Monoclonal antibody against tumour necrosis factor alpha-associated leukoencephalopathy in rheumatoid arthritis

• Project/Area Number: 21790526
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Applied pharmacology
• Research Institution: Fukuoka University
• Principal Investigator: NISHIOKU Tsuyoshi Fukuoka University, 薬学部, 助教 (90435115)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 生物学的製剤 / 白質脳症 / 関節リウマチ / 血液脳関門 / 白質障害 / 免疫抑制 / アデノシン

Research Abstract

Rheumatoid arthritis (RA) is an autoimmune disease associated with chronic inflammation of the joints. RA has been shown to increase the morbidity of and mortality due to cardiovascular and cerebrovascular diseases. This study was aimed at evaluating a role of S 100A4 in the mediation of blood-brain barrier (BBB) dysfunction in CIA mice. Cerebrovascular permeability and serum levels of S 100A4 were increased in CIA mice. Increased S I00A4 levels in the serum are closely correlated with hyperpermeability of the cerebrovascular endothelium. S 100A4 increased paracellular permeability of the mouse brain capillary endothelial cells (MBECs). S100A4 reduced the expression of occludin, a tight junction protein in MBECs. These findings suggest that S100A4 increases paracellular permeability of MBECs by decreasing expression levels of occludin. The present study highlights a potential role for S 100A4 in BBB dysfunction underlying cerebrovascular diseases in patients with RA.

