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達富, 真司
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金沢大学医学部医学科
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崔, 弘
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[原著/ Originals]
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Koriyama, Yoshiki ; Chiba, Kenzo ; Yamazaki, Matsumi ; Suzuki, Hirokazu ; Muramoto, Ken-ichiro ; Kato, Satoru
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金沢大学医薬保健研究域医学系<br />金沢大学理工研究域電子情報学系<br />Previously, we reported that genipin, a herbal iridoid, had neuritogenic and ne
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uroprotective actions on PC12 cells. Although nitric oxide (NO)-activated signalings were proposed to be neuritogenic, the neuroprotective action of genipin remains to be elucidated. From the standpoint of NO activation, we tested a possible protective mechanism through the nitrosative Kelch-like ECH-associated protein (Keap1)/NF-E2-related factor 2 (Nrf2)-antioxidant response element pathway in rat retinal ganglion cells (RGC-5 cells) in culture, and in vivo, against hydrogen peroxide and optic nerve injury (ONI), respectively, using a long-acting (1R)-isoPropyloxygenipin (IPRG001). IPRG001 induced NO generation and the expressions of antioxidative enzymes, such as heme oxygenase-1 (HO-1), in RGC-5 cells. The protective action of IPRG001 depended on HO-1 and NO induction. We found that S-nitrosylation of Keap1 by IPRG001 may contribute to translocation of Nrf2 to the nucleus and triggered transcriptional activation of antioxidative enzymes. Furthermore, apoptotic cells were increased and 4-hydroxy-2-nonenal was accumulated in rat retina following ONI. Pre-treatment with IPRG001 almost completely suppressed apoptosis and accumulation of 4-hydroxy-2-nonenal in RGCs following ONI accompanied by HO-1 induction. These data demonstrate for the first time that IPRG001 exerts neuroprotective action in RGCs in vitro and in vivo, through the Nrf2/antioxidant response element pathway by S-nitrosylation against oxidative stress. © 2010 International Society for Neurochemistry.
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郡山, 恵樹
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The retina has been regarded as 'an approachable part of the brain' for investigating central nervous system (CNS). The optic nerve injury is a well-accepted model to study the mechanisms of neural degeneration and/or axonal
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regeneration after trauma in the CNS. Nitric oxide (NO) is a gaseous messenger molecule biosynthesized from L-arginine and molecular oxygen by NO synthase. Many reports suggest that excess production of NO plays a crucial role in neuronal cell death including in death of retinal ganglion cells (RGCs). In contrast, several lines of evidence indicate that NO can prevent neuronal death. In general, NO mediates neuroprotection through two main signaling pathways: the NO/cyclic guanosine monophosphate (cGMP) pathway and the S-nitrosylation pathway. Especially, whether S-nitrosylation of proteins promotes RGCs survival and its axonal regeneration after injury is unclear. Thus, we focused on the S-nitrosylation-dependent mechanism of RGCs survival and axonal regeneration by NO after nerve injury.
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Koriyama, Yoshiki ; Takagi, Yusuke ; Chiba, Kenzo ; Yamazaki, Matsumi ; Arai, Kunizo ; Matsukawa, Toru ; Suzuki, Hirokazu ; Sugitani, Kayo ; Kagechika, Hiroyuki ; Kato, Satoru
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Genipin, a herbal iridoid, is known to have both neuroprotective and neuritogenic activity in neuronal cell lines. As it
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is structurally similar to tetrahydrobiopterin, its activity is believed to be nitric oxide (NO)-dependent. We previously proposed a novel neuroprotective activity of a genipin derivative, (1R)-isoPropyloxygenipin (IPRG001), whereby it reduces oxidative stress in RGC-5, a neuronal precursor cell line of retinal origin through protein S-nitrosylation. In the present study, we investigated another neuritogenic property of IPRG001 in RGC-5 cells and retinal explant culture where in we focused on the NO-cGMP-dependent and protein S-nitrosylation pathways. IPRG001 stimulated neurite outgrowth in RGC-5 cells and retinal explant culture through NO-dependent signaling, but not NO-dependent cGMP signaling. Neurite outgrowth with IPRG001 requires retinoic acid receptor β (RARβ) expression, which is suppressed by an RAR blocking agent and siRNA inhibition. Thereby, we hypothesized that RARβ expression is mediated by protein S-nitrosylation. S-nitrosylation of histone deacetylase 2 is a key mechanism in chromatin remodeling leading to transcriptional gene activation. We found a parallelism between S-nitrosylation of histone diacetylase 2 and the induction of RARβ expression with IPRG001 treatment. The both neuroprotective and neuritogenic activities of genipin could be a new target for the regeneration of retinal ganglion cells after glaucomatous conditions. © 2011 International Society for Neurochemistry.
