Decreased cerebrovascular brain-derived neurotrophic factor-mediated neuroprotection in the diabetic brain.
Decreased cerebrovascular brain-derived neurotrophic factor-mediated neuroprotection in the diabetic brain.
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作者：
Navaratna D;Guo SZ;Hayakawa K;Wang X;Gerhardinger C;Lo EH
糖尿病是中风的独立危险因素。然而，糖尿病如何导致这种风险的潜在机制还没有完全了解。我们假设糖尿病患者脑内皮细胞分泌神经营养因子，如脑源性神经营养因子(BDNF)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伤害。我们用Western blotting和免疫组织化学方法检测了链脲佐菌素诱导的糖尿病大鼠模型中BDNF的蛋白水平。采用酶联免疫吸附试验和免疫细胞化学方法检测晚期糖基化终产物(AGE)-BSA作用于人脑微血管内皮细胞后，脑源性神经营养因子(BDNF)总蛋白和分泌蛋白的表达水平。在体外缺氧损伤模型中，比较了来自正常健康内皮细胞的条件培养液和经AGE处理的内皮细胞的神经保护效果。6月龄糖尿病大鼠皮质内皮细胞脑血管BDNF蛋白表达减少。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的早期。用AGE处理脑微血管内皮细胞后，BDNF蛋白和分泌也以细胞外信号相关激酶依赖的方式类似地减少。在介质转移实验中，来自经AGE处理的内皮细胞的条件培养液对低氧损伤的神经保护作用较弱，因为分泌的BDNF减少。综上所述，我们的研究结果表明，糖尿病患者微血管神经保护的进行性丧失会增加包括中风和神经变性在内的各种中枢神经系统疾病的神经元损伤风险。
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.
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影响因子：
4
作者：
Ergul, Adviye;Li, Weiguo;Elgebaly, Mostafa M.;Bruno, Askiel;Fagan, Susan C.
通讯作者：
Fagan, Susan C.
影响因子：
2.9
作者：
del Zoppo, Gregory J.
通讯作者：
del Zoppo, Gregory J.
影响因子：
4.8
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Kim, H;Li, Q;Madri, JA
通讯作者：
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影响因子：
8.2
作者：
Krabbe, K. S.;Nielsen, A. R.;Pedersen, B. K.
通讯作者：
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影响因子：
7.7
作者：
JAKOBSEN, J;SIDENIUS, P;OSTERBY, R
通讯作者：
OSTERBY, R