Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation
Neuroprotection and neuronal dysfunction upon repetitive inhibition of oxidative phosphorylation
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DOI：
10.1016/s0014-4886(03)00127-4
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发表时间：
2003-10-01
影响因子：
5.3
通讯作者：
Riepe, MW
中科院分区：
文献类型：
--
作者：
Hellweg, R;von Arnim, CAF;Riepe, MW
氧化磷酸化的重复抑制是一种已建立的神经变性模型。相比之下，单一的温和治疗可以神经保护-化学预处理。因此，氧化磷酸化的重复化学抑制可能是研究细胞缺氧耐受性的恶化和改善以及随后在同一模型中细胞反应的差异调节的工具。我们研究了小鼠海马功能后，重复腹腔注射3-硝基丙酸（3-NP; 20毫克/公斤体重），线粒体复合物II的抑制剂。用3-NP重复体内处理2天的间隔，群体峰电位振幅的产后恢复低于对照。相反，即使在以4天间隔用3-NP进行9次体内处理后，也观察到群体尖峰幅度几乎完全恢复。通过ELISA评估的神经生长因子（NGF）和β-淀粉样前体蛋白（APP）mRNA的表达在9次治疗后以2天的间隔增加，但在4天的间隔保持在对照水平。与此相反，脑源性神经营养因子（BDNF）的ELISA评估增加与后者的治疗。腺苷-A1和腺苷-A3受体以及内皮和神经元型一氧化氮合酶的mRNA表达在两个给药间隔均保持在对照水平。我们的结论是，轻度，亚临床重复抑制氧化磷酸化之间的时间间隔决定海马神经元损伤和完整性和调制不同的NGF和BDNF。因此，在短时间间隔重复抑制氧化磷酸化后，缺氧耐受性降低和APP表达增加可能引发恶性循环，并成为脑缺氧和神经退行性疾病中神经元功能障碍的辅助因子。(C)2003 Elsevier Science（美国）。All rights reserved.
Repetitive inhibition of oxidative phosphorylation is an established model of neurodegeneration. In contrast, a single mild treatment can be neuroprotective- chemical preconditioning. Repetitive chemical inhibition of oxidative phosphorylation may thus be a tool to study deterioration and improvement of cellular hypoxic tolerance and subsequent differential regulation of cellular responses in the same model. We investigated murine hippocampal function upon repetitive intraperitoneal injections of 3-nitropropionate (3-NP; 20 mg/kg body weight), an inhibitor of mitochondrial complex II. With a 2-day interval of repetitive in vivo treatment with 3-NP, posthypoxic recovery of population spike amplitude was below control. In contrast, even after nine in vivo treatments with 3-NP at 4-day intervals, an almost complete recovery of population spike amplitude was observed. Nerve growth factor (NGF) as assessed by ELISA and expression of beta-amyloid precursor protein (APP) mRNA increased upon nine treatments at 2-day intervals, but remained at control levels with 4-day intervals. In contrast, brain-derived neurotrophic factor (BDNF) as assessed by ELISA increased with the latter treatment. Expression of mRNA for adenosine-A1 and -A3 receptors and endothelial and neuronal nitric oxide synthase remained at control level for both treatment intervals. We conclude that the time interval between mild, subclinical repetitive inhibition of oxidative phosphorylation determines hippocampal neuronal impairment and integrity and modulates NGF and BDNF differently. Decreased hypoxic tolerance and increased APP expression upon repetitive inhibition of oxidative phosphorylation at short time intervals may thus trigger a vicious cycle and be a cofactor for neuronal dysfunction in cerebral hypoxia and neurodegenerative diseases. (C) 2003 Elsevier Science (USA). All rights reserved.