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AIHARA Noritaka

    Graduate School of Medical Sciences Department of Neurosurgery　Associate Professor
Contact： aiharamed.nagoya-cu.ac.jp
Last Updated :2024/03/19

Researcher Information

J-Global ID

Research Interests

  • cerebral hemorrhage   神経移植   モニタリング   脳腫瘍   

Research Areas

  • Life sciences / Neurosurgery

Published Papers

Books etc

  • 術中脳脊髄モニタリングの指針 2022
    (Contributor脳幹聴覚誘発電位（B A E P）pp96-100)診断と治療社 2022
  • NS NOW 低侵襲時代の頭蓋底手術
    村上信五; 相原徳孝 (ContributorMiddle cranial fossa approach:聴神経腫瘍 pp82-92)メジカルビュー社 2009
  • 脳神経外科大系
    (Contributor神経外傷 総論 中枢神経系の再生医学 pp49-53)（株）中山書店 2005
  • Brain Science
    (Contributor脳出血に対する神経細胞移植研究 pp175-180)（株）星和書店 2003

MISC

Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2010 -2012 
    Author : YAMADA Kazuo; KATANO Hiroyuki; MASE Mitsuhito; UMEMURA Atsushi; AIHARA Noritaka; TANIKAWA Motoki
     
    Carotid stenosis is increasing in number in the Japanese population. Some of the carotid stenosis becomes symptomatic and the others remain asymptomatic. For establishment of surgical indication for carotid endarterectomy or carotid stenting, we have analyzed carotid plaques with special interest of calcification and fragile plaques. We routinely used 3D-CT angiography (3D-CTA) for evaluation of carotid stenosis. We therefore tested relation between calcified carotid plaques and surgical pathology and found that partly calcified plaques can be treatable by stenting but whole calcification plaque is hard to treat by stenting. Carotid endarterectomy can handle any of calcified plaques. T o detect intraplaque neovascularization, we immunostained endarterectomy specimens with hypoxia-inducible factor 1 alpha (HIF1-α) and vascular endothelial growth factor (VEGF). The plaques form the symptomatic cases were more stained with HIF1-αand VEGF than asymptomatic cases suggesting plaque hypoxia and neovascularization is an important factor for symptomatic changes. We collected 807 cases of asymptomatic carotid stenosis from 39 institutions in Japan and followed up for two years. We are on the way of collecting the data. At present status, about 50% of the cases was followed for 2 years, and we found that symptomatic rate for asymptomatic cases with medical treatment was 2.4%/year, which is similar to the US study (ACAS) or Britain study (ACST).
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2005 -2006 
    Author : MASE Mitsuhito; YAMADA Kazuo; AIHARA Noritaka
     
    The author investigated the expression of aquaporin (AQP) -1 and 4 in kaolin-induced hydrocephalus in rats. The induction of AQP-1 mRNA was observed in the choroids plexus and at the cerebral base 2, 4, and 9 weeks after the injection of kaolin, and gradually increased in tandem with the development of ventricular dilatation. The protein for AQP-1 was expressed within the same time course and at the same sites but did not augment incrementally. Both of the gene and protein down regulated after cerebrospinal fluid (CSF) shunting. The expression of either AQP-4 mRNA or its protein was not detected in any brain tissue throughout the time course. The present study showed that experimental hydrocephalus induced by kaolin caused the gene and protein for AQP-1 to be expressed, but not AQP-4. The expression of AQP-1 may be evoked to counteract stagnation caused by impairment of the CSF circulation. AQP-1 regulation may continue to play a new role in the treatment of hydrocephalus.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2005 -2006 
    Author : YAMADA Kazuo; KATANO Hiroyuki; AIHARA Noritaka; MASE Mitsuhito; ASAI Kiyofumi
     
