Department of Health Science, Faculty of Psychological and Physical Science, Aichi Gakuin University, 12 Araike, Iwasaki-cho, Nisshin, Aichi 470-0195, Japan.
Curr Pharm Des. 2011;17(5):410-23. doi: 10.2174/138161211795164167.
Midkine (MK) is a heparin-binding cytokine, and promotes growth, survival, migration and other activities of target cells. After describing the general properties of MK, this review focuses on MK and MK inhibitors as therapeutics for diseases in the central nervous system. MK is strongly expressed during embryogenesis especially at the midgestation period, but is expressed only at restricted sites in adults. MK expression is induced upon tissue injury such as ischemic brain damage. Since exogenously administered MK or the gene transfer of MK suppresses neuronal cell death in experimental systems, MK has the potential to treat cerebral infarction. MK might become important also in the treatment of neurodegenerative diseases such as Alzheimer's disease. MK is involved in inflammatory diseases by enhancing migration of leukocytes, inducing chemokine production and suppressing regulatory T cells. Since an aptamer to MK suppresses experimental autoimmune encephalitis, MK inhibitors are promising for the treatment of multiple sclerosis. MK is overexpressed in most malignant tumors including glioblastoma, and is involved in tumor invasion. MK inhibitors may be of value in the treatment of glioblastoma. Furthermore, an oncolytic adenovirus, whose replication is under the control of the MK promoter, inhibits the growth of glioblastoma xenografts. MK inhibitors under development include antibodies, aptamers, glycosaminoglycans, peptides and low molecular weight compounds. siRNA and antisense oligoDNA have proved effective against malignant tumors and inflammatory diseases in experimental systems. Practical information concerning the development of MK and MK inhibitors as therapeutics is described in the final part of the review.
中期因子 (MK) 是一种肝素结合细胞因子，可促进靶细胞的生长、存活、迁移和其他活动。在描述了 MK 的一般特性后，本综述重点介绍了 MK 和 MK 抑制剂作为治疗中枢神经系统疾病的药物。MK 在胚胎发生过程中强烈表达，特别是在中期妊娠期间，但在成人中仅在有限的部位表达。MK 表达在组织损伤后诱导，如缺血性脑损伤。由于外源性给予 MK 或 MK 的基因转移可抑制实验系统中的神经元细胞死亡，因此 MK 具有治疗脑梗死的潜力。MK 在阿尔茨海默病等神经退行性疾病的治疗中也可能变得重要。MK 通过增强白细胞迁移、诱导趋化因子产生和抑制调节性 T 细胞而参与炎症性疾病。由于针对 MK 的适体可抑制实验性自身免疫性脑脊髓炎，因此 MK 抑制剂有望治疗多发性硬化症。MK 在大多数恶性肿瘤中过度表达，包括神经胶质瘤，并参与肿瘤侵袭。MK 抑制剂可能对治疗神经胶质瘤有价值。此外，复制受 MK 启动子控制的溶瘤腺病毒可抑制神经胶质瘤异种移植物的生长。正在开发的 MK 抑制剂包括抗体、适体、糖胺聚糖、肽和低分子量化合物。siRNA 和反义寡核苷酸在实验系统中已被证明对恶性肿瘤和炎症性疾病有效。在综述的最后部分描述了作为治疗剂开发 MK 和 MK 抑制剂的实用信息。
