Mizuno Akira, Cherepanov Stanislav M, Kikuchi Yusuke, Fakhrul Azam Akm, Akther Shirin, Deguchi Kisaburo, Yoshihara Toru, Ishihara Katsuhiko, Shuto Satoshi, Higashida Haruhiro
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Department of Basic Research on Social Recognition, Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan.
Brain Sci. 2015 Jan 20;5(1):3-13. doi: 10.3390/brainsci5010003.
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.
催产素（OT）是一种九肽激素，分泌至大脑和血液循环中。OT不仅在雌性生殖期子宫收缩和排乳过程中发挥经典的神经激素作用，还在两性的社会认知和互动中具有新的关键神经调节作用。通过鼻腔喷雾单次给予OT可增强健康受试者和精神疾病患者的相互认知和信任，这表明OT是治疗自闭症谱系障碍、精神分裂症及其他一些精神疾病的潜在治疗药物。尽管其作用机制尚不完全清楚，但OT很可能能够转运至大脑，在那里激活OT受体以发挥其功能。然而，转运至大脑的量可能较低。为确保等效效果，一种具有长效且有效血脑屏障穿透特性的OT类似物作为治疗药物将更有益。在此，我们设计并合成了一种新的催产素类似物，脂化催产素-1（LOT-1），其中两个棕榈酰基团分别与OT分子中半胱氨酸9残基的氨基和酪氨酸8残基的酚羟基共轭。为确定LOT-1是否真的对中枢神经系统有作用，我们在帕金森病非运动性精神症状的CD157基因敲除模型小鼠中检测了其效果。与OT相似，该类似物在CD157基因敲除小鼠腹腔注射30分钟后，在中央区域有社会目标的旷场试验中可缓解焦虑样行为和社会回避。在注射后24小时检测时，用LOT-1处理的小鼠比给予OT的小鼠恢复得更好。结果表明，LOT-1在恢复社会行为障碍方面具有功能优势，如由神经退行性疾病、自闭症谱系障碍和精神分裂症引起的障碍。