    We have studied mRNA and protein expression of myelencephalon-specific protease (MSP) in the brain ischemia and brain injury model in rats, because MSP is oligodendrocyte-specific serine protease and MSP expression is relating to axonal regeneration. As a result, we have detected MSP mRNA and protein expression in the oligodendrocytes locating at peri-ischemic area 3 to 7 days after cerebral ischemia. Question then arises whether MSP expression is caused by direct ischemic injury to the peri-ischemic oligodendrocytes or indirect effect of edema fluid formation on oligodendrocytes. To answer this question, we developed cold injury model in which edema developed around lesion but ischemic injury to the oligodendrocyte was not occurring. We detected in the cold injury model that MSP expression occurred on the 5^ day after cold injury. With this result we concluded that edema fluid extending to the surrounding lesion might activate oligodendrocytes and express MSP mRNA and protein expression. We did double immunostaining of MSP and oligodendrocyte-specific marker CNPase, and identified that both markers were co-localizing in the same oligodendrocyte. The results suggest that edema fluid activates oligodendrocytes and act for regeneration of axons. We also did Western blotting of the MSP and identified that MSP proteins has bands at 19kDa (authentic MSP protein) and 37, 40 and 50kDa's. The 37kDa bands increased its volume at 6 hours and 5-7days after cold injury. Those two peaks of reactive production suggested two mechanism of oligodendrocytes activation, initial direct stimulation through neuronal network and secondary indirect stimulation through edema fluid extension. That similar result was also identified in the subarachnoid hemorrhage model and intracerebral hemorrhage model.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2004 -2005 
    Author : KATANO Hiroyuki; MASE Mitsuhito; UMEMURA Atsushi; AIHARA Noritaka; YAMADA Kazuo; ASAI Kiyofumi
     
    MSP(myelencephalic-specific protease) is often found in human brain and spinal white matter, especially in oligodendrocytes, microglias and neurons. Trypsin-like activity leads to the possibility of function related to regeneration of the basement membrane and extracellular matrix, growth of oligodendrocyte, hydolysis of myelin, neural growth and synaptic plasticity. We confirmed expression of MSP mRNA in rat brain using middle cerebral artery occlusion model. In situ hybridization (ISH) of MSP mRNA demonstrated a higher level in the corpus callosum and around the ischemic area from 12h to 14days after MCA reperfusion, with the peak of expression coming 3days after reperfusion in both regions. Immunohistochemically, the expression of protein was found 1day autoradiography, immunostaining and double immunohistochemical labeling revealed the expression of MSP to be located mainly in the oligodendrocytes. Analysis of MSP mRNA after cryogenic injury by ISH revealed a higher level of expression around the cryogenic area than on the contralateral side at 2-7 days after injury, with peak expression occurring 7days. Immunohistochemical analysis demonstrated expression of MSP protein at 1day after injury, in the area around the lesion. Double immunohistochemical labeling revealed that MSP was expressed mainly in oligodendrocytes. These results suggest that expression of MSP may be related to the turnover of myelin-associated proteins and extracellular matrix proteins after cold injury. We performed quantitative evaluation of white matter damage in diffuse axonal injury (DAI) with silver impregnation method using modified Marmarou's model, which revealed the number of dark axons at the cerebral peduncle increased during the experimental period. There was a significant difference between the number of dark axons 180 days after the injury and 1, 3, 7, 30, or 60 days after the injury. Since this model showed 20% motality rate, we decided to employ DAI model using fluid percussion injury with higher reproducibility and to equip fluid percussion injury machine (Dragonfly) in our laboratory. According to the method by Kita et al., central fluid percussion (maximum positive pressure 1000mg, maximum negative pressure 160mg) is supposed to be delivered through bone window on parietal region of Wister rats, making DAI with histologically confirmation. Unfortunately, we could not elicit the whole result of our project, we are planning to examine the expression of MSP mRNA and protein using this model and to perform transfection of the gene in ventricles with liposome, followed by analysis of the effect of suppression by siRNA.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2003 -2004 
    Author : YAMADA Kazuo; AIHARA Noritaka; MASE Mitsuhito; KATANO Hiroyuki
     
    We have developed a new model of rat spontaneous intracerebral hemorrhage. The model can be induced by intracerebra]. injection of collagenase type IV with which hemorrgae occurred in the striatum and mimicked the human intracerebral hemorrhage. The animal developed hemiplegia, reduced motion and specific rotation movement induced by methamphetamine. The rotation was correlated with amount of hemorrhage. Histological analysis indicated infiltration of macrophage/microglia in the lesion-side substantia nigra, which is followed by degeneration of the substantia nigra. In situ hybridization study indicated upregulation of Na/myoinositol cotransporter in the lesion-side substantia nigra. Degeneration of the lesion-side substantia nigra might be related to the methamphetamine-induced rotation. The brain-derived neurotrophic factor (BDNF) was indiced in the perihemorrhage striatum providing suitable condition for transplantation of the neural stem cell. We, therefore developed stem-cell transplantation study for this hemorrhage model, but transplanted-cell rate was rather low as compared to the fetal tissue transplant. We planned gene transfer to stem cell, yet we could not finish the project in this term.
  • アンチセンス法を用いた活性化マイクログリア制御による頭部外傷後神経変性防止の試み
    Date (from‐to) : 2003 -2004
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2002 -2004 
    Author : MOTOKI Tanikawa; YAMADA Kazuo; MASE Mitsuhito; AIHARA Noritaka; YAMAMOTO Kenichi
     
