ANGIOGENIC INHIBITION OF SPINORPHIN , A POTENT ANALGESIC AND ANTIINFLAMMATORY SUBSTANCE

螺旋啡的血管生成抑制作用，一种有效的镇痛和抗炎物质

• 批准号: 13672410
• 负责人: SHIMAMURA Marko
• 金额: $ 0.83万
• 依托单位: TOKYO METROPOLITAN ORGANIZATION OF MEDICAL SCIENCE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672410/
• 关键词: angiogenesis; spinorphin; analgesia; CAM; endothelial cells; enkephalin; enzyme inhibitor; bradykinin; 抗炎症作用; 血管新生阻害; ブラジキニン

Angiogenesis is the formation of new blood vessels and is essential for tissue development, regeneration and remodeling. Angiogenesis also plays an important role in many pathological processes, such as growth and metastasis of solid tumor, diabetic retinopathy, rheumatoid arthritis and psoriasis. The inhibition of angiogenesis results in suppression of these diseases. On the other hand, we previously found a small peptide with inhibiting activity against proteases that degraded endogenous opioid peptide, enkephalin in human spinal fluid and purified it named as spinorphin from bovine spinal cord. Spinorphin is a peptide that consists seven amino acid residues, LVVYPWT. Spinorphin potently inhibited enkephalin-degrading enzymes and exhibited analgesic activity in mice and inflammatory responses such as chemotaxis, O_2-generation and exocytosis by human polymorphonuclear nutrophils.In this study, we investigated the antiangiogenic activity of spinorphin using in vivo and in vitro assays … More . First we examined its antiangiogenic activity using a chick embryo chorioallantoic membrane (CAM). Spinorphin potently inhibited angiogenesis, dose-dependently. This activity increased by simultaneous addition of an aminopeptidase inhibitor, leuhistin since spinorphin was degraded by aminopeptidase in CAM assay. The mechanism of this inhibition was examined using endothelial cells. This compound did not inhibit proliferation or tube formation of bovine pulmonary artcrial endothelial (BPAE)cells. Previously, spinorphin was reported to inhibit bradykinin-induced nociceptive flexor responses in mice. This suggested that spinorphin may bind bradykinin receptors. We examined antiangiogenic activity of bradykinin antagonists and they showed potent inhibition of angiogenesis in CAM. However, spinorphin did not inhibit binding of bradykinin to bradykinin receptors. Moreover, a specific receptor for spinorphin was suggested to exist in rat spinal cord. In contrast, some inhibitors of angiotensin-converting enzyme (ACE) or aminopeptidase (AP) suppressed angiogenesis in CAM. As spinorphin inhibits enzyme activities of ACE and AP, antiangiogenic activity of spinorphin may depend on its enzyme regulation. Less

血管生成是新血管的形成，是组织发育、再生和重塑所必需的。血管生成也在实体瘤的生长和转移、糖尿病视网膜病变、类风湿性关节炎和银屑病等许多病理过程中发挥重要作用。血管生成的抑制导致这些疾病的抑制。另一方面，我们以前发现了一种具有抑制酶活性的小肽，可以降解人脊髓液中的内源性阿片肽-脑啡肽，并将其从牛脊髓中纯化出来，命名为Spin。旋诺芬是一种由七个氨基酸残基组成的多肽，即LVVYPWT。Spinogin能有效地抑制脑啡肽降解酶的活性，并在小鼠体内表现出镇痛活性，并表现出对人多形核白细胞的趋化、产氧和胞吐等炎症反应。在本研究中，我们采用…法研究了Spinogin的体内和体外抗血管生成活性更多。首先，我们使用鸡胚绒毛尿囊膜(CAM)检测了它的抗血管生成活性。旋诺芬有效地抑制血管生成，呈剂量依赖关系。由于在CAM试验中，Spin被氨基肽酶降解，因此同时加入氨基肽酶抑制剂亮氨酸亮氨酸可以提高这种活性。用内皮细胞研究了这种抑制作用的机制。该化合物不抑制牛肺动脉内皮细胞(BPAE)的增殖或管状形成。此前，Spin被报道能抑制缓激肽诱导的小鼠伤害性屈肌反应。这提示Spin可能与缓激肽受体结合。我们检测了缓激肽拮抗剂的抗血管生成活性，它们显示出对CAM中血管生成的有效抑制。然而，Spin并不抑制缓激肽与缓激肽受体的结合。此外，还发现在大鼠脊髓中存在一种特异性的Spin受体。相反，一些血管紧张素转换酶(ACE)或氨基肽酶(AP)的抑制剂抑制了CAM中的血管生成。由于Spin抑制血管紧张素转换酶(ACE)和碱性磷酸酶(AP)的活性，其抗血管生成活性可能依赖于其酶调节作用。较少

项目成果

Yamamoto, Y. et al.: "Spinorphin as an Endogenous Inhibitor of Enkepjalin-degrading Enzymes : Roles in Pain and Inflammation"Current Protein and Peptide Sciences. 587-599 (2002)

Yamamoto, Y. 等人：“Spinorphin 作为 Enkepjalin 降解酶的内源抑制剂：在疼痛和炎症中的作用”当前蛋白质和肽科学。

Yamamoto, Y., Ono, H., Ueda, A., Shimamura, M., Nishimura, K. and Hazato, T.: "Spinorphinas an endogenous inhibitor of enkephalin-degrading enzymes: Roles in pain and inflammation"Current Protein and Peptide Sciences. 3. 587-599 (2002)

Yamamoto, Y.、Ono, H.、Ueda, A.、Shimamura, M.、Nishimura, K. 和 Hazato, T.：“Spinorphinas 是脑啡肽降解酶的内源性抑制剂：在疼痛和炎症中的作用”当前蛋白质和

Kasai, S., Nagasawa, H., Shimamura, M., Uto, Y. and Hori, H.: "Design and synthesis of antiangiogenic/heparin-binding arginine dendrimer mimicking the surface of endostatin"Bioorg.Med. Chem.Lett.. 12. 951-954 (2002)

Kasai, S.、Nagasawa, H.、Shimamura, M.、Uto, Y. 和 Hori, H.：“模拟内皮抑素表面的抗血管生成/肝素结合精氨酸树枝状聚合物的设计和合成”Bioorg.Med。

Nagasawa, H., Yamashita, M., Mikamo, N., Shimamura, M., Oka, S., Uto, Y. and Hori, H.: "Design, synthesis and biological activities of antiangiogenic hypoxic cytotoxin, triazine-N-oxide derivatives"Comp. Biochem. Physiol. A Mol. Integr. Physiol.. 132. 33-

Nagasawa, H.、Yamashita, M.、Mikamo, N.、Shimamura, M.、Oka, S.、Uto, Y. 和 Hori, H.：“抗血管生成缺氧细胞毒素三嗪-N 的设计、合成和生物活性

Shimamura, M., Hazato, T.et al.: "A hypoxia-dependent nitroimidazole KIN-841 inhibits tumor-specific angiogenesis by blocking production of angiogenic factor"Brit. J. Cancer. 88. 307-313 (2003)

Shimamura, M., Hazato, T.等人：“缺氧依赖性硝基咪唑 KIN-841 通过阻断血管生成因子的产生来抑制肿瘤特异性血管生成”Brit。