Research Products

• [Journal Article] Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood-brain barrier in mice. (2011)
  • Author(s): Yamauchi A, Dohgu S, Takata F, Watanabe T, Nishioku T, Matsumoto J, Ohkubo Y, Shuto H, Kataoka Y.
  • Journal Title: Life Sci. 88(11-12) Pages: 529-534
  • Peer Reviewed
• [Journal Article] Autocrine and paracrine up-regulation of blood-brain barrier function by plasminogen activator inhibitor-1. (2011)
  • Author(s): Dohgu S, Takata F, Matsumoto J, Oda M, Harada E, Watanabe T, Nishioku T, Shuto H, Yamauchi A, Kataoka Y.
  • Journal Title: Microvasc Res. 81(1) Pages: 103-107
  • Peer Reviewed
• [Journal Article] Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood-brain barrier in mice. (2011)
  • Author(s): Yamauchi A, Dohgu S, Takata F, Watanabe T, Nishioku T, Matsumoto J, Ohkubo Y, Shuto H, Kataoka Y.
  • Journal Title: Life Sciences Volume: 88(11-12) Pages: 529-34
  • Peer Reviewed
• [Journal Article] Disruption of the blood-brain barrier in collagen-induced arthritic mice. (2010)
  • Author(s): Nishioku T, Yamauchi A, Takata F, Watanabe T, Furusho K, Shuto H, Dohgu S, Kataoka Y.
  • Journal Title: Neurosci Lett. 482(3) Pages: 208-211
  • Peer Reviewed
• [Journal Article] Cyclosporin A induces hyperpermeability of the blood-brain barrier by inhibiting autocrine adrenomedullin-mediated up-regulation of endothelial barrier function. (2010)
  • Author(s): Dohgu S, Sumi N, Nishioku T, Takata F, Watanabe T, Naito M, Shuto H, Yamauchi A, Kataoka Y.
  • Journal Title: Eur J Pharmacol. 644(1-3) Pages: 5-9
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor-alpha mediates the blood-brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells. (2010)
  • Author(s): Nishioku T, Matsumoto J, Dohgu S, Sumi N, Miyao K, Takata F, Shuto H, Yamauchi A, Kataoka Y.
  • Journal Title: J Pharmacol Sci. 112(2) Pages: 251-254
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-activated microglia induce dysfunction of the blood-brain barrier in rat microvascular endothelial cells co-cultured with microglia. (2010)
  • Author(s): Sumi N, Nishioku T, Takata F, Matsumoto J, Watanabe T, Shuto H, Yamauchi A, Dohgu S, Kataoka Y.
  • Journal Title: Cell Mol Neurobiol. 30(2) Pages: 247-253
  • Peer Reviewed
• [Journal Article] Autocrine and paracrine up-regulation of blood-brain barrier function by plasminogen activator inhibitor-1. (2010)
  • Author(s): Dohgu S, Takata F, Matsumoto J, Oda M,Harada E, Watanabe T, Nishioku T, Shuto H, Yamauchi A, Kataoka Y.
  • Journal Title: Microvascular Research Volume: 81(1) Pages: 103-7
  • Peer Reviewed
• [Journal Article] Disruption of the blood-brain barrier in collagen-induced arthritic mice. (2010)
  • Author(s): Nishioku T, Yamauchi A, Takata F, Watanabe T, Furusho K, Shuto H, Dohgu S, Kataoka Y.
  • Journal Title: Neuroscience Letters Volume: 482(3) Pages: 208-11
  • Peer Reviewed
• [Journal Article] Cyclosporin A induces hyperpermeability of the blood-brain barrier by inhibiting autocrine adrenomedullin-mediated up-regulation of endothelial barrier function. (2010)
  • Author(s): Dohgu S, Sumi N, Nishioku T, Takata F, Watanabe T, Naito M, Shuto H, Yamauchi A, Kataoka Y.
  • Journal Title: European Journal of Pharmacology Volume: 644(1-3) Pages: 5-9
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor-alpha mediates the blood-brain barder dysfunction induced by activated microglia in mouse brain microvascular endothelial cells (2010)
  • Author(s): Nishioku T, Matsumoto J, Dohgu S, Sumi N, Miyao K, Takata F, Shuto H, Yamauchi A, Kataoka Y.
  • Journal Title: Journal of Pharmacological Sciences 112(2) Pages: 251-4
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide-Activated Microglia Induce Dysfunction of the Blood-Brain Bamer in Rat Microvascular Endothelial Cells Co-Cultured with Microglia (2010)
  • Author(s): Sumi N, Nishioku T, Takata F, Matsumoto J, Watanabe T, Shuto H, Yamauchi A, Dohgu S, Kataoka Y.
  • Journal Title: Cellular and Molecular Neurobiology 30(2) Pages: 247-53
  • Peer Reviewed
