Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury.
Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury.
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DOI：
10.1186/1471-2202-11-51
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发表时间：
2010-04-23
期刊：
影响因子：
2.4
通讯作者：
Gharib B
中科院分区：
文献类型：
--
作者：
Cornille E;Abou-Hamdan M;Khrestchatisky M;Nieoullon A;de Reggi M;Gharib B
羟基丁酸酮体和乙酰乙酸酮体的施用已知对与脑病相关的代谢紊乱发挥保护作用。这表明，增强其内源性生产可能是一种合理的治疗方法。酮体是由脂肪酸β氧化产生的，这是一个涉及线粒体氧化还原酶超家族的过程，以脂肪酸-辅酶a硫酯为底物。在本报告中，重点是该过程的倒数第二步，即l- 3-羟基丁基辅酶a脱氢酶活性。我们测定了帕金森病MPTP小鼠模型中酶活性和循环酮体水平的变化。由于辅酶a的活性部分是泛氨酸，因此小鼠接受了天然形式的泛氨酸治疗。泛氨酸的优点是被认为是一种抗炎和降血脂剂，副作用很小。我们发现脱氢酶活性和循环酮体水平被神经毒素MPTP大大降低，而泛氨酸治疗克服了这些不良反应。泛氨酸防止多巴胺能神经元的丧失和运动障碍。体内和体外实验表明，这种保护作用与增强谷胱甘肽（GSH）的产生以及恢复呼吸链复合体I的活性和线粒体ATP水平有关。值得注意的是，pantethine治疗提高了mptp中毒小鼠的循环酮体水平，但在正常动物中没有。这些发现证明了增强内源性酮体产生的可行性，并为帕金森病以及其他神经退行性疾病提供了有希望的治疗方法。
The administration of the ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating ketone body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects. We found that dehydrogenase activity and circulating ketone body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH) production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating ketone body levels in MPTP-intoxicated mice, but not in normal animals. These finding demonstrate the feasibility of the enhancement of endogenous ketone body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders.
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影响因子：
2.5
作者：
Annepu, J;Ravindranath, V
通讯作者：
Ravindranath, V
影响因子：
4.2
作者：
Imamura, Keiko;Takeshima, Takao;Nakashima, Kenji
通讯作者：
Nakashima, Kenji
影响因子：
8.6
作者：
Klein, RC;de Jong, BM;Leenders, KL
通讯作者：
Leenders, KL
影响因子：
2.9
作者：
HARTMANN, D;PHILIPP, R;TROMMER, WE
通讯作者：
TROMMER, WE
DOI：
10.1016/j.bbrc.2007.10.188
发表时间：
2008-03-28
影响因子：
3.1
作者：
Filling, Charlotta;Keller, Brigitte;Oppermann, Udo
通讯作者：
Oppermann, Udo