    Recent evidence has suggested apoptosis as an important component of degenerative processes after spinal cord injury (SCI). We tried to confirm this relationship, and to apply the hypothermia therapy, that included systemic method by using specific blanket, and local method by intrathecal-administration of cold saline. However, we could not get any significant results from each experiment, because it might be difficult to keep body temperature of rats for a certain period. We tried to improve those methods, yet we could not do that in this term.. On the other hand, we clarified that expressions of SMIT and myelincephalon specific protease (MSP) increased around injured site. Those molecules might be related to apoptosis and secondary injury of neuronal tissue. We think that there will be some possibility for neuronal protection from secondary injury by further experiments, such as inhibition of functions of those molecules
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2002 -2003 
    Author : 山田 和雄; 谷川 元紀; 相原 徳孝; 間瀬 光人
     
    白質損傷後の脳機能再生を図るため、遺伝子導入したシュワン細胞を脳内移植し、脳機能変化をみることを本研究の主眼として始めた。本年度は白質損傷モデルとして、脳梁損傷モデル、凍結損傷による脳梁機能障害モデル、虚血性脳梁損傷モデルを用いて上記試みの準備研究を進めた。まずラット凍結脳損傷モデルを用い、白質オリゴデンドロサイト活性の指標として、MSP遺伝子と蛋白の発現を検討した。MSP(Myelencephalon-specific protease)は新規のセリンプロテアーゼで、白質のオリゴデンドロサイト、ミクログリア、神経細胞に多く存在し、ミエリンの代謝に関与することが知られている。その結果、凍結損傷後1-3日して損傷直下の白質にMSPmRNAと蛋白陽性のオリゴデンドロサイトが出現し、浮腫の進展に応じて、損傷遠隔部位の白質まで、陽性細胞が出現することを確かめた。また、mRNAと蛋白の発現は同時に並行して変化することも確かめられた。ついでラット脳虚血モデルを用いて、MSPの発現を検討すると、虚血周囲の白質に虐血後1-3日して発現することが認められた。これらの所見から、各種の白質損傷モデルでは損傷に応じてオリゴデンドロサイトの活性化がおこり、これが損傷後のミエリン修復に関与することが明らかとなった。同時にbrain derived neurotrophic factor (BDNF)およびinterferon gammaを組み込んだレトロウィルスベクターを作成し、それを用いてWisterラットから採取したシュワン細胞に遺伝子導入した。遺伝子導入されたシュワン細胞をジェネシチン(G418)でセレクションをかけながら、シングルコロニーを採取してシングルクローンとした。そうして得られた遺伝子組み換えシュワン細胞のシングルクローンのうち、増殖などに問題の無かったものを選択して増殖させ、移植の準備段階は整えることができた。研究期間は終了してしまったが、次の段階として作成した遺伝子組み換えシュワン細胞をラット脳梁損傷モデルに移植するなど、今後も研究を継続していく予定である。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2001 -2002 
    Author : YAMADA Kazuo; SHIMADA Syoichi; AIHARA Noritaka; MASE Mitsuhito; ASAI Kiyofumi
     
    To detect changes in channel transporter, we used models of cerebral ischemia, cold-induced edema, subarachnoid hemorrhage (SAH) and intracerebral hemorrhage in rat. The transporters we detected are aquaporin type 1, 4,5 and 8, and myoinositol osmolyte transporter. In the cerebral ischemia, aquaporin type 4 mRNA is expressed in 3 to 7 days after ischemia, and aquaporin type 4 protein is increased in soma and disappearing from vascular foot, indicating turnover of aquaporin 4 is occurring. Similar findings are detected in the cold-induced edema model, indicating that aquaporin type 4 is functioning for resolution of brain edema. On the other hand aquaporins 1,4,5 and 8 is expressed in the cultured astrocyte exposed to hypoxia, indicating multipotential nature of aquaporins. Myoinositol transporter, one of the osmolyte transporters, is expressed in the neurons facing subarachnoid blood of SAH model, indicating osmotic pressure changes in SAH. Myoinositol transporter mRNA is also expressed in the neurons exposed to transient ischemia after SAH, indicating osmolyte changes in cerebral ischemia. We have detected cell death in substantial nigra after striatal hemorrhage in rat. During this process nigral neurons expressed myoinositol mRNA expression, which may relate to cell death. In Summary, channel transporter plays important role in brain injury and its recovery. Treatment trial must be focused in this area.
  • てんかん焦点形成におけるN-cadherinの役割とその制御による治療法の開発
    Date (from‐to) : 2001 -2002
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1999 -2000 
    Author : YAMADA Kazuyo; IWATA Akira; AIHARA Noritaka; MASE Mitsuhito; SHIMADA Shoichi
     