• [Journal Article] Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen. (2009)
  • Author(s): Sanchez-Lemus E, Benicky J, Pavel J, Larrayoz IM, Zhou J, Baliova M, Nishioku T, Saavedra JM.
  • Journal Title: Am J Physiol Regul Integr Comp Physiol. 296(5)
  • Peer Reviewed
• [Journal Article] Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain barrier caused by lipopolysaccharide-induced sepsis in mice. (2009)
  • Author(s): Nishioku T, Dohgu S, Takata F, Eto T, Ishikawa N, Kodama K.B, Nakagawa S, Yamauchi A, Kataoka Y.
  • Journal Title: Cell Mol Neurobiol. 29(3) Pages: 309-316
  • Peer Reviewed
• [Journal Article] Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen (2009)
  • Author(s): Sanchez-Lemus E, Benicky J, Pavel J, Larrayoz IM, Zhou J, Baliova M, Nishioku T, Saavedra JM.
  • Journal Title: Amedcan journal of physiology. Regulatory, integrative and comparative physiology 296(5)
  • Peer Reviewed
• [Journal Article] Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain bamer caused by lipopolysaccharide-induced sepsis in mice (2009)
  • Author(s): Nishioku T, Dohgu S, Takata F, Eto T, Ishikawa N, Kodama K.B, Nakagawa S, Yamauchi A, Kataoka Y.
  • Journal Title: Cellular and Molecular Neurobiology 29(3) Pages: 309-16
  • Peer Reviewed
• [Presentation] 関節炎モデルマウスの血液脳関門機能障害におけるS100A4の役割 (2011)
  • Author(s): 冨田彩乃、西奥剛、大石裕晃、三浦哲平、道具伸也、山内淳史、首藤英樹、片岡泰文
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: (誌上開催)
• [Presentation] コラーゲン誘導関節炎マウスのパンヌスにおけるCyclophilin AとCD147の発現増加とその局在 (2011)
  • Author(s): 三浦哲平、西奥剛、大石裕晃、津曲康輔、山内淳史、首藤英樹、片岡泰文
  • Organizer: 第131回日本薬学会年会
  • Place of Presentation: (誌上開催)
• [Presentation] コラーゲン誘導関節炎マウスのパンヌスにおけるCyclophilin AとCD147の発現増加とその局在 (2010)
  • Author(s): 三浦哲平、西奥剛、大石裕晃、津曲康輔、山内淳史、首藤英樹、片岡泰文
  • Organizer: 第131回日本薬学会年会
  • Place of Presentation: 誌上
  • Year and Date: 2010-03-30
• [Presentation] 関節炎モデルマウスの血液脳関門機能障害におけるS100A4の役割 (2010)
  • Author(s): 冨田彩乃、西奥剛、大石裕晃、三浦哲平、道具伸也、山内淳史、首藤英樹、片岡泰文
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 誌上
  • Year and Date: 2010-03-24
• [Presentation] 関節炎モデルマウスにおける血液脳関門障害 (2010)
  • Author(s): 古庄弘宜, 西奥剛, 三浦哲平, 冨田彩乃, 道具伸也, 高田芙友子, 渡辺拓也, 山内淳史, 首藤英樹, 片岡泰文
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪市
  • Year and Date: 2010-03-17
• [Presentation] 関節炎モデルマウスにおける血液脳関門障害 (2010)
  • Author(s): 古庄弘宜, 西奥剛, 三浦哲平, 冨田彩乃, 道具伸也, 高田芙友子, 渡辺拓也, 山内淳史, 首藤英樹, 片岡泰文
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2010-03-17
• [Presentation] Activation of microglia and migration of brain pericytes are involved in disruption of the blood-brain barrier caused by lipopolysaccharide (2009)
  • Author(s): Tsuyoshi Nishioku, Noriko Sumi, Shinya Dohgu, Fuyuko Takata, Takashi Machida, Hideki Shuto, Atsushi Yamauchi, Yasufumi Kataoka
  • Organizer: 第1回アジア神経精神薬理学会
  • Place of Presentation: 京都市
  • Year and Date: 2009-11-14
• [Presentation] Activation of microglia and migration of brain pericytes are involved in disruption of the blood-brain barrier caused by lipopolysaccharide (2009)
  • Author(s): Tsuyoshi Nishioku, Noriko Sumi, Shinya Dohgu, Fuyuko Takata, Takashi Machida, Hideki Shuto, Atsushi Yamauchi, Yasufumi Kataoka
  • Organizer: 第1回アジア神経精神薬理学会
  • Place of Presentation: 国立京都国際会館(京都市)
  • Year and Date: 2009-11-14
• [Presentation] Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain barrier caused by lipopolysaccharide-induced sepsis in mice. (2009)
  • Author(s): Tsuyoshi Nishioku, Shinya Dohgu, Fuyuk o Takata, Shinsuke Nakagawa, Hideki Shuto, Atsushi Yamauchi, Masami Niwa, Yasufumi Kataoka
  • Organizer: 8^<th> Cerebral Vascular Biology
  • Place of Presentation: 仙台市
  • Year and Date: 2009-06-30
• [Presentation] Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain barrier caused by lipopolysaccharide-induced sepsis in mice (2009)
  • Author(s): Tsuyoshi Nishioku, Shinya Dohgu, Fuyuko Takata, Shinsuke Nakagawa, Hideki Shuto, Atsushi Yamauchi, Masami Niwa, Yasufumi Kataoka
  • Organizer: 8^<th> Cerebral Vascular Biology
  • Place of Presentation: 仙台エクセルホテル東急(仙台市)
  • Year and Date: 2009-06-30