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Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat

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Abstract

Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52–64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter. Using the TUNEL method, the number of cells showing DNA fragmentation increased three- to eightfold between 3 and 30 days post-surgery compared to sham-operated animals. Double labeling with TUNEL and immunohistochemistry for markers of either astroglia or oligodendroglia showed that DNA fragmentation occurred in both of these glia. Messenger RNA for caspase-3 increased approximately twofold versus the sham-operated rats between 1 and 30 days post-surgery. Immunohistochemistry revealed up-regulation of caspase-3 in the oligodendroglia of the white matter, and also in the astroglia and neurons of the gray matter. Molecules involved in apoptotic signaling such as TNF-α and Bax were also up-regulated in glial cells. These results indicate that chronic cerebral hypoperfusion induces white matter degeneration in association with DNA fragmentation in oligodendroglia.

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Acknowledgements

This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Japanese Ministry of Education, Science and Culture (H.T). We are indebted to Miss. Hitomi Nakabayashi for excellent technical assistance.

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Authors and Affiliations

  1. Department of Neurology, Faculty of Medicine, Kyoto University, Sakyo-ku, 606-8507, Kyoto

    H. Tomimoto, M. Ihara, H. Wakita, R. Ohtani, J.-X. Lin, I. Akiguchi & H. Shibasaki

  2. Department of Molecular Oncology, Faculty of Medicine, Kyoto University, Sakyo-ku, 606, Kyoto, Japan

    M. Kinoshita

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  1. H. Tomimoto
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  2. M. Ihara
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Correspondence to H. Tomimoto.

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Tomimoto, H., Ihara, M., Wakita, H. et al. Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat. Acta Neuropathol 106, 527–534 (2003). https://doi.org/10.1007/s00401-003-0749-3

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  • DOI: https://doi.org/10.1007/s00401-003-0749-3

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