Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainate injury.
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 microM) 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.
He
Xin
X
Department of Anatomy, National University of Singapore, Singapore, and New England Biomedical Research Center and VA Connecticut Healthcare System, Newington, CT, USA.
Jenner
Andrew M
AM
Ong
Wei-Yi
WY
Farooqui
Akhlaq A
AA
Patel
Shutish C
SC
D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D004791:Enzyme Inhibitors / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006888:Hydroxycholesterols / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D007653:Ketocholesterols / Q000378:metabolism; D008148:Lovastatin / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013250:Steroid Hydroxylases / Q000378:metabolism
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D018696:Neuroprotective Agents; C044563:24-hydroxycholesterol; D002784:Cholesterol; D008148:Lovastatin; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; C003001:7-ketocholesterol; D007608:Kainic Acid