Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice.
Lipo-oxytocin-1, a Novel Oxytocin Analog Conjugated with Two Palmitoyl Groups, Has Long-Lasting Effects on Anxiety-Related Behavior and Social Avoidance in CD157 Knockout Mice.
复制标题
DOI：
10.3390/brainsci5010003
复制
发表时间：
2015-01-20
期刊：
影响因子：
3.3
通讯作者：
Higashida H
中科院分区：
文献类型：
--
作者：
Mizuno A;Cherepanov SM;Kikuchi Y;Fakhrul AA;Akther S;Deguchi K;Yoshihara T;Ishihara K;Shuto S;Higashida H
催产素(OT)是一种非肽类激素，分泌到大脑和血液循环中。催产素不仅在女性生殖阶段的子宫收缩和乳汁排出中具有经典的神经激素作用，而且还被证明在两性的社会认知和互动中具有新的关键神经调节作用。通过鼻腔喷雾给药一次，可以增加健康受试者和精神病人的相互认可和信任，这表明OT是治疗自闭症谱系障碍、精神分裂症和其他一些精神疾病的潜在药物。尽管其机制尚不清楚，但OT很可能被转运到大脑中，在那里它激活OT受体以发挥其在大脑中的功能。然而，输送到大脑中的量可能很低。为了确保同等效果，具有持久和有效的血脑屏障穿透特性的OT类似物将有利于作为治疗药物使用。在这里，我们设计并合成了一种新的催产素类似物，脂催产素-1(Lot-1)，其中两个棕榈酰基连接在OT分子半胱氨酸9残基的氨基和酪氨酸8残基的酚羟基上。为了确定LOT-1是否确实对中枢神经系统有影响，我们在帕金森氏病非运动性精神症状的CD157基因敲除模型小鼠中检测了它的影响。与OT类似，该类似物在CD157基因敲除小鼠腹腔注射30min后，在中央区域与社会靶点进行的旷场测试中，拯救了焦虑样行为和社交回避。注射后24小时检查，Lot-1组小鼠的恢复情况明显好于OT组。结果表明，Lot-1在神经退行性疾病、自闭症谱系障碍和精神分裂症引起的社会行为障碍的恢复方面具有功能优势。
Oxytocin (OT) is a nonapeptide hormone that is secreted into the brain and blood circulation. OT has not only classical neurohormonal roles in uterine contraction and milk ejection during the reproductive phase in females, but has also been shown to have new pivotal neuromodulatory roles in social recognition and interaction in both genders. A single administration of OT through nasal spray increases mutual recognition and trust in healthy subjects and psychiatric patients, suggesting that OT is a potential therapeutic drug for autism spectrum disorders, schizophrenia, and some other psychiatric disorders. Although the mechanism is not well understood, it is likely that OT can be transported into the brain where it activates OT receptors to exert its function in the brain. However, the amount transported into the brain may be low. To ensure equivalent effects, an OT analog with long-lasting and effective blood-brain barrier penetration properties would be beneficial for use as a therapeutic drug. Here, we designed and synthesized a new oxytocin analog, lipo-oxytocin-1 (LOT-1), in which two palmitoyl groups are conjugated at the amino group of the cysteine9 residue and the phenolic hydroxyl group of the tyrosine8 residue of the OT molecule. To determine whether LOT-1 actually has an effect on the central nervous system, we examined its effects in a CD157 knockout model mouse of the non-motor psychiatric symptoms of Parkinson’s disease. Similar to OT, this analog rescued anxiety-like behavior and social avoidance in the open field test with the social target in a central arena 30 min after intraperitoneal injection in CD157 knockout mice. When examined 24 h after injection, the mice treated with LOT-1 displayed more recovery than those given OT. The results suggest that LOT-1 has a functional advantage in recovery of social behavioral impairment, such as those caused by neurodegenerative diseases, autism spectrum disorders, and schizophrenia.