Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.
Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.
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DOI：
10.1371/journal.pone.0014401
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发表时间：
2010-12-22
期刊：
影响因子：
3.7
通讯作者：
Lechleiter JD
中科院分区：
文献类型：
--
作者：
Zheng W;Watts LT;Holstein DM;Prajapati SI;Keller C;Grass EH;Walter CA;Lechleiter JD
改善水肿和缺血性脑卒中神经学结局的治疗方法非常有限。在这里，我们提出了第一个在体内单细胞图像的皮质小鼠星形胶质细胞记录的影响，单血管光血栓对细胞毒性水肿和脑梗死。表达绿色荧光蛋白（GFP）的星形胶质细胞的体积在缺血3小时内增加超过600%。随着星形胶质细胞溶解，GFP荧光消失，很容易跟踪脑梗死的后续生长。通过嘌呤能配体2-甲硫基腺苷5′二磷酸（2-MeSADP）治疗，细胞毒性水肿和缺血性病变的程度显著降低，2-MeSADP是一种对嘌呤能受体1型亚型（P2 Y1 R）具有高度特异性的激动剂。在24小时时，星形胶质细胞中的细胞毒性水肿在半暗带处仍然明显，并且在定义梗死的细胞溶解之前。在初始血栓形成后24小时延迟2 MeSADP治疗也显著减少了细胞毒性水肿和脑梗死的持续生长。药理学和遗传学的证据表明，2 MeSADP的保护介导的增强星形胶质细胞线粒体代谢通过增加肌醇三磷酸（IP 3）依赖的Ca 2+释放。我们认为，线粒体在缺血性病变的半影区星形胶质细胞能量代谢中起关键作用，其中低ATP水平被广泛认为是细胞毒性水肿的原因。这种能量来源的增强可能对广泛的脑损伤具有类似的保护作用。
Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5′ diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y1R). At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP3)-dependent Ca2+ release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries.
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影响因子：
6.5
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