Comparative Intracerebroventricular and Intrathecal Administration of a Nanomolar Macrocyclic Melanocortin Receptor Agonist MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro]) Decreases Food Intake in Mice.
Comparative Intracerebroventricular and Intrathecal Administration of a Nanomolar Macrocyclic Melanocortin Receptor Agonist MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro]) Decreases Food Intake in Mice.
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DOI：
10.1021/acschemneuro.0c00409
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发表时间：
2020-10-07
影响因子：
5
通讯作者：
Haskell-Luevano C
中科院分区：
文献类型：
--
作者：
Adank DN;Lunzer MM;Ericson MD;Koeperich ZM;Wilber SL;Fleming KA;Haskell-Luevano C
迫切需要找到安全的疗法来治疗日益肥胖的人口和与能量稳态失衡相关的疾病。黑素皮质素-3受体(MC3R)和黑素皮质素-4受体(MC4R)配体长期以来一直是帮助科学家了解能量平衡和摄食行为调节的焦点。在这里，我们使用纳米分子大环黑素皮质素受体激动剂配体MDE6-5-2c(c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro)]来研究鞘内(IT)直接注入脊髓与脑室(ICV)直接注入大脑的代谢和能量止血特性。总体而言，中央脑室注射MDE6-5-2c以剂量依赖的方式导致食物摄入量减少，并降低呼吸交换率(RER)。比较IT和icv给药MDE6-5-2c的结果表明，MDE6-5-2c通过IT对小鼠的取食行为和RER均有较长的作用时间。比较C-肽、Ghrelin、GIP、瘦素、IL-6和抵抗素血浆激素和生物标志物的变化。与脑室给药对照组相比，脑室注射MDE6-5-2c组的血浆抵抗素水平降低。鞘内注射可显著降低炎症细胞因子白介素6(IL-6)水平。对非选择性MC3R和MC4R大环激动剂MDE6-5-2c分子的研究揭示了基于ICV或IT给药途径的摄食量、RER和血浆生物标志物的差异，并将这种新的分子化学类型表征为研究体内黑素皮质素系统的分子探针。
There is a critical need to find safe therapeutics to treat an increasingly obese population and diseases associated with an imbalance in energy homeostasis. The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) ligands have long been the focus to help scientists understand energy homeostasis and the regulation of feeding behavior. Herein, we use a nanomolar macrocyclic melanocortin receptor agonist ligand MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro) to examine metabolic and energy hemostasis profiles upon intrathecal (IT) administration directly into the spinal cord as compared to intracerebroventricular (ICV) administration directly into the brain. Overall, central ICV administration of MDE6-5-2c resulted in decreased food intake, in a dose-dependent manner, and decreased respiratory exchange ratio (RER). Comparison of IT versus ICV routes of MDE6-5-2c administration resulted in MDE6-5-2c possessing a longer duration of action on both feeding behavior and RER via IT. The C-peptide, ghrelin, GIP, leptin, IL-6, and resistin plasma hormones and biomarkers were compared using IT versus ICV MDE6-5-2c routes of administration. Plasma resistin levels were decreased upon ICV treatment of MDE6-5-2c, as compared to ICV vehicle control treatment. Intrathecal treatment resulted in significantly decreased inflammatory cytokine interleukin-6 (IL-6) levels compared to ICV administration. Investigation of the nonselective MC3R and MC4R macrocyclic agonist MDE6-5-2c molecule revealed differences in food intake, RER, and plasma biomarker profiles based upon ICV or IT routes of administration and characterize this novel molecular chemotype as a molecular probe to study the melanocortin system in vivo.
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影响因子：
3
作者：
Chen, AS;Metzger, JM;Van der Ploeg, LHT
通讯作者：
Van der Ploeg, LHT
DOI：
10.1006/bbrc.1993.2125
发表时间：
1993-09-15
影响因子：
3.1
作者：
CHHAJLANI, V;MUCENIECE, R;WIKBERG, JES
通讯作者：
WIKBERG, JES
影响因子：
4.8
作者：
Haskell-Luevano, Carrie;Schaub, Jay W.;Xiang, Zhimin
通讯作者：
Xiang, Zhimin
影响因子：
3.5
作者：
CASTELL, JV;GOMEZLECHON, MJ;HEINRICH, PC
通讯作者：
HEINRICH, PC
影响因子：
14.2
作者：
Boehm, Markus;Apel, Mara;Raap, Ulrike
通讯作者：
Raap, Ulrike