Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainate injury
Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainate injury
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DOI：
10.1097/01.jnen.0000225906.82428.69
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发表时间：
2006-07-01
影响因子：
3.2
通讯作者：
Patel, Shutish C.
中科院分区：
文献类型：
--
作者：
He, Xin;Jenner, Andrew M.;Patel, Shutish C.
本研究旨在阐明脑渗透性他汀类药物（洛伐他汀）对兴奋性毒素海人酸诱导的神经元损伤后海马胆固醇和氧固醇水平的影响。红藻氨酸损伤后，在大鼠海马中观察到胆固醇和氧固醇生物合成酶（胆固醇24-羟化酶）的免疫标记增加。这是伴随着胆固醇，24-羟基胆固醇（胆固醇24-羟化酶的酶活性的产品），和7-酮胆固醇的变性海马匀浆中检测到的气相色谱/质谱水平的增加。与仅用红藻氨酸治疗的大鼠或器官切片相比，用红藻氨酸加洛伐他汀治疗的大鼠或器官切片的海马胆固醇、24-羟基胆固醇和7-酮胆固醇水平显著降低。洛伐他汀也调制海人藻酸盐治疗后，在体内和体外海马神经元的损失。在海马切片培养物中，发现红藻氨酸处理后体内检测到的24-羟基胆固醇水平（> 50 μ M）是神经毒性的。这些结果表明，脑渗透性他汀类药物，如洛伐他汀，可以通过限制发生神经变性的脑区域中的氧化固醇水平而具有神经保护作用。
This study was carried out to elucidate the effect of a brain-permeable statin (lovastatin) on cholesterol and oxysterol levels of the hippocampus after neuronal injury induced by the excitotoxin, kainic acid. Increased immunolabeling to cholesterol and the oxysterol biosynthetic enzyme, cholesterol 24-hydroxylase, was observed in the rat hippocampus after kainate lesions. This was accompanied by increased levels of cholesterol, 24-hydroxycholesterol (product of cholesterol 24-hydroxylase enzymatic activity), and 7-ketocholesterol in homogenates of the degenerating hippocampus as detected by gas chromatography/mass spectrometry. Hippocampi from rats or organotypic slices that had been treated with kainate plus lovastatin showed significantly lower levels of cholesterol, 24-hydroxycholesterol, and 7-ketocholesterol, compared with those that had been treated with kainate only. Lovastatin also modulated hippocampal neuronal loss after kainate treatment in vivo and in vitro. The level of 24-hydroxycholesterol detected in vivo after kainate treatment (> 50 mu M) was found to be neurotoxic in hippocampal slice cultures. These results suggest that brain-permeable statins such as lovastatin could have a neuroprotective effect by limiting the levels of oxysterol in brain areas undergoing neurodegeneration.