The Study of Heme Oxygenase Induction in the Hippocampus by Brain Ischemia and Hypoxia.

脑缺血缺氧诱导海马血红素加氧酶的研究。

• 批准号: 10672162
• 负责人: TANIGUCHI Takashi
• 金额: $ 1.47万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672162/
• 关键词: Brain ischemia; Hippocampus; Heme Oxygenase; Microglia; Astrocyte; Oxidative Stress; Bilverdin; Nonsteroidal Anti-inflammatory Drug (NSAID); 一酸化窒素合成酵素(iNOS); グルタミン酸受容体; プロティンキナーゼC; Peroxisome Proliferator-activated receptor-γ(PPARγ); 一過性前脳虚血 /

It is known that glial cells such as microglia and astrocytes are relatively resistance to stress of cell injury in comparison with neuronal cells. Under severe injury in the brain, glial cells induced inducible nitric oxide (NO) synthase (iNOS) and produced massive NO amount, and then surrounding neuronal cells underwent to apoptotic cell death. It is also known that biliverdin, which is produced by heme oxygenase (HO), is a potent endogenous anti-oxidant . Therefore, we focused the heme oxygenase and studied HO function in this research project. In the models of hippocampal injury such as 1) transient forebrain ischemia, 2) intracerebroventricular microinjection of kainate and 3) intrahippocampal microinjection of lipopolysaccharide and interferon-γ, the protein level of inducible HO(HO-1) was significantly increased in the hippocampus, but the lever of constitutive HO (HO-2) did not changed. One day after transient ischemia, HO-1 was markedly induced in hippocampal CA1 neurons, but subsequently, HO-1 level was decreased and neuronal loss was occurred. On the other hand, microglia and astrocytes continuously induced HO-1 and then did not die in these hippocampal injury models. Thus, the cells continuously expressing HO-1 may resistance to die.Next we searched drugs which markedly induce HO-1, The agonists of metabotropic glutamate receptor induced HO-1 mediated by activation of protein kinase C. Surprisingly, nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin, and ligands of transcription factor PPARγsuch as 15-d PGJィイD22ィエD2 inhibited induction of iNOS and NO production, but markedly induced HO-1 in cultured glial cells. These results suggest that several NSAIDs and PRARγligands are useful for cell protection on the brain injury.

众所周知，小胶质细胞和星形胶质细胞等胶质细胞与神经元细胞相比，对细胞损伤的应激具有相对的抵抗力。脑内严重损伤时，神经胶质细胞诱导诱导型一氧化氮合酶（NO）产生大量NO，周围神经元细胞发生细胞凋亡。众所周知，由血红素加氧酶（HO）产生的胆绿素是一种有效的内源性抗氧化剂。因此，本课题以血红素加氧酶为研究重点，研究HO的功能。海马损伤模型(1)短暂性前脑缺血、2)脑室内微量注射海碱盐、3)海马内微量注射脂多糖和干扰素-γ)中，海马诱导型HO（HO-1）蛋白水平显著升高，而组成型HO（HO- 2）水平未发生变化。短暂性缺血1 d后，海马CA1神经元HO-1被明显诱导，但随后HO-1水平降低，神经元丢失。另一方面，在海马损伤模型中，小胶质细胞和星形胶质细胞持续诱导HO-1而未死亡。因此，持续表达HO-1的细胞可能会抵抗死亡。接下来我们搜查了药物明显诱发HO-1,诱导HO-1 metabotropic谷氨酸受体介导的受体激动剂激活蛋白激酶c。令人惊讶的是,非甾体类抗炎药(非甾体抗炎药)如消炎痛、和配体的转录因子PPARγ等十五排d PGJィイD22摊位ィエD2抑制诱导进气阀打开,没有生产,但明显诱导HO-1培养的神经胶质细胞。这些结果表明，几种非甾体抗炎药和prar γ配体对脑损伤的细胞保护是有用的。

项目成果

松岡 康治: "一過性前脳虚血におけるヘムオキシゲナーゼの誘導:虚血性神経細胞死" 山嶋哲盛編:サイメッド・パブリケーションズ社, 5頁(総頁数:190) (1998)

Yasuharu Matsuoka：“短暂前脑缺血中血红素加氧酶的诱导：缺血性神经元死亡”，山岛哲森编辑：Cymed Publications，5页（总页数：190）（1998年）

Yoshihisa Kitamura: "Acivators of peroxisome proliferator-activated receptor-γ(PPARγ)inhibit inducible NO synthase expression but increase heme oxygense-1 expression in rat glial cells."Neuroscience Letters. 262・2. 129-132 (1999)

Yoshihisa Kitamura：“过氧化物酶体增殖物激活受体-γ (PPARγ) 的激活剂抑制诱导型 NO 合酶表达，但增加大鼠神经胶质细胞中血红素氧合酶 1 的表达。”神经科学快报 262・2 (1999)。

Yasuji Matsuoka, et al.: "Induction of heme oxygenase-1 and major histocompatibility complex antigens in transient forebrain ischemia"J.Cereb. Blood Flow Metab.. 85(4). 824-832 (1998)

Yasuji Matsuoka 等人：“短暂性前脑缺血中血红素加氧酶-1 和主要组织相容性复合物抗原的诱导”J.Cereb。

Yasuji Matsuoka, et al.: "Expression of heme oxygenase-1 mediated by non-NMDA and metabotropic receptors in glial cells-Possible involvement of reactive oxygene species production and protein kinase C activation."Neuropharmacology. 38(6). 825-834 (1999)

Yasuji Matsuoka 等人：“神经胶质细胞中非 NMDA 和代谢型受体介导的血红素加氧酶 1 的表达 - 可能参与活性氧物质的产生和蛋白激酶 C 的激活。”神经药理学。

Yasuji Matsuoka: "Expression of heme oxygense-1 mediated by non-NMDA and metabotropic receptors in glial cells:Possible involvement of reactive oxygene species production and protein kinase C activation."Neuropharmacology. 38・6. 825-834 (1999)

Yasuji Matsuoka：“神经胶质细胞中非 NMDA 和代谢型受体介导的血红素氧酶-1 的表达：可能涉及活性氧物质的产生和蛋白激酶 C 的激活。” 38・6 (1999)。