D-β-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease
D-β-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease
复制标题
DOI：
10.1073/pnas.97.10.5440
复制
发表时间：
2000-05-09
影响因子：
11.1
通讯作者：
Veech, RL
中科院分区：
文献类型：
--
作者：
Kashiwaya, Y;Takeshima, T;Veech, RL
海洛因类似物1-甲基-4-苯基吡啶，MPP+，在体外和体内，通过抑制线粒体NADH脱氢酶多酶复合物，产生多巴胺能质黑质细胞死亡，产生与帕金森病难以区分的综合征。同样，淀粉样蛋白a β(1-42)片段对海马细胞是致命的，产生阿尔茨海默病特征的近期记忆缺陷。本研究表明，添加4mm d - β -羟基丁酸可保护培养的中脑神经元免受MPP+毒性和海马神经元免受A β(1-42)毒性。我们之前在心脏的工作表明，酮体，正常的代谢物，可以纠正线粒体能量产生的缺陷。酮体在培养中保护神经元的能力表明，线粒体能量产生的缺陷有助于这两种脑部疾病的病理生理。这些发现进一步表明，酮体可能在这些最常见的人类神经退行性疾病中发挥治疗作用。
The heroin analogue 1-methyl-4-phenylpyridinium, MPP+, both in vitro and in vivo, produces death of dopaminergic substantia nigral cells by inhibiting the mitochondrial NADH dehydrogenase multienzyme complex, producing a syndrome indistinguishable from Parkinson's disease. Similarly, a fragment of amyloid protein, A beta(1-42) is lethal to hippocampal cells, producing recent memory deficits characteristic of Alzheimer's disease. Here we show that addition of 4 mM D-beta-hydroxybutyrate protected cultured mesencephalic neurons from MPP+ toxicity and hippocampal neurons from A beta(1-42) toxicity. Our previous work in heart showed that ketone bodies, normal metabolites, can correct defects in mitochondrial energy generation. The ability of ketone bodies to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases. These findings further suggest that ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.