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Lovastatin Modulates Increased Cholesterol and Oxysterol Levels and Has a Neuroprotective Effect on Rat Hippocampal Neurons After Kainate Injury
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Lovastatin Modulates Increased Cholesterol and Oxysterol Levels and Has a Neuroprotective Effect on Rat Hippocampal Neurons After Kainate Injury
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Journal Article
Lovastatin Modulates Increased Cholesterol and Oxysterol Levels and Has a Neuroprotective Effect on Rat Hippocampal Neurons After Kainate Injury
2006
Overview
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 μM) 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.
Publisher
American Association of Neuropathologists, Inc,Lippincott Williams & Wilkins,Oxford University Press
Subject
/ Anticholesteremic Agents - metabolism
/ Anticholesteremic Agents - pharmacology
/ Biological and medical sciences
/ Cell Survival - drug effects
/ Drug toxicity and drugs side effects treatment
/ Enzyme Inhibitors - metabolism
/ Excitatory Amino Acid Agonists - administration & dosage
/ Excitatory Amino Acid Agonists - metabolism
/ Excitatory Amino Acid Agonists - toxicity
/ Hydroxycholesterols - metabolism
/ Injuries of the nervous system and the skull. Diseases due to physical agents
/ Kainic Acid - administration & dosage
/ Ketocholesterols - metabolism
/ Neuroprotective Agents - metabolism
/ Neuroprotective Agents - pharmacology
/ Pharmacology. Drug treatments
/ Rats
/ Steroid Hydroxylases - metabolism
