摘要
目的新型异丁酸锂-L-脯氨酸螯合物尼布林(IsoLiPro)合成及表征分析,观察其药代动力学及抗躁狂作用。方法采用单一溶剂析晶法制备IsoLiPro,并采用粉末X射线衍射(XRD)、氢核磁共振波谱(NMRS)和傅里叶变换红外光谱(FTIR)对所得的IsoLiPro进行鉴定和解析;采用电感耦合等离子体质谱(ICP-MS)检测灌胃给药不同时点IsoLiPro和Li_(2)CO_(3)2组大鼠血浆及肾脏、脑组织中锂元素含量,并进行药代动力学分析;蛋白质印迹检测体外培养小鼠海马神经元细胞系细胞经IsoLiPro处理后cAMP反应元件结合蛋白(CREB)、糖原合酶激酶-3β(GSK-3β)、细胞外调节蛋白激酶(Erk1/2)以及脑源性神经生长因子(BDNF)信号通路蛋白的表达及磷酸化程度;通过旷场行为学实验考察IsoLiPro对苯丙胺诱导的小鼠躁狂样症状的作用。结果各表征结果表明制得的IsoLiPro有别于异丁酸锂和脯氨酸,且相关参数表明其为单斜晶体结构;药代动力学结果表明IsoLiPro在大鼠血浆中存在良好的线性关系,药动学参数优于Li_(2)CO_(3)组;蛋白质电泳结果表明与同浓度Li_(2)CO_(3)组相比,IsoLiPro可显著增加p-GSK-3β、p-CREB、p-Erk1/2和BDNF的表达,差异有统计学意义(P<0.05),表明IsoLiPro具有良好的体外生物学活性;旷场行为学实验结果表明IsoLiPro可有效改善由苯丙胺诱导的小鼠过度运动行为,表现出较好的抗躁狂作用,且作用强于Li_(2)CO_(3)(P<0.05)。结论本研究成功制备新型螯合锂-IsoLiPro,该化合物在药代动力学和抗躁狂作用等方面均优于临床常用的Li_(2)CO_(3)。
Objective To observe the synthesis and representations of a novel Lithium isobutyrate-L-proline chelate(IsoLiPro),and investigate its pharmacokinetics and antimanic effects.Methods IsoLiPro was prepared by single solvent crystallization,and powder X-ray diffraction,hydrogen nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy were used to identify and analyze IsoLiPro.Inductively coupled plasma mass spectrometry was used to detect the content of Lithium in plasma and tissues of rats at different time points of gavage administration of IsoLiPro,and pharmacokinetic analysis was carried out.Protein electrophoresis detected the expression and activity changes of CREB,GSK-3β,Erk1/2,and BDNF signaling pathway proteins in vitro cultured HT22 cells after IsoLiPro treatment.The effect of IsoLiPro on amphetamine-induced mania-like symptoms of mice was investigated by open field experiments.Results The representation results showed that the prepared IsoLiPro molecules were different from those of Li isobutyrate and proline,and the relevant parameters indicated a monoclinic crystal structure.The mass spectrometry showed that IsoLiPro could exist in molecular form in 50% methanol aqueous solution.The pharmacokinetic results showed that there was a good linear relationship between IsoLiPro in rat plasma and there was significant difference in pharmacokinetic parameters compared with Li_(2)CO_(3).The results of protein electrophoresis showed that IsoLiPro significantly increased the expression of p-GSK-3β,p-CREB,p-Erk1/2,and BDNF,and had good in vitro biological activity.IsoLiPro effectively improved the excessive exercise behavior of mice caused by amphetamines,showing better anti-manic effect,which was stronger than Li_(2)CO_(3).Conclusion In this study a novel Li chelated IsoLiPro is successfully prepared and characterized,which is superior to Li_(2)CO_(3) used in clinical practice in terms of pharmacokinetics and anti-manic effect.
作者
唐勤敏
陈江
訾聃
李崧
谭俊
TANG Qinmin;CHEN Jiang;ZI Dan;LI Song;TAN Jun(Key Laboratory of Medical Biology,Guizhou Medical University,Guiyang 550004,Guizhou,China;Department of Obstetrics and Gynecology,Guizhou Provincial People's Hospital,Guiyang 550002,Guizhou,China;Research Institute of Neurological Diseases,the First Affiliated Hospital of Dalian Medical University,Dalian 116021,Liaoning,China)
出处
《贵州医科大学学报》
CAS
2024年第4期469-478,共10页
Journal of Guizhou Medical University
基金
国家自然科学基金面上项目(82171423)。
关键词
螯合锂盐
躁狂
单一析晶法
药代动力学
药效学
苯丙胺
lithium-complex
mania
single-crystallization
pharmacokinetic
pharmacodynamics
amphetamine