Pharmacokinetics and Tissue Distribution of Humanin and Its Analogues in Male Rodents
Pharmacokinetics and Tissue Distribution of Humanin and Its Analogues in Male Rodents
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DOI：
10.1210/en.2012-2004
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发表时间：
2013-10-01
期刊：
影响因子：
4.8
通讯作者：
Cohen, Pinchas
中科院分区：
文献类型：
--
作者：
Chin, Yung-Ping;Keni, Jyotsna;Cohen, Pinchas
Humanin （HN）是一种由24个氨基酸组成的线粒体衍生肽，具有多种细胞保护作用，包括在糖尿病中的新作用。本研究的目的是检测具有巨大治疗潜力的人类类似物（HNG和非igfbp -3结合物HNGF6A）的药代动力学。11周龄雄性IGFBP-3（-/-）和野生型（WT）小鼠分为3组：HNG组WT小鼠、HNGF6A组WT小鼠和HNG组IGFBP-3（-/-）小鼠。小鼠腹腔注射HN类似物后，取血浆，ELISA法测定HN水平。用HNGF6A处理的WT小鼠和用HNG处理的IGFBP-3（-/-）小鼠的HN半衰期比用HNG处理的WT小鼠长。注射HNG后，IGF-1和IGFBP-3水平均随时间下降。同时给成年雄性sd大鼠注射HNG， ELISA法测定其在血浆、肝脏、心脏、脑等组织中的HN水平。发现大鼠的HN半衰期比小鼠长。在大鼠中，HN水平在血浆中最高，在肝脏中存在，在大脑和心脏中检测不到。目前的研究提供了HN和IGFBP-3在循环中的关联的证据，并表明天然HN可能调节IGF-1和IGFBP-3的分布。结果还证明了HN类似物在啮齿动物中的不同动力学特征和种间变异。血浆中循环HN的持续水平强调了HN类似物作为一种新的糖尿病治疗干预手段的潜在价值。
Humanin (HN) is a novel 24-amino acid mitochondrial-derived peptide that has demonstrated diverse cytoprotective effects, including an emerging role in diabetes. The purpose of this study was to examine the pharmacokinetics of humanin analogues, which show great potential as therapeutic agents (HNG and the non-IGFBP-3 binding, HNGF6A). 11-week-old male IGFBP-3(-/-) and wild type (WT) mice were divided into 3 groups: WT mice treated with HNG, WT mice treated with HNGF6A, and IGFBP-3(-/-) mice treated with HNG. Plasma was obtained from mice following ip injection with HN analogues, and HN levels were measured with ELISA. WT mice treated with HNGF6A and IGFBP-3(-/-) mice treated with HNG displayed a longer half-life of HN compared with WT mice treated with HNG. Following HNG injection, both IGF-1 and IGFBP-3 levels decreased over time. Adult male Sprague Dawley rats were also ip injected with HNG, and HN levels were measured in various tissues (plasma, liver, heart, and brain) by ELISA. The half-life of HN was found to be longer in rats compared with mice. In rats, HN levels were found to be highest in plasma, present in liver, and undetectable in brain or heart. The current study provides evidence of HN and IGFBP-3 association in the circulation and suggests that native HN may modulate the distribution of IGF-1 and IGFBP-3. The results also demonstrate varying kinetic profiles of HN analogues and interspecies variation in rodents. Sustainable levels of circulating HN measured in plasma underline the potential value of HN analogues as a new therapeutic intervention in the treatment of diabetes.