    Subarachnoid hemorrhage (SAH) cause various type of neurologic deficits. Some of those are caused by cerebrovascular spasm, but others are caused by impact of SAH. The present project was designed to study the impact to the brain. Rat model of SAH was developed in our laboratory and used for in situ hybridization. We identified that apoptosis promoting bax and ice genes ware expressed in the CA1 of hippocampus within 24 hours after SAH. The bcl-2, apoptosis suppressing gene, was also expressed in those areas, but the ratio of bax/bcls tended to increase. Immediate early gene, c-fos and c-jun are expressed in the CA1 area of hippocampus. When monitoring intracranial pressure, SAH induced steep increase of ICP and perfusion pressure was low for 5- 15 minutes. Therefore, transient ischemia occurred in the brain and most vulnerable CA1 area was affected. TUNEL staining showed positive cells at CA1 area 2 days post ictus. Osmolyte channel transporter was also increased its mRNA expression at CA1. These data clearly demonstrate stress of SAH may induce neurological dysfunction and may relate neurological sequelae caused by SAH.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1999 -2000 
    Author : MASAGO Atsuo; AIHARA Noritaka; KATO Taiji; YAMADA Kazuo; MASE Mitsuhito
     
    Hyperthermia is one of the effective therapeutic methods for malignant glioma. Many clinical trials are going on in the world. However, the details of anti-tumor mechanism haven't been well resolved. We already reported A172 glioma cells underwent G1 arrest and apoptotic cell death by heat shock stimulation. In the meantime, apoptosis related factors such as bax mRNA, Bax and p53 protein were induced. These phenomena had close relation with cell cycle. One of the cyclin dependent kinase inhibitors (CKIs), p21, was activated simultaneously (Fuse T et al, Biochem Biophys Res Commun, 1996). P53 has been reported to regulate p21 directly. We showed T98G glioma cells, which had mutant type p53, suffered apoptotic cell death by heat shock. The activation of p21 was not accompanied by p53 induction. Our data means there is alternative signal pathway to CKIs besides p53 related transduction (Fuse T et al, Neurosurgery 1998). Malignant gliomas manifest resistance against many anti-tumor drugs. Prostaglandin A1 series (PGA1s) have anti-proliferative activity for many cancers in vivo and in vitro, and PGA1s are potentially useful in chemotherapy of malignant tumors. We showed PGA1 inhibited cell growth and caused G1 arrest in A172 glioma cells. PGA1 induced the expression of p21 mRNA and protein. On the other hand, cycline E dependent kinase activity was markedly reduced. PGA1 seem to inhibit tumor cell growth through two distinct pathways : the induction of p21 and the suppression of cyclin E (Tanikawa M et al, J Biol Chem 1998). Although the molecular and cellular mechanisms remain elusive, p21 plays an important role in growth regulation of glioma cells and therapeutic strategy. Hyperthermia and PGA1 would be potentially useful in glioma therapy.
  • アンチセンス法を用いたオリゴデンドロサイト機能抑制による中枢神経移植効果の改善
    Date (from‐to) : 1999 -2000
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1998 -1999 
    Author : MASE Mitsuhito; AIHARA Noritaka; YAMADA Kazuo; MASAGO Atsuo; KATO Taiji; IWATA Akira
     
