药学学报, 2019, 54(9): 1680-1687
庞璐璐, 高艳, 张丽花, 马金秋, 朱思庆, 朱林, 杜丽娜, 金义光. 治疗创伤后应激障碍的粉防己碱鼻用温敏凝胶研究[J]. 药学学报, 2019, 54(9): 1680-1687.
PANG Lu-lu, GAO Yan, ZHANG Li-hua, MA Jin-qiu, ZHU Si-qing, ZHU Lin, DU Li-na, JIN Yi-guang. Intranasal tetrandrine temperature-sensitive gel for treatment of post-traumatic stress disorder[J]. Acta Pharmaceutica Sinica, 2019, 54(9): 1680-1687.

庞璐璐1,2, 高艳2, 张丽花1,2, 马金秋1,2, 朱思庆2,3, 朱林2, 杜丽娜1,2,3, 金义光2,3
1. 山东中医药大学药学院, 山东 济南 250355;
2. 军事科学院军事医学研究院辐射医学研究所, 北京 100850;
3. 安徽医科大学, 安徽 合肥 230032
创伤后应激障碍(post-traumatic stress disorder,PTSD)以传统全身给药方式起效慢,不良反应明显。本文制备了粉防己碱鼻用温敏凝胶(intranasal tetrandrine temperature-sensitive gel,TTG),鼻内给药治疗小鼠PTSD。以泊洛沙姆为基质制备TTG,胶凝温度合适(低于32℃)、胶凝时间短(1.32 min),流变学考察表明TTG具有温度敏感性,小动物活体成像证明TTG鼻腔滞留时间长,蟾蜍上腭纤毛毒性实验表明制剂安全性高。所有动物实验经军事科学院军事医学研究院辐射医学研究所伦理委员会批准且实验均按照相关指导原则和规定进行。用单次延长应激(single prolonged stress,SPS)、足底电击方法建立小鼠PTSD模型,使其产生焦虑、恐惧行为。用高架十字迷宫评价SPS模型小鼠,其中开臂进入次数百分比(percentages of open arm entry numbers,OE)、开臂进入潜伏期(latency of open arm entries,OL)及开臂滞留时间(residence time of open arm entries,OT)均表明模型建立成功。TTG鼻腔给药7天后,SPS小鼠的OE和OT明显增加,OL明显降低;TTG还可明显减少条件恐惧箱中足底电击模型小鼠的不动时间。苏木精-伊红病理切片与c-fos免疫组化结果表明,TTG能明显改善PTSD模型小鼠海马、前额叶皮层及杏仁核部位的病理变化。因此,TTG是一种使用方便、安全有效的抗PTSD药物,为PTSD临床治疗提供新选择。
关键词:    创伤后应激障碍      粉防己碱      温敏凝胶      鼻腔给药      行为学     
Intranasal tetrandrine temperature-sensitive gel for treatment of post-traumatic stress disorder
PANG Lu-lu1,2, GAO Yan2, ZHANG Li-hua1,2, MA Jin-qiu1,2, ZHU Si-qing2,3, ZHU Lin2, DU Li-na1,2,3, JIN Yi-guang2,3
1. College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China;
2. Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China;
3. Anhui Medical University, Hefei 230032, China
The traditional systemic treatment of post-traumatic stress disorder (PTSD) requires a long time period for an effect and has obvious side effects. In this study, tetrandrine temperature-sensitive gel (TTG) was prepared for treatment of PTSD in mice by nasal administration. TTG was prepared with poloxamer as matrix, the gelation temperature was suitable (<32℃) and the gelation time was short (1.32 min). Rheology experiments demonstrated that TTG has temperature sensitivity. In vivo imaging system of small animals proved that TTG nasal cavity retention time was so long. The cilia toxic test of toad showed that the formulation was safe. Animal experiments were approved by the Ethics Committee of Beijing Institute of Radiation Medicine, Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. The mice were randomly assigned into healthy group, model group and TTG group. The PTSD model of mice was established by single prolonged stress (SPS) and foot-shock method to generate anxiety and fear behavior. On the day 0 of TTG administration, SPS model mice were evaluated by the elevated plus maze (EPM). Percentages of open arm entries number (OE), latency of open arm entries (OL) and the residence time of open arm entries (OT) all indicated that the SPS model was successfully established. On the 7th day of TTG administration, TTG increased the OE and OT, decreased the OL of SPS mice. The feard behavior of mice in the foot-shock model was tested using conditioned fear box, 7 days of TTG treatment can reduce the freezing time of the mice obviously. The pathological changes of hippocampus, prefrontal cortex and amygdala were observed by H&E histological sections and c-fos immunohistochemical expression. The main influenced areas of PTSD were revealed to be the CA1 of hippocampus, prefrontal cortex and amygdala. All of the above indicated that TTG is a convenient, safe and effective drug for PTSD treatment, and will provide a new choice for clinical management of PTSD.
Key words:    post-traumatic stress disorder    tetrandrine    temperature-sensitive gel    nasal administration    behavior   
收稿日期: 2019-06-26
DOI: 10.16438/j.0513-4870.2019-0510
通讯作者: 杜丽娜,Tel:86-10-66930216,E-mail:dulina@188.com;金义光,Tel:86-10-66931220,E-mail:jinyg@sina.com
Email: dulina@188.com;jinyg@sina.com
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[1] Jerud A, Pruitt L, Zoellner L, et al. The effects of prolonged exposure and sertraline on emotion regulation in individuals with posttraumatic stress disorder[J]. Behav Res Ther, 2016, 77:62-67.
[2] Georgopoulos AP, James LM, Christova P, et al. A two-hit model of the biological origin of posttraumatic stress disorder (PTSD)[J]. J Ment Health Clin Psychol, 2018, 2:9-14.
[3] Berke D, Kline N, Wachen J, et al. Predictors of attendance and dropout in three randomized controlled trials of PTSD treatment for active duty service members[J]. Behav Res Ther, 2019, 118:7-17.
[4] Seo EJ, Fischer N, Efferth T. Phytochemicals as inhibitors of NF-kappaB for treatment of Alzheimer's disease[J]. Pharmacol Res, 2018, 129:262-273.
[5] Qin G, Gui B, Xie J, et al. Tetrandrine alleviates nociception in a rat model of migraine via suppressing S100B and p-ERK activation in satellite glial cells of the trigeminal ganglia[J]. J Mol Neurosci, 2018, 64:29-38.
[6] Que X, Su J, Guo P, et al. Study on preparation, characterization and multidrug resistance reversal of red blood cell membrane-camouflaged tetrandrine-loaded PLGA nanoparticles[J]. Drug Deliv, 2019, 26