Upregulation of ceramide and its regulating mechanism in a rat model of chronic cerebral ischemia.
Ceramide is a key mediator of apoptosis, and is involved in the cellular stress response. We examined the alterations in the ceramide levels and their synthetic/degradative pathway in a rat model of chronic cerebral ischemia, in which ischemic white matter (WM) lesions occur in association with oligodendroglial cell apoptosis. Chronic cerebral ischemia was induced by clipping both common carotid arteries in male Wistar rats. After predetermined periods of 1, 3, 7 and 14 days, the animals were subjected to immunohistochemical and biochemical investigations for ceramide in the region containing the frontal cortex and corpus callosum (region 1), and the region containing the internal capsule and globus pallidus (region 2). After 14 days, the myelin was degraded in the corpus callosum, internal capsule and the optic tract in Klüver-Barrera staining. There was a significant increase in the ceramide level and the activity of its synthetic enzyme, acidic sphingomyelinase (SMase), whereas its degrading enzyme, glucosylceramide synthase (GCS), was downregulated in both regions 1 and 2 as compared to the sham-operated rats. Simultaneously, ceramide immunoreactive glia increased in number in the corpus callosum and the internal capsule after 3, 7 and 14 days. Double labeling for ceramide with glial fibrillary acidic protein but not with leukocyte common antigen indicated the astroglial nature of these glia. These findings indicate that chronic cerebral ischemia induces an increased ceramide level in astroglia as a result of downregulation of GCS and an upregulation of ASMase activity.
Ohtani
Ryo
R
Department of Neurology, Kyoto University Graduate School of Medicine, Sakyo, Kyoto 606-8507, Japan. ryokyoto@kuhp.kyoto-u.ac.jp
Tomimoto
Hidekazu
H
Kondo
Tadakazu
T
Wakita
Hideaki
H
Akiguchi
Ichiro
I
Shibasaki
Hiroshi
H
Okazaki
Toshiro
T
D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism*; D002518:Ceramides / Q000032:analysis / Q000096:biosynthesis*; D002908:Chronic Disease; D004195:Disease Models, Animal; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000502:physiology*
D002518:Ceramides