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Age-Related Decline in Oligodendrogenesis Retards White Matter Repair in Mice
Miyamoto, Nobukazu,Pham, Loc-Duyen D.,Hayakawa, Kazuhide,Matsuzaki, Toshinori,Seo, Ji Hae,Magnain, Caroline,Ayata, Cenk,Kim, Kyu-Won,Boas, David,Lo, Eng H.,Arai, Ken American Heart Association, Inc. 2013 Stroke Vol.44 No.9
<P><B>Background and Purpose—</B></P><P>Aging is one of the major risk factors for white matter injury in cerebrovascular disease. However, the effects of age on the mechanisms of injury/repair in white matter remain to be fully elucidated. Here, we ask whether, compared with young brains, white matter regions in older brains may be more vulnerable in part because of decreased rates of compensatory oligodendrogenesis after injury.</P><P><B>Methods—</B></P><P>A mouse model of prolonged cerebral hypoperfusion was prepared by bilateral common carotid artery stenosis in 2-month and 8-month-old mice. Matching in vitro studies were performed by subjecting oligodendrocyte precursor cells to sublethal 7-day CoCl<SUB>2</SUB> treatment to induce chemical hypoxic stress.</P><P><B>Results—</B></P><P>Baseline myelin density in the corpus callosum was similar in 2-month and 8-month-old mice. But after induction of prolonged cerebral hypoperfusion, older mice showed more severe white matter injury together with worse deficits in working memory. The numbers of newborn oligodendrocytes and their precursors were increased by cerebral hypoperfusion in young mice, whereas these endogenous responses were significantly dampened in older mice. Defects in cyclic AMP response element-binding protein signaling may be involved because activating cyclic AMP response element-binding protein with the type-III phosphodiesterase inhibitor cilostazol in older mice restored the differentiation of oligodendrocyte precursor cells, alleviated myelin loss, and improved cognitive dysfunction during cerebral hypoperfusion. Cell culture systems confirmed that cilostazol promoted the differentiation of oligodendrocyte precursor cells.</P><P><B>Conclusions—</B></P><P>An age-related decline in cyclic AMP response element-binding protein–mediated oligodendrogenesis may compromise endogenous white matter repair mechanisms, and therefore, drugs that activate cyclic AMP response element-binding protein signaling provide a potential therapeutic approach for treating white matter injury in aging brains.</P>
Miyamoto, Tomofumi,Yamamoto, Atsushi,Sakai, Maki,Tanaka, Hiroyuki,Shoyama, Yukihiro,Higuchi, Ryuichi The Korean Society for Marine Biotechnology 2006 한국해양바이오학회지 Vol.1 No.4
In this study, we establish a thin-layer chromatography (TLC) immunostaining method for detecting starfish gangliosides. A new monoclonal antibody (MAb) against AG-2, the major gangliosides molecular species of Acanthaster planci, was produced by fusing hybridoma with splenocytes immunized to liposomal AG-2. BALB/c male mice were injected with liposomal AG-2 antigen, and immunized. Their splenocytos were isolated and fused with hypoxanthine-aminopterine-thimidine (HAT)-sensitive mouse myeloma cells. Hybridomas producing MAb reactive to AG-2 were cloned using the limited dilution method. Established hybridomas were cultured in eRDF medium. Crude MAb produced from clone 8D4 was purified with a magnesium pyrophosphate column. Enzyme immunoassay and TLC immunostaining of AG-2 were performed using the purified MAb. Structurally related gangliosides did not cross-react with anti-AG-2 antibodies. The detection limit of TLC immunostaining was 50 ng of AG-2. The newly established immunostaining method was further developed for detecting AG-2 distribution and qualitative analysis in tissues and/or organs. Our results show that the majority of AG-2 is present in the stomach of male A. planci, while AG-2 is distributed not only in the stomach but also in the the pyloric caeca of female A. planci.
Oxidative Stress Interferes With White Matter Renewal After Prolonged Cerebral Hypoperfusion in Mice
Miyamoto, Nobukazu,Maki, Takakuni,Pham, Loc-Duyen D.,Hayakawa, Kazuhide,Seo, Ji Hae,Mandeville, Emiri T.,Mandeville, Joseph B.,Kim, Kyu-Won,Lo, Eng H.,Arai, Ken American Heart Association, Inc. 2013 Stroke Vol.44 No.12
<P><B>Background and Purpose—</B></P><P>White matter injury caused by cerebral hypoperfusion may contribute to the pathophysiology of vascular dementia and stroke, but the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that oxidative stress interferes with endogenous white matter repair by disrupting renewal processes mediated by oligodendrocyte precursor cells (OPCs).</P><P><B>Methods—</B></P><P>In vitro, primary rat OPCs were exposed to sublethal CoCl<SUB>2</SUB> for 7 days to induce prolonged chemical hypoxic stress. Then, OPC proliferation/differentiation was assessed. In vivo, prolonged cerebral hypoperfusion was induced by bilateral common carotid artery stenosis in mice. Then, reactive oxygen species production, myelin density, oligodendrocyte versus OPC counts, and cognitive function were evaluated. To block oxidative stress, OPCs and mice were treated with the radical scavenger edaravone.</P><P><B>Results—</B></P><P>Prolonged chemical hypoxic stress suppressed OPC differentiation in vitro. Radical scavenging with edaravone ameliorated these effects. After 28 days of cerebral hypoperfusion in vivo, reactive oxygen species levels were increased in damaged white matter, along with the suppression of OPC-to-oligodendrocyte differentiation and loss of myelin staining. Concomitantly, mice showed functional deficits in working memory. Radical scavenging with edaravone rescued OPC differentiation, ameliorated myelin loss, and restored working memory function.</P><P><B>Conclusions—</B></P><P>Our proof-of-concept study demonstrates that after prolonged cerebral hypoperfusion, oxidative stress interferes with white matter repair by disrupting OPC renewal mechanisms. Radical scavengers may provide a potential therapeutic approach for white matter injury in vascular dementia and stroke.</P>
Miyamoto, Yoichi,Umeki, Hiroyuki,Ohsawa, Hideaki,Naito, Morimasa,Nakano, Katsushi,Makino, Hitoshi,Shimizu, Kazuhiko,Seo, Toshihiro Korean Nuclear Society 2006 Nuclear Engineering and Technology Vol.38 No.6
Ensuring sufficient supplies of clean, economic and acceptable energy is a critical global challenge for the 21st century. There seems little alternative to a greatly expanded role for nuclear power, but implementation of this option will depend on ensuring that all resulting wastes can be disposed of safely. Although there is a consensus on the fundamental feasibility of such disposal by experts in the field, concepts have to be developed to make them more practical to implement and, in particular, more acceptable to key stakeholders. By considering global trends and using illustrative examples from Japan, key areas for future R&D are identified and potential areas where the synergies of international collaboration would be beneficial are highlighted.