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Cui, Hong ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Du, Wa ; Takuwa, Noriko ; Zhang, Wei ; Asano, Masahide ; Shibamoto, Toshishige ; Takuwa, Yoh
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Background: Sphingosine-1-phosphate receptor 2 (S1P2) is expressed in vascular endothelial cells (ECs). However, the rol
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e of S1P2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective: We tested the hypothesis that endothelial S1P2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods: Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results: S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2-null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr-null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2-null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2-null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2-deficient ECs showed more severe disassembly of adherens junctions with augmented S-nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion: S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis. © 2013 American Academy of Allergy, Asthma & Immunology.
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Cui, Hong ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Du, Wa ; Takuwa, Noriko ; Zhang, Wei ; Asano, Masahide ; Shibamoto, Toshishige ; Takuwa, Yoh
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Background Sphingosine-1-phosphate receptor 2 (S1P2) is expressed in vascular endothelial cells (ECs). However, the role
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of S1P 2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective We tested the hypothesis that endothelial S1P 2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2-null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr-null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2-null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2-null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2-deficient ECs showed more severe disassembly of adherens junctions with augmented S-nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis. © 2013 American Academy of Allergy, Asthma & Immunology.
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朝倉, 英策 ; Asakura, Hidesaku
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播種性血管内凝固症候群(DIC)モデルは、生体(ラット)に組織因子(TF)またはlipopolysaccharide(LPS)を投与することにより作成される。これまでの検討により、TF誘発DICモデルは、臨床の線溶優位型DICに、LPS誘発
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DICモデルは凝固優位(線溶抑制)型DICに病型が類似することを示してきた。今回、血管作動性物質の観点から、病態の解析を行った。その結果、前者はエンドセリン(ET)の上昇はみられないが、一酸化窒素(NO)が著増すること、後者はETは著増するがNOは中程度増加することが明らかになった。さらに、LPSモデルに対してET受容体拮抗薬を投与すると臓器障害や微小血栓形成が抑制されるが、TFモデルに対して投与しても何の影響もないことが明らかになり、LPSモデルにおけるETの病態への関与が示唆された。また、LPSモデルに対して特異的誘導型NO合成酵素(iNOS)インヒビターであるL-NILを投与すると、臓器障害や微小血栓形成および血圧低下の抑制がみられることが明らかになり、同DICモデルにおいてiNOSが病態の悪化に寄与していることが明らかになった。最後に、PGI2誘導体をLPSモデルに対して投与したところ、TNF、IL-6といった炎症性サイトカイン生成は有意に抑制され、凝血学的マーカー、臓器障害、微小血栓形成も有意に抑制された。また、NO代謝産物であるNOXの産生は有意に抑制されたが、ETに対する影響はみられなかった。以上、血管作動性物質の調整物質や、抗サイトカイン作用を合わせ持つ薬剤は、今後のDIC治療法として有望ではないかと考えられた。