The mechanisms of enhanced acidosis on ischemic neuronal damage

酸中毒增强对缺血性神经元损伤的机制

• 批准号: 10670610
• 负责人: KATSURA Kenichiro
• 金额: $ 1.98万
• 依托单位: Nippon Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670610/
• 关键词: Hyperglycemia; Acidosis; Cerebral ischemia; Apoptosis; Protein kinase C; calcium; calmodulin-dependent protein kinase II

Acidification is reported to be able to activate protein phosphorylation, protein synthesis and immediate-early-gene transcription. Our aim is to study the changes in subcellular redistributions of protein kinases C during complete ischemia, changing intraischemic acidotic levels by either injecting glucose (Hyperglycemic, HG) or adding CO2 (Hypercapnic, HC). The translocation of PKC from the cytosolic fraction to particulate fraction was enhanced under ischemia with severe acidosis. Overactivation (the enhanced traslocation) of the enzyme seems to be harmful to the neuronal survival after ischemia (Katsura et al. Brain Research 1999).The PKC translocation was significantly increased in the goups with enhanced acidosis. These results raise questions whether the enhanced acidosis affects the lipid metabloism, especially the release of free fatty acids (FFAs) and diacylglycerides (DAGs). The parietal cortex was chosen since the ischemic damage was significantly aggravated by both HG and HC ; besides, we know the change of pH during ischemia. Countrary to our expectations, the FFA and DAG contents were less in the animals with superimposed acidosis. Thus, animals with enhanced acidosis showed significantly decreased levels of DAGs at 10 min when the PKC translocation is significantly enhanced. The reasons are still to be studied, however, the massive influx of calcium upon cellular deporalization and liberation of various FFAs may decrease the necessity and dependence of DAGs for PKC translocation (paper in preparation).

据报道，酸化能够激活蛋白质磷酸化、蛋白质合成和即时早期基因转录。我们的目的是研究完全缺血时蛋白激酶C亚细胞再分布的变化，通过注射葡萄糖（高血糖，HG）或添加二氧化碳（高碳酸，HC）改变缺血内酸中毒水平。在缺血伴严重酸中毒的情况下，PKC从胞质部分向颗粒部分的易位增强。该酶的过度激活（增强的转运）似乎对缺血后的神经元存活有害（Katsura等）。大脑研究1999)。酸中毒加重组PKC易位明显增加。这些结果提出了酸中毒是否会影响脂质代谢，特别是游离脂肪酸（FFAs）和二酰基甘油酯（dag）的释放的问题。由于HG和HC均显著加重了脑缺血损伤，因此选择顶叶皮质；此外，我们还知道缺血时pH值的变化。与我们的预期相反，叠加性酸中毒动物的FFA和DAG含量较低。因此，当PKC易位显著增强时，酸中毒增强的动物在10分钟时dag水平显著降低。其原因仍有待研究，然而，在细胞脱离和各种游离脂肪酸的释放过程中，钙的大量涌入可能会降低PKC易位中dag的必要性和依赖性（论文正在准备中）。

项目成果

"高血糖の脳虚血後のエネルギー代謝および細胞内pHに及ぼす影響"Brain Hypoxia. 12. 83-91 (1998)

“脑缺血后高血糖对能量代谢和细胞内 pH 值的影响”Brain Hypoxia。12. 83-91 (1998)

桂 研一郎: "Acidosis enhances translocation of protein kinase C but not Ca2+/calmodulin-dependent protein kinase II to cell membranes during complete cerebral ischemia"Brain Research. 849. 119-127 (1999)

Kenichiro Katsura：“在完全脑缺血期间，酸中毒会增强蛋白激酶 C 的易位，但不会增强 Ca2+/钙调蛋白依赖性蛋白激酶 II 向细胞膜的易位”，《脑研究》，849. 119-127 (1999)。

桂研一郎 他: "Acidosis enhances translocation of protein kinase C but not Ca2+/calmodulin-dependent protein kinase II to cell membranes during complete cerebral ischemia"Brain Research. 849. 119-127 (1999)

Kenichiro Katsura 等人：“在完全脑缺血期间，酸中毒会增强蛋白激酶 C 的易位，但不会增强 Ca2+/钙调蛋白依赖性蛋白激酶 II 向细胞膜的易位”，《大脑研究》849. 119-127 (1999)。

Katsura et al.: "Acidosis enhances translocation of protein kinase C but not Ca2+/calmodulin-dependent protein kinase II to cell membranes during complete cerebral ischemia"Brain Research. 849. 119-127 (1999)

Katsura 等人：“在完全脑缺血期间，酸中毒会增强蛋白激酶 C 向细胞膜的易位，但不会增强 Ca2 /钙调蛋白依赖性蛋白激酶 II 向细胞膜的易位”。

Katsura and Siesjo: ""Acid-Base Metabolism in Ischemia" PH and Brain Function"Kai Kaila and Bruce R. Ransom.

Katsura 和 Siesjo：“缺血中的酸碱代谢”PH 和脑功能”Kai Kaila 和 Bruce R. Ransom。