脱髄性疾患 Demyelinating Disorders
P2-1-187 mPGES-1は多発性硬化症のマウスモデルにおいて脊髄の炎症と脱髄を増悪させる Microsomal prostaglandin E synthase-1 aggravates inflammation and demyelination in a mouse model of multiple sclerosis ○竹宮孝子1, 竹内千仙2, 山形要人3 ○Takako Takemiya1, Chisen Takeuchi2, Kanato Yamagata3 東京女子医大・総合研究所・研究部1, 都北療育医療センター・神経内科2, 都医学研・神経可塑性3 Med Res Insti, Tokyo Women's Med Univ, Tokyo1, Kita Med and Rehabili center for Disabled, Tokyo2, Neural Plasticity Proj, Tokyo Metro Insti of Med Sci3 Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme required for prostaglandin E2 (PGE2) biosynthesis. In this study, we examined the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We induced EAE with myelin oligodendrocyte glycoprotein35-55 peptide in mPGES-1-deficient (mPGES-1-/-) and wild-type (WT) mice. First, we examined the histopathology in the early and late phases of EAE progression. Next, we measured the concentration of PGE2 in the spinal cord and investigated the expression of mPGES-1 using immunohistochemistry. We demonstrate that WT mice showed extensive inflammation and demyelination, whereas mPGES-1-/- mice exhibited significantly smaller and more localized changes in the perivascular area. Moreover, the inflammatory cells were mostly macrophages and perivascular T lymphocytes. The density of infiltrating cells was very low and extremely localized in the spinal cord of mPGES-1-/- mice compared with WT mice. In particular, parenchymal T cell infiltration was not observed in mPGES-1-/- mice. The T cells expressed two types of chemokine receptors, CXCR3 and CCR6. CXCR3 is preferentially expressed on Th1 cells, and CCR6 is preferentially expressed on Th17 cells, therefore, CXCR3+CCR6+CD4+ T cells are called Th1Th17 cells. In addition, the mPGES-1 protein was induced in vascular endothelial cells and microglia around inflammatory foci, and PGE2 production was increased in WT mice but not mPGES-1-/- mice. These results suggest that central PGE2 derived from non-neuronal mPGES-1 aggravates the disruption of the vessel structure, leading to the spread of inflammation and local demyelination in the spinal cord. The inhibition of mPGES-1 may be useful for the treatment of human MS.	P2-1-188 バゾプレシン受容体拮抗薬による慢性低Na血症の急速補正は浸透圧性脱髄症候群を惹起する危険性がある Overly rapid correction of severe hyponatremia with vasopressin receptor antagonists poses a risk of inducing osmotic demyelination syndrome ○高木博史1, 椙村益久1, 泉田久和1, 藤沢治樹1, 竹内誠治1, 落合啓史1, 清田篤志1, 須賀英隆1, 大磯ユタカ1 ○Hiroshi Takagi1, Yoshihisa Sugimura1, Hisakazu Izumida1, Haruki Fujisawa1, Seiji Takeuchi1, Hiroshi Ochiai1, Atsushi Kiyota1, Hidetaka Suga1, Yutaka Oiso1 名古屋大学大学院　医学系研究科　糖尿病・内分泌内科学1 Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Aichi1 Osmotic demyelination syndrome (ODS) is a central demyelinating disease commonly associated with an overly rapid correction of chronic hyponatremia. Recent days, vasopressin receptor antagonists (VAs) are beginning to be applied to the treatment of hyponatremia. It is not clear whether the treatment with VAs for severe hyponatremia is associated with an increased risk of ODS. Therefore, we investigated whether rapid correction of hyponatremia with tolvaptan has a risk of inducing ODS in SIADH model rats. Hyponatremia was induced by liquid diet feeding and subcutaneous desmopressin infusion using osmotic pumps. 7 days later, hyponatremia (approximately 105mEq/l) was corrected by the following ways; (1) administration of hypertonic saline (HS), (2) tolvaptan of 1mg/kg/day (T1), (3) 10mg/kg/day (T10), or (4) removal of osmotic pumps (PO). We also evaluated a preventive effect of minocycline. The serum sodium levels were increased approximately by 30 mEq/l in 24 hours and there were no significant differences in serum sodium levels among the groups. 5 days after the correction, the incidence of neurological impairment was 75%, 46%, 60%, and 88% in HS, T1, T10, and PO group, respectively. There was a significant difference in the severity of neurological impairment between T1 and other groups. Immunohistochemical analysis confirmed demyelinative lesions and the accumulation of microglia in all groups. In some brains of T10 and PO groups, demyelinative lesions accompanied hemorrhage, which rarely happened in HS group. This suggests rapid blockage of vasopressin function has different effects on the central nervous system from HS administration. Minocycline treatment prevented ODS in T1 group by inhibition of microglial activation. In conclusion, our results suggest that overly rapid correction of severe hyponatremia with VAs associated with water diuresis poses a risk of inducing ODS and that minocycline can prevent ODS induced by VAs.