<br />Disseminated intravascular coagulation (DIC) is induced by tissue-factor (TF) or lipopolysaccharide (LPS) in rats. Our previous studies have demonstrated that TF-induced DIC mimics clinical DIC with enhanced fibrinolysis and LPS-induced DIC mimics clinical DIC with suppressed fibrinolysis. In this time, we have investigated the pathophysiology of DIC from the point of vasoactive substances. Plasma levels of endothelin (ET) were markedly increased in LPS-induced DIC but not at all in TF-induced DIC. On the other hand, plasma levels of NOX (metabolites of nitric oxide) were moderately increased in the former and markedly increased in the latter. Moreover, ET receptor antagonist improved organ dysfunction and glomerular fibrin deposition in LPS-induced DIC, while had no effect on the pathophysiology in TF-induced DIC. Thus, it was suggested that ET plays an important role in LPS-induced DIC. An inducible NO synthase inhibitor (L-NIL) improved organ dysfunction, glomerular fibrin deposition and depressed blood pressure, which could demonstrate that NO also plays an important role in LPS-induced DIC. In the last, PGI2 antagonist suppressed plasma levels of proinflammatory cytokines such as TNF and IL-6, and improved hemostatic markers, organ dysfunction and glomerular fibrin deposition. PGI2 antagonist suppressed plasma levels of NOX but not ET. These results suggest that the modulator of vasoactive substances or proinflammatory cytokines may be novel therapeutic methods in future.<br />研究課題/領域番号:16591808, 研究期間(年度):2004-2005<br />出典：「組織因子およびLPS誘発DICモデルにおける血管作動性物質発現機序と微小循環障害」研究成果報告書 課題番号16591808 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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長谷川, 光広 ; Hasegawa, Mitsuhiro
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金沢大学医学系研究科<br />中枢神経の再生をめざして、neurotrophins、neural cytokine、接着因子などのいわゆる神経成長栄養因子が、また一方で多彩な潜在能力を持つさまざまな幹細胞の治療への応用の可能性が報告されて
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いる。しかしながら、損傷されたmotoneuronの機能回復に関しては、いまだ治療へのbreakthroughが得られていない。我々は、定位脳的手技により顔面神経軸索損傷を脳幹内で作成した。頭蓋骨外の末梢部分での軸索損傷では顔面神経細胞は9割以上が生存しているにもかかわらず、脳幹内損傷ではほぼすべての顔面神経細胞は逆行性変性に陥った.その経時的生存率は,健常側に比して第14病日で25±3%,第28病日で3±1%であった。この顔面神経核の逆行性変性モデルの変性過程における一酸化窒素(NO)と内在性エリスロポエチン(EPO)ならびにEPO受容体(EPO-R)の発現の詳細を調べ,さらに遺伝子組み替えヒトエリスロポエチン(rhEPO)の腹腔内投与による神経細胞保護効果の可能性を検討した.組織学的検討にでは,正常組織では星状膠細胞膜がEPO陽性,顔面神経細胞膜がEPO-R陽性,かつそれぞれの細胞はNADPH-diaphorase陰性であった.顔面神経軸索損傷により,顔面神経核周辺にEPO陽性星状膠細胞が集積した.一方,生存顔面神経細胞に占めるNADPH-diaphorase陽性細胞の比率は,第4病日で20±3%,第7病日で47±3%,第14病日で99±7%,第28病日で91±3%であった.rhEPOを連日腹腔内投与(5000U/kg)することにより,NADPH-diaphorase陽性顔面神経細胞の比率は有意に低下し,第7病日で35±1%,第14病日で75±5%,第28病日で81±5%であった。一方、生存神経細胞は,第7病日で61±3%,第14病日で43±7%,第28病日で8±1%と有意に増加した.以上の結果より,ラット顔面神経脳幹内損傷軸索に対してrhEPOを外因性に投与することで,顔面神経細胞の逆行性変性,脱落を抑制することができた.これは,脳幹内損傷顔面神経細胞の逆行性変性・脱落にNOによる酸化ストレスが関与し,外因性rhEPOがこれを抑制することにより神経保護作用を示すことが推察された。今後さらに逆行性変性の過程の詳細を検討し、その抑制機構と再生促進因子の作用機序を追及することで、単に神経脱落の現象を理解するにとどまらず、再生能力に乏しい中枢性軸索の生存保持・再生の糸口をつかむことが可能となると考えられた。