2001 Fiscal Year Final Research Report Summary
Analysis of mechanisms of reperfusion injury after cerebral ischemia
| Project/Area Number |
11670639
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Keio University |
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Principal Investigator |
TANAKA Kortaro Keio University, School of Medicine, Associate Professor, 医学部, 専任講師 (90129528)
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| Co-Investigator(Kenkyū-buntansha) |
DEMBO Tomohisa Keio University, School of Medicine, Instructor, 医学部, 助手 (50306700)
SUZUKI Shigeaki Keio University, School of Medicine, Instructor, 医学部, 助手 (50276242)
NOGAWA Shigeru Keio University, School of Medicine, Instructor, 医学部, 助手 (50208310)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Cerebral ischemia / Cerebral infarction / Reperfusion injury / cyclic AMP / Signal transduction / Transcription factor / Oligodendrocyte / CREB |
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| Research Abstract |
Phosphorylation of cyclic AMP response element binding protein (CREB) was examined immunohistochemically in the corpus callosum of the rat brain at various time points after 90-min focal cerebral ischemia. Focal ischemia was induced by occlusion of the middle cerebral artery (MCA) using the intraluminal suture method. The sham animals showed that numerous oligodendrocytes (OLGs) constitutively express unphosphorylated CREB. Local cerebral blood flow (1GBF) measured by the ^<14>C-iodoantipyrine method was reduced from 44.2±15.4 (ml/100 g/min) to 18.4±3.8 and from 53.9±14.4 to 4.8±4.5 in the medial and the lateral regions of the corpus callosum, respectively, during MCA occlusion. After release of the MCA occlusion, 1CBF recovered to the control level in each region. The medial region of the corpus callosum showed a marked increase in phosphorylated CREB-positive OLGs at 3.5 hours of recirculation, and it remained increased until 2 weeks of recirculation as it gradually declined. The activation of CREB phosphorylation in the OLGs was accompanied by expression of anti-apoptotic protein bcl-2, normal staining with cresyl violet, and negative TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate, nick-end labeling) staining. Myelination detected by immunostaining with anti-myelin basic protein (MBP) antibody and antimyelin associated glycoprotein (MAG) antibody remained normal in the medial region of the corpus callosum. The lateral region of the corpus callosum showed a significant but only transient increase in phosphorylated CREB-positive OLGs at 3.5 hours of recirculation, which was followed by a rapid decrease during the subsequent recirculation period. Expression of bcl-2 was suppressed in this region, and demyelination became apparent. These findings suggest that signal transduction via CREB phosphorylation may be closely associated with survival of OLGs and maintenance of myelination in the corpus callosum after cerebral ischemia.
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