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Changes in Brain Cholesterol Metabolome After Excitotoxicity

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Abstract

Excitotoxicity due to excess stimulation of glutamate receptors in neurons is accompanied by increased Ca2+ influx, stimulation of Ca2+-dependent enzymes, ATP depletion, increase in lipid peroxidation products, and loss of glutathione. These changes resemble neurochemical alterations in acute neuronal injury (stroke, spinal cord injury, and traumatic brain injury) and chronic neurodegenerative diseases such as Alzheimer’s disease. Intracerebroventricular injection of the potent glutamate analog kainate in rats results in increased cholesterol concentration in the hippocampus at short to medium time intervals, i.e., 3 days–1 week post-injection, as detected by gas chromatography–mass spectrometry in the lesioned hippocampus. This is accompanied by an early increase in levels of cholesterol biosynthetic precursors and increases in both enzymatically derived oxysterols such as 24-hydroxycholesterol and cholesterol oxidation products (COPs) generated by reactive oxygen species, including cholesterol epoxides and 7-ketocholesterol. In contrast to COPs, no change in concentration of the neurosteroid pregnenolone was found after KA injury. Cholesterol and COPs significantly increase exocytosis in cultured PC12 cells and neurons, and both oxysterols and COPs are able to induce cytotoxic and apoptotic injuries in different cell types, including neurons. Together, the findings suggest that increased cholesterol and COPs after KA excitotoxicity could themselves lead to disturbed neuronal ion homeostasis, increased neurotransmitter release, and propagation of excitotoxicity.

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Acknowledgments

This work was supported by grants from the National Medical Research Council of Singapore (NMRC/EDG/0012/2007 and NMRC/EDG/0060/2009).

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Authors and Affiliations

  1. Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore

    Wei-Yi Ong & Ji-Hyun Kim

  2. Aging/Neurobiology Research Programme, National University of Singapore, Singapore, Singapore

    Wei-Yi Ong & Andrew M. Jenner

  3. Department of Anatomy, Beijing University of Chinese Medicine, Beijing, China

    Xin He

  4. School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore, Singapore

    Peng Chen

  5. Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH, USA

    Akhlaq A. Farooqui

  6. Department of Biochemistry, National University of Singapore, Singapore, 119260, Singapore

    Andrew M. Jenner

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  1. Wei-Yi Ong
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  2. Ji-Hyun Kim
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  3. Xin He
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  4. Peng Chen
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  5. Akhlaq A. Farooqui
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  6. Andrew M. Jenner
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Correspondence to Wei-Yi Ong or Andrew M. Jenner.

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Ong, WY., Kim, JH., He, X. et al. Changes in Brain Cholesterol Metabolome After Excitotoxicity. Mol Neurobiol 41, 299–313 (2010). https://doi.org/10.1007/s12035-010-8099-3

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  • DOI: https://doi.org/10.1007/s12035-010-8099-3

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