<br />This study was aimed to find out whether recombinant human erythropoietin (rhEPO) might have neuroprotective effect on the lesioned facial nucleus after axotomy of the central portion in brain stem. In the facial nerve transection in brain stem, compared with the control side, the survival ratio of the facial motoneurons was 25.0±2.4% (175±18.4/703±37.1) on day 14 and 2.8±1.4%(22.3±12.7/783±58.5) on day 28. Immunohistochemically, EPO were detected on astrocyte and EPO-R were detected on facial motoneurons in control. EPO expression was localized to reactive astrocytes in lesioned side on day 14. Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry to detect the neuronal nitric oxide synthase (nNOS) showed that the facial motoneurons were not positive for NADPH-d in control and on day 1. On the contrary, increased NADPH-d activity was seen in the facial motoneurons on day 4. The number of NADPH-d positive neurons and the intensity increased along with survival time, and nearly all survived motoneurons were stained on day 14. Administration of rhEPO (5000 U/kg) decreases the enzymatic expression of the number and staining intensity on day14(75.3±4.9%(481±128/636±144). The rats received rhEPO daily at dose of 5000 U/kg showed the 42.6±6.7% of the survival ratio of facial motoneurons on day 14, and 8.2±0.5%(57.3±11.2/703±145) on day 28. On the basis of these findings, it is suggested that rhEPO could act as one of the neuroprotective factors either by suppressing the nNOS activity or reducing the NO-mediated neurotoxicity in the lesioned motoneurons.<br />研究課題/領域番号:16591434, 研究期間(年度):2004 – 2005<br />出典：「軸索損傷による中枢神経細胞の逆行性変性の抑制と再生促進にかかわる機構の解明」研究成果報告書 課題番号16591434（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-16591434/165914342005kenkyu_seika_hokoku_gaiyo/)を加工して作成
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白尾, 裕 ; Shirao, Yutaka
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金沢大学医学部<br />ストレプトゾトシン(STZ)-DMラットおよび自然発症DMラット(OLETFラット)を用いた。STZ-DMラットでは、網膜電図律動様小波(Oscillatory Potential、OP)が遅延しその時には網膜血管
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から色素は漏出しなかったが、その後インスリン治療によってOPは正常化し、OPが正常化した時期に網膜血管から色素が漏出した。網膜循環時間はOP遅延・復旧に一致して延長・復旧した。ウサギ摘出眼杯では酸素分圧の微細な低下でOPが可逆的に遅延した。正常ラットで、無選択性一酸化窒素合成酵素(nitric oxide synthase、NOS)阻害剤あるいは選択的神経型NOS阻害剤の投与はいずれも脈絡膜血流を減少させた。脈絡膜には誘導型NOS活性はほとんどなかった。神経網膜の全NOS活性は正常ラットとSTZ-DMラットとの間で等しかったが、網膜色素上皮―脈絡膜の全NOS活性は後者で低下しており、これは主に神経型に由来した。DMにおけるOP遅延には、神経網膜および脈絡膜の双方における低灌流-低酸素状態が関与する可能性がある。ドパミン系物質がSTZ-DMラットで有意に減少し、γ-アミノ酪酸、アスパラギン酸、グルタミン酸、タウリンは変化しなかった。高血糖が網膜内ドパミン合成を障害しOP振幅の減弱を招くらしいが、OP遅延とドパミン減少の時期は一致せず、他の実験でもドパミン系薬剤は振幅のみに影響したから、OP遅延と振幅減弱の機序は異なるらしい。自由摂食OLETFラットにおけるOP振幅は同系正常ラットに比べて大きく食餌制限OLETFラットに比べて小さかった。自由摂食OLETFラットにおいては高血糖でもコレシストキニンA受容体の異常によってOPが増大したが、食餌制限OLETFラットでは高血糖による減弱分だけさらにOP振幅が増大したと解釈される。自由摂食OLETFラットでは食餌制限OLETFラットに比較して、OPは遅延していた。網膜内ドパミン量およびチロシン水酸化酵素活性は増大していたが、γ-アミノ酪酸、アスパラギン酸、グルタミン酸、タウリンは変化しなかった。自由摂食LETFラットでは同系正常ラットに較べて血管内皮増殖因子mRNA、最終糖化産物物量も増加していた。高血糖は、網膜血流および脈絡膜血流を低下させて軽度の網膜低酸素状態をもたらしこれがOP遅延させ、また別の未解明の機序によって網膜内ドパミン代謝低下をもたらしこれがOP振幅減弱させ、OP遅延をもたらす変化は発生後短期間であれば可逆的である。