Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke
Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke
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DOI：
10.1046/j.1460-9568.2003.02713.x
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发表时间：
2003-06-01
影响因子：
3.4
通讯作者：
Kokaia, Z
中科院分区：
文献类型：
--
作者：
Gustafsson, E;Andsberg, G;Kokaia, Z
为了探讨脑源性神经营养因子在脑卒中后纹状体神经元存活和生成中的作用，我们在大脑中动脉闭塞同侧30分钟前4-5周将携带脑源性神经营养因子或绿色荧光蛋白基因的重组腺相关病毒载体注射到右侧大鼠黑质。脑源性神经营养因子-重组腺相关病毒转导显著增加了黑质细胞脑源性神经营养因子蛋白的产生。纹状体神经肽y阳性中间神经元的肥厚反应揭示了脑源性神经营养因子顺行转运到纹状体并以生物活性形式释放。用脑源性神经营养因子重组腺相关病毒转导的动物也表现出身体姿势和运动的异常，包括身体向右倾斜，左前肢和头部的舞蹈状运动，以及自发的沿着其长轴的所谓“桶”旋转。脑源性神经营养因子的持续传递对脑卒中后纹状体投射神经元的存活没有影响，但会加剧胆碱能、小白蛋白和神经肽y阳性、γ -氨基丁酸能中间神经元的损失。脑源性神经营养因子在中风动物体内的高水平也导致纹状体细胞表达双皮质素（一种迁移神经母细胞的标记物）和有丝分裂标记物（5-溴-2′-脱氧尿苷-5′单磷酸）和早期神经元（Hu）或纹状体神经元（Meis2）标记物)双重标记的细胞数量增加。我们的研究结果表明，长期顺行递送高水平的脑源性神经营养因子增加纹状体中间神经元对中风引起的损伤的脆弱性。同时，脑源性神经营养因子至少在早期阶段增强了卒中诱导的神经源性反应。
To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.