徳島大学脳神経外科

脳梗塞研究

徳島大学医歯薬学研究部脳神経外科研究室

脳血管障害研究（脳動脈瘤、脳梗塞、脳動静脈奇形）

脳梗塞研究

脳梗塞の危険因子として加齢、男性、高血圧、糖尿病、脂質異常症、喫煙、肥満、大量の飲酒、過剰塩分摂取、ストレス、などが挙げられます。発症予防に薬物療法に加えて脳神経外科的治療として、頸動脈狭窄に対する頸動脈内膜剥離術（CEA）やステント留置術が行われ、②発症後には血栓溶解療法・血栓除去術や降圧療法、高脂血症に対する薬物治療などが行われています。CEAで摘出されたプラークと血中酸化LDLの解析を昭和大学薬学部との共同研究で行い、macrophageの浸潤が多い不安定プラーク症例では血中酸化LDLが高く（右上図）、石灰化の頻度も高く、プラークの不安定性と関係することを報告しています。

一方、ラットの脳梗塞モデルにおいて脳梗塞早期には炎症性変化が亢進しているため、Peroxisome proliferator-activated receptor γ（PPARγ）agonistによる脳梗塞後早期のIL－6抑制作用と亜急性期の骨髄由来細胞誘導による内因性神経再生促進作用によって脳梗塞後の症状が改善される可能性を報告しています（右図）。今後、さらに脳梗塞モデルを臨床に近いモデルに改善し、神経再生に有効な治療法について検討を加えると共に、臨床では脳梗塞発症後の運動機能障害の治療方策についても検討を進めています。