<br />The oscillatory potentials (Ops) of the electroretinogram were delayed in streptozotocin (STZ)-induced diabetic rats as long as they were hyperglycemic and were restored to normal as long as they became normoglycemic by a subsequent insulin treatment, which chronologically coincided with a decrease and an increase in the retinal blood flow but not with the degree of retinal vascular leakage. The Ops of excised rabbit eye cups were very sensitively delayed to minute hypoxia. In control rats, nitric oxide synthase (NOS) inhibitors, non-selective or neuronal NOS-selective, similarly decreased the choroidal blood flow. Inducible NOS was hardly detected in the rat choroid. Total NOS activity in the retinal pigment epithelium (RPE)-choroid decreased in STZ-induced diabetic rats, while that in the neural retina was not. Neuronal NOS was supposedly responsible for the abovementioned decrease in the NOS activity. These results suggest that the OP delay in diabetes is underlain by hypoperfusion-hypoxia in both the neural retina and the choroid.The intra-neural retinal contents of dopamine and its metabolites were significantly lower in STZ-induced diabetic rats, while that of other putative intra-retinal neurotransmitters such as gamma-amino butylic acid, aspartic acid, glutamic acid and taurine was not. The intra-neural retinal content of dopamine was chronologically correlated to the OP amplitude but not to the degree of OP delay. Our previous study had revealed dopamine enhances the OP amplitude but has no effect on the OP time course. These results suggest that the delay and the attenuation of the Ops in diabetes may derive from separate mechanisms.Genetically-programmed spontaneously diabetic rats (OLETF rats) on ad-libitum feeding (hyperglycemic) had larger OP than the non-diabetes-programmed rats of the same strain (normoglycemic) and smaller OP than the OLETF rats on diet (normoglycemic). This result can be interpreted as the OLETF rats on ad-libitum feeding showed larger-than-normal Ops because of their inherited defect of cholecystokinnin-A receptor and the OLETF rats on diet gained further OP amplitude by the amount of hyperglycemia-dependent decrease. The OLETF rats on ad-libitum feeding showed delayed Ops compared with the OLETF rats on diet. The intra-neural retinal content of dopamine and the activity of the rate-limiting enzyme for dopamine synthesis were significantly lower in the OLETF rats on ad-libitum feeding, while intra-neural retina content of other putative intra-retinal neurotransmitters such as gamma-amino butylic acid, aspartic acid, glutamic acid and taurine was not. The OLETF rats on ad-libitum feeding had significantly higher levels of vascular endothelial growth factor and advanced glycation end-product.Hyperglycemia supposedly decreases the blood flow in both the neural retina and the choroid, which may manifest as the OP delay ; and diminishes the neural retinal dopamine metabolism, which may manifest as the OP attenuation. The mechanism responsible for the OP delay is reversible as long as hyperglycemia persists within the order of weeks.<br />研究課題/領域番号:10671637, 研究期間(年度):1998 – 1999<br />出典：「自然発症糖尿病ラットにおける網膜機能異常の解明と治療」研究成果報告書 課題番号10671637（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-10671637/106716371999kenkyu_seika_hokoku_gaiyo/）を加工して作成
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