title: Ischemic damage and subsequent proliferation of oligodendrocytes in focal cerebral ischemia.
abstract: In order to achieve a better understanding of the pathophysiology of ischemic white matter lesions, oligodendrocytic degeneration and subsequent proliferation were examined in the mouse model of middle cerebral artery occlusion. In situ hybridization histochemistry for proteolipid protein messenger RNA was employed as a sensitive and specific marker of oligodendrocytes, and immunohistochemistry for myelin basic protein was used as a compact myelin marker. Immunohistochemistry for microtubule-associated protein 2 and albumin was employed to monitor neuronal degeneration and the breakdown of the blood brain barrier, respectively. In the ischemic core of the caudoputamen, the immunoreactivity for microtubule-associated protein 2 disappeared and massive albumin extravasation occurred several hours after vessel occlusion, while proteolipid protein messenger RNA signals remained relatively strong at this time. The messenger RNA signals began to attenuate 12 h after ischemia and were hardly detectable 24 h after ischemia in the whole ischemic lesion. In situ end-labeling of fragmented DNA showed some cells with proteolipid protein messenger RNAs to have DNA fragmentation at this period. In contrast to proteolipid protein messenger RNA signals, the immunoreactivity for myelin basic protein was detected as long as five days after ischemia. An apparent increase in the cells possessing strong proteolipid protein messenger RNA signals was found five days after ischemia, mainly in the corpus callosum and the cortex bordering the infarcted areas. A double simultaneous procedure with in situ hybridization for proteolipid protein messenger RNA and immunohistochemistry for glial fibrillary acid protein or lectin histochemistry for macrophages/microglia showed proliferating oligodendrocytes to be co-localized with reactive astrocytes and macrophages/microglia. These findings show that oligodendrocytic damage occurred following ischemic neuronal damage and the breakdown of the blood brain barrier, but preceded the breakdown of myelin proteins in the ischemic lesion, that an apoptosis-like process was involved in ischemic oligodendrocytic death, and that surviving oligodendrocytes responded and proliferated in the outer border of the infarcted area.
authors.affiliation: First Department of Medicine, Osaka University Medical School, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mandai
authors.forename: M
authors.initials: M
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Kitagawa
authors.forename: K
authors.initials: K
authors.lastname: Matsushita
authors.forename: T
authors.initials: T
authors.lastname: Ohtsuki
authors.forename: T
authors.initials: T
authors.lastname: Mabuchi
authors.forename: D R
authors.initials: DR
authors.lastname: Colman
authors.forename: T
authors.initials: T
authors.lastname: Kamada
authors.forename: T
authors.initials: T
authors.lastname: Yanagihara
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D004676:Myelin Basic Protein / Q000096:biosynthesis; D018991:Myelin Proteolipid Protein / Q000096:biosynthesis; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012016:Reference Values; D015424:Reperfusion; D012709:Serum Albumin / Q000096:biosynthesis
chemical_list: D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012709:Serum Albumin