    Calcineurin, serin/threonine phosphatase, has an important role for the differentiation/growth of immune cells and pathology of immune diseases because it acitvates T-cell. FK-506 (tacrolimus), a new immunosuppressant, contributes to success in organ transplantation. The immunosuppressing mechanism of FK-506 is known to be an inhibition of calcineurin activity by complex formation of calcineurin and FK-506 with immunophilin. Calcineurin widely distributes in hippocampus, striatum, and cerebral cortex. FK-506 has neuroprotective effects against glutamate toxicity, focal, and transient global cerebral ischemia. Marked apoptosis occurred in calcineurin activated gene transfected cells under serum-free conduction, which is inhibited by direct combination with Bcl-2. We suspected that calcineurin had some roles on apoptosis in various cerebral damages. In the present study, we clarified changes of expression of immediate early genes (c-fos, c-jun) and apoptosis related gene in some conditions, increased intracranial pressure, impact injury, and cryogenic injury. Then, we produced diffuse axonal injury model using rats, and analyzed changes of IEGs, apoptosis related genes, and amyloid precursor protein (APP) expression after calcineurin administration. However, we could not obtain significant changes of these parameters.
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 1997 -1999 
    Author : 山田 和雄; 神谷 健; 岩田 明; 相原 徳孝; 山下 伸子; 山田 和雄
     
    本研究の主目的はでは血管内に挿入したカテーテルから頭蓋内圧を推定することであり3年間の研究を行った。平成9年度の動物を用いた基礎研究で血管内圧の変化から頭蓋内圧を推定することが可能になった。平成10年度はヒトの脳血管内手術時に血管内圧を測定し、同時に腰椎クモ膜下腔に留置したカテーテルから頭蓋内圧を測定した。その結果、血管内手術用のカテーテルから血管内圧を測定することは可能であること、カテーテルを進めることにより、頭蓋内の各部位での血管内圧が測定可能である。それらに差のあることが明らかとなった。平成11年度には各種脳血管障害で血管内治療をする場合脳血管内圧と脳脊髄圧を測定し、両者を対比した。その結果、脳血管内圧、ならびにその波形から、ある程度頭蓋内圧を予想することが可能となった。この研究と平行して、本研究の基礎データを得るため試作したラットの硬膜外頭蓋内圧測定装置を用いて、水頭症モデル、くも膜下出血モデルで頭蓋内圧を測定し、頭蓋内圧とラット脳のストレス遺伝子、アポトーシス関連遺伝子の発現を検討し、いくつかの知見を得ることができた。とくに水頭症性の頭蓋内圧亢進では著しい頭蓋内圧亢進状態になるまで脳神経細胞は高頭蓋内圧状態に耐えられること、一方くも膜下出血モデルでは出血直後に頭蓋内圧が数分間体血圧近くまで上昇し、潅流圧低下による全脳虚血状態ができること、これに伴い脳神経細胞には著しいストレス反応がもたらされることが明らかとなった。さらに本年度は脳血管内治療を行った動脈瘤患者の髄液を採取して、prostaglandin D synthaseがヒト髄液内に産生されていることを明らかにした。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 1997 -1998 
    Author : YAMADA Kazuo; IWATA Akira; AIHARA Noritaka; NAKANISHI Makoto; KATO Taiji; MASAGO Atsuo; FUSE Takahisa; KOMATSU Hiroaki
     
    We have detected p21 mRNA expression in various types of brain injury models, which includes focal cerebral ischemia, neurotrauma and subarachnoid hemorrhage. The p21 mRNA expression was compared to the other gene expression such as heat shock protein (hsp)-70, c-fos and c-jun. In the focal ischemia, p21 expression was detected in the area of ischemia and penumbra zone with maximal expression at 12-24 hours after ischemi. Hippocampal pyramidal cells of the ischemia side also showed p21 mRNA expression. The p21 mRNA expression has time delay as compared to expression of c-fos, c-jun and hsp-70, indicating different intracellular signalling pathway. Neurons showed more p21 mRNA expression than glia. Western blot study confirmed p21 protein expression in the ischemic hemisphere. Similar results were obtained in the neurotrauma model indicating p21 response as an ubiquitous response of neurons against injury. We detected p21 mRNA expression in the subarachnoid hemorrhage model which caused apoptosis due to mild ischemia in the pefforated side hippocampus. The peak expression in subarachnoid hemorrhage lasted from 24 hours till 120 hours. Neuronal apoptosis in this model occurred within 48 hours. These data suggest that p21 did not cause apoptosis but act as cell recovery from stress. We then detected regurating substance for p21 gene expression in the glioma cell line. In this study, p21 mRNA were upregulated with prostanoids indicating possible cell cycle-regulating drugs.
  • クモ膜下出血後のDINDとDNDとの関連及びその治療
    Date (from‐to) : 1996 -1998

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