P2-1-189 脱髄モデルマウスにおける髄鞘と軸索の形態学的解析 CNS myelin and axon morphology in murine models of CNS demyelinating disease ○板東良雄1, 野村太一1, 村上公一1, 田中達英1, 暮地本宙己2, 渡部剛2, 吉田成孝1 ○Yoshio Bando1, Taichi Nomura1, Koichi Murakami1, Tatsuhide Tanaka1, Hiroki Bochimoto2, Tsuyoshi Watanabe2, Shigetaka Yoshida1 旭川医科大学　解剖学講座　機能形態学分野1, 旭川医科大学　解剖学講座　顕微解剖学分野2 Dept Functional Anat & Neurosci., Asahikawa Medical University, Asahikawa1, Dept of Microscopic Anat & Cell biol., Asahikawa Medical University, Asahikawa2 Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Demyelination and axonal damage are responsible for neurological deficits in MS. However, the mechanisms of demyelination and axonal damage are not fully understood. To address this issue, myelin basic protein-deficient shiverer mice and mice with experimental autoimmune encephalomyelitis (EAE) were examined how the morphological differences of myelin and the axon were induced by dysmyelination and demyelination. Here we used osmium-maceration scanning electron microscopic (SEM) analysis.Osmium-maceration SEM displayed clear variations in the ultrastructural abnormalities of myelin structure and axonal organelles in the white matter of the EAE spinal cord. For example, myelin detachment and excess myelin formation were observed as typical abnormalities of myelin during demyelination in EAE. Importantly, compact myelin was well preserved even though in these situations. SEM images also showed the morphological changes of axonal intracellular organelles during demyelination. Enriched mitochondria and well-developed sER-like structures were observed in the axons of the EAE spinal cord. These observations were also found in the axon of shiverer mice. Taken together, these results indicate that there is a close relationship between myelin and axon morphology during demyelination.	P2-1-190 多発性硬化症における新規バイオマーカーLOTUS LOTUS as a new biomarker for Multiple Sclerosis ○高橋慶太1,2, 栗原祐司1, 五嶋良郎3, 鈴木ゆめ2, 田中章景2, 竹居光太郎1 ○Keita Takahashi1,2, Yuji Kurihara1, Yoshio Goshima3, Yume Suzuki2, Fumiaki Tanaka2, Kohtaro Takei1 横浜市立大学医学群生体システム医科学系生命医科学部門1, 横浜市立大学大学院　医学研究科　神経内科学教室2, 横浜市立大学大学院　医学研究科　分子薬理神経生物学教室3 Div. of Med. Life Sci., Sch. of Med., Yokohama City Univ., Yokohama, Japan1, Dept. of Neurol., Yokohama City Univ. Grad. Sch. of Med. Yokohama, Japan2, Dept. of Mol. Pharmacol. and Neurobiol., Yokohama City Univ. Grad. Sch. of Med. Yokohama, Japan3 Acute onset including relapse of Multiple Sclerosis (MS) is usually judged using magnetic resonance imaging (MRI) and biomarkers such as oligoclonal bands in cerebrospinal fluid (CSF). However, it is well known that these examinations are not sensitive nor sufficient for correct judgment of the disease onset and relapse of MS. Therefore, a new biomarker that leads to the early and accurate diagnosis is required. It has been recently reported that Nogo-A and Nogo receptor-1 (Ngr-1) were involved in inhibition of axonal regrowth in MS. As we previously reported, lateral olfactory tract usher substance (LOTUS) is an endogenous NgR-1 antagonist and we speculate that it might be useful for treatment and/or diagnosis of MS. Accordingly we first examined expression of LOTUS in CSF from patients with MS comparing with those from patients with control neurological diseases and normal control subjects by western blot. LOTUS concentration in CSF from patients in relapsing stage of MS was significantly decreased, while that in patients in remitting stage remained normal level. Neuromyelitis optica (NMO) patients showed similar decrease of LOTUS as observed in MS patients. These findings suggest that LOTUS in CSF could be a new biomarker for MS/NMO in relapsing stage as well as in first onset stage in terms of evaluation of MS activity.
P2-1-191 脱髄、神経変性、虚血過程での神経細胞およびグリア細胞におけるStearoyl-CoA desaturaseアイソフォームの発現変化 Expression changes of Stearoyl-CoA desaturase isoforms in neuronal and glial cells during the processes of demyelination, neurodegeneration and ischemia ○中島健太郎1, 加藤千惠子1, 宋時栄1 ○Kentaro Nakashima1, Chieko Kato1, Si-Young Song1 徳島文理大学　神経科学研究所1 Inst. Neurosci., Tokushima Bunri Univ., Kagawa, Japan1 Stearoyl-CoA desaturase (SCD) is an enzyme involved in the synthesis of monounsaturated fatty acid such as oleic acid from saturated fatty acid such as stearic acid. Two isoforms (SCD1 and SCD5) and four isoforms (SCD1-4) were identified in human and mice, respectively. It has been reported that oleic acid synthesized by SCD constitutes myelin sheath and induces the expression of MAP2 in neurons and its transition from soma to dendrites, and that oleic acid works as a kind of neurotrophic factor in the recovery processes from neuronal injury. Recently it has been reported that the expression of SCD is increased in patients with Alzheimer's disease. These data suggest that monounsaturated fatty acid metabolism is involved in differentiation and repair responses of the brain. However, cell identity to express SCD and its subtype during these processes are not fully understood. RT-PCR revealed that SCD1 and SCD2 were mainly expressed in mice brain and in situ hybridization using specific probes for SCD1 and SCD2 detected mainly SCD2 in neurons and oligodendroglia. Immunohistochemical analyses using an antibody for SCD1 and SCD2 indicated that increased SCD-immunoreactivity in astrocytes and neurons at a peak of demyelination induced by feeding ICR mice with cuprizone containing diet for 6 weeks. Similar increased SCD-immunoreactivity in neurons was observed in a central part of stratum radiatum of hippocampal CA1 region of 3 x Tg Alzheimer model mice at postnatal day 200 as compared with control mice. Increased SCD-immunoreactivity in astrocytes was also detected in Mongolian gerbil brain at recovery phase from transient ischemia by clipping of hemilateral common carotid artery. These data suggest that SCD is involved in neuronal and glial responses to various brain injury including demyelination, neurodegeneration and ischemia. Quantitative PCR combined with laser capture microdissection was used to identify SCD subtype expressed in these responses.

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