発表論文

  1. Ishihara M, Nakanishi N, Tsutsumi R, Hara K, Machida K, Yamamoto N, Kanematsu Y, Sakaue H, Oto J, Takagi Y. Elevated Urinary Titin and its Associated Clinical Outcomes after Acute　Stroke.　J Stroke Cerebrovasc Dis. 2021 Mar;30(3):105561.
  2. Hioka A, Tada Y, Kitazato K, Kanematsu Y, Mizobuchi Y, Mure H, Shimada K, Okazaki T, Korai M, Akazawa N, Matsumoto Y, Harada M, Takagi Y, Nagahiro S Activation of mirror neuron system during gait observation in sub-acute strokepatients and healthy persons..J Clin Neurosci. 2019;60:79-83
  3. Yamaguchi I, Kanematsu Y, Shimada K, Korai M, Miyamoto T, Shikata E, Yamaguchi T, Yamamoto N, Yamamoto Y, Kitazato KT, Okayama Y, Takagi Y. Active Cancer and Elevated D-Dimer Are Risk Factors for In-Hospital Ischemic Stroke. Cerebrovasc Dis Extra. 2019;9(3):129-138.
  4. Okazaki T, Kanematsu Y, Shimada K, Korai M, Satomi J, Uno M, Nagahiro S, Takagi Y of Carotid Endarterectomy with Patch Graft. Neurol Med Chir (Tokyo). 2019;59:231-237
  5. Kinouchi T, Kitazato KT, Shimada K, Yagi K, Tada Y, Matsushita N, Kurashiki Y, Satomi J, Sata M, Nagahiro S. Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats. Transl Stroke Res. 2018 Jun;9(3):306-316.
  6. Sogabe S, Satomi J, Tada Y, Kanematsu Y, Kuwayama K, Yagi K, Yoshioka S, Mizobuchi Y, Mure H, Yamaguchi I, Abe T, Yamamoto N, Kitazato KT, Kaji R, Harada M, Nagahiro S.　Intra-arterial high signals on arterial spin labeling perfusion images predict the occluded internal carotid artery segment.Neuroradiology. 2017;59:587-595
  7. Yamamoto N, Satomi J, Yamamoto Y, Shono K, Kanematsu Y, Izumi Y, Nagahiro S, Kaji R. Risk Factors of Neurological Deterioration in Patients with Cerebral Infarction due to Large-Artery Atherosclerosis. J Stroke Cerebrovasc Dis. 2017;26:1801-1806
  8. Shono K, Satomi J, Tada Y, Kanematsu Y, Yamamoto N, Izumi Y, Kaji R, Harada M, Nagahiro S Optimal Timing of Diffusion-Weighted Imaging to Avoid False-Negative Findings in Patients With Transient Ischemic Attack.Stroke. 2017; 48:1990-1992
  9. Kageji T, Obata F, Oka H, Kanematsu Y, Tabata R, Tani K, Bando H, Nagahiro S. Drip-and-Ship Thrombolytic Therapy Supported by the Telestroke System for Acute Ischemic Stroke Patients Living in Medically Under-served Areas.Neurol Med Chir (Tokyo). 2016 Dec 15;56(12):753-758
  10. Tada Y, Yagi K, Uno M, Matsushita N, Kanematsu Y, Kuwayama K, Shimada K, Nishi K, Hirasawa M, Satomi J, Kitazato KT, Kageji T, Matsuura E, Nagahiro S Improvement of Plasma Biomarkers after Switching Stroke Patients from Other Angiotensin II Type I Receptor Blockers to Olmesartan. J Stroke Cerebrovasc Dis. 2015 Jul;24(7):1487-92
  11. Sumiyoshi M, Kitazato KT, Yagi K, Miyamoto T, Kurashiki Y, Matsushita N, Kinouchi T, Kuwayama K, Satomi J, Nagahiro S.　The accumulation of brain water-free sodium is associated with ischemicdamage independent of the blood pressure in female rats. Brain Res. 2015 Aug 7;1616:37-44. 
  12. Sumiyoshi M, Satomi J, Kitazato KT, Yagi K, Shimada K, Kurashiki Y, Korai M, Miyamoto T, Suzue R, Kuwayama K, Nagahiro S.PPARgamma-Dependent and -Independent Inhibition of the HMGB1/TLR9 Pathway by Eicosapentaenoic Acid Attenuates IschemicBrain Damage in Ovariectomized Rats. J Stroke Cerebrovasc Dis. 2015 Jun;24(6):1187-95
  13. Kinouchi T, Kitazato KT, Shimada K, Yagi K, Tada Y, Matsushita N, Sumiyoshi M, Satomi J, Kageji T, Nagahiro S Activation of signal transducer and activator of transcription-3 by a peroxisome proliferator-activated receptor gamma agonist contributes to neuroprotection in the peri-infarct region after ischemia in oophorectomized rats.　Stroke. 2012 Feb;43(2):478-83
  14. Yagi K, Kitazato KT, Uno M, Tada Y, Kinouchi T, Shimada K, Nagahiro S.Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator.Stroke. 2009 Feb;40(2):626-31..
  15. Uno M, Kitazato KT, Nishi K, Itabe H, Nagahiro S Raised plasma oxidised LDL in acute cerebral infarction..J Neurol Neurosurg Psychiatry. 2003 Mar;74(3):312-6.
  16. Liu H, Kitazato KT, Uno M, Yagi K, Kanematsu Y, Tamura T, Tada Y, Kinouchi T, Nagahiro S. Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies. J Hypertens. 2008 Jul;26(7):1435-45.
  17. Nakano T, Seo M, Komoda T, Kitazato KT, Uno M, Hamaoki M, Nagata A。 Immunoreactive circulating oxidized HDL concentrations do not increase in patients undergoing carotid endarterectomy: a comparative study for oxidized HDL and oxidized LDL concentrations in plasma. Clin Chim Acta. 2007 Jun;381(2):179-81
  1. Suzue A, Uno M, Kitazato KT, Nishi K, Yagi K, Liu H, Tamura T, Nagahiro S Comparison between early and late carotid endarterectomy for symptomatic carotid stenosis in relation to oxidized low-density lipoprotein and plaque vulnerability..J Vasc Surg. 2007;46(5):870-5.
  2. Uno M, Harada M, Takimoto O, Kitazato KT, Suzue A, Yoneda K, Morita N, Itabe H, Nagahiro S.　Elevation of plasma oxidized LDL in acute stroke patients is associated with ischemiclesions depicted by DWI and predictive of infarct enlargement.　Neurol Res. 2005;27(1):94-102.
  3. Nishi K, Itabe H, Uno M, Kitazato KT, Horiguchi H, Shinno K, Nagahiro S. Oxidized LDL in carotid plaques and plasma associates with plaque instability. Arterioscler Thromb Vasc Biol.2002 Oct 1;22(10):1649-54
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