Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats
Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats
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DOI：
10.1161/01.str.0000236025.44089.e1
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发表时间：
2006-09-01
期刊：
影响因子：
8.3
通讯作者：
Lindvall, Olle
中科院分区：
文献类型：
--
作者：
Kobayashi, Tohru;Ahlenius, Henrik;Lindvall, Olle
背景和目的：卒中可促进啮齿类动物脑室下区(SVZ)神经前体细胞的增殖，并在受损的纹状体中产生中等刺状神经元。探讨脑内注射胶质细胞源性神经营养因子(GDNF)是否能促进卒中后神经再生。方法成年大鼠大脑中动脉闭塞(MCAO)2小时。在MCAO后1周向缺血区注入GDNF，然后直接处死动物，或在第3、4周，1周后处死大鼠。分别在第7天和第2周用5‘-溴-2’-脱氧尿苷(BrdU)标记新细胞。用抗BrdU抗体和神经元、神经胶质细胞或祖细胞标记物免疫细胞化学方法评估神经发生。应用逆转录-聚合酶链式反应和免疫细胞化学方法分析GDNF受体在SVZ组织和神经球中的表达。结果注射GDNF可促进MCAO后同侧SVZ细胞的增殖和新的神经母细胞向纹状体的募集，提高新成熟神经元的存活率。GDNF受体GFRα1在MCAO后1周在SVZ区表达上调，并与分裂祖细胞标志物共表达。结论脑缺血后纹状体内注射GDNF可促进卒中后纹状体神经发生的多个步骤，部分是通过直接作用于SVZ祖细胞实现的。由于GDNF在人脑中具有生物学效应，我们的数据表明，给予该因子可能会促进中风患者的神经再生反应。
Background and Purpose-Stroke triggers increased progenitor proliferation in the subventricular zone (SVZ) and the generation of medium spiny neurons in the damaged striatum of rodents. We explored whether intrastriatal infusion of glial cell line-derived neurotrophic factor (GDNF) promotes neurogenesis after stroke.Methods-Adult rats were subjected to 2-hour middle cerebral artery occlusion (MCAO). GDNF was infused into the ischemic striatum either during the first week after MCAO, with the animals being killed directly thereafter, or during the third and fourth weeks, with the rats being killed 1 week later. New cells were labeled with 5'-bromo-2'deoxyuridine (BrdU) on day 7 or during the second week, respectively. Neurogenesis was assessed immunocytochemically with antibodies against BrdU and neuronal, glial, or progenitor markers. GDNF receptor expression was analyzed in SVZ tissue and neurospheres by reverse transcription-polymerase chain reaction and immunocytochemistry.Results-GDNF infusion increased cell proliferation in the ipsilateral SVZ and the recruitment of new neuroblasts into the striatum after MCAO and improved survival of new mature neurons. The GDNF receptor GFR alpha 1 was upregulated in the SVZ 1 week after MCAO and was coexpressed with markers of dividing progenitor cells.Conclusions-Intrastriatal infusion of GDNF in the postischernic period promotes several steps of striatal neurogenesis after stroke., partly through direct action on SVZ progenitors. Because delivery of GDNF has biological effects in the human brain, our data suggest that administration of this factor may promote neurciregenerative responses in stroke patients.