在机制尚不完全清楚。我们假设大脑内皮细胞（如脑源性神经营养因子，BDNF）分泌的神经营养因子受到抑制。因此，这种累积的神经保护缺陷使神经元更容易受到损伤。
我们通过 Western blot 和免疫组织化学检测了链脲佐菌素诱导的糖尿病大鼠模型中 BDNF 蛋白水平。通过酶联免疫吸附试验和免疫细胞化学检测了人脑血管内皮细胞暴露于晚期糖基化终产物（AGE）-BSA 后总分泌型和分泌型 BDNF 蛋白的水平。在介质转移实验中，比较了正常健康内皮细胞条件培养基与 AGE 处理内皮细胞在体外缺氧损伤模型中的神经保护效果。
6 个月糖尿病大鼠皮质血管内皮细胞中脑血管 BDNF 蛋白减少。6 周糖尿病脑切片的免疫组织化学分析表明，BDNF 的减少发生在糖尿病诱导后早期。AGE 处理的脑微血管内皮细胞以细胞外信号相关激酶依赖的方式导致 BDNF 蛋白和分泌减少。在介质转移实验中，由于分泌型 BDNF 的减少，AGE 处理内皮细胞的条件培养基对缺氧损伤的神经保护作用降低。
综上所述，我们的研究结果表明，糖尿病中小血管神经保护的逐渐耗竭增加了多种中枢神经系统疾病（包括中风和神经退行性变）神经元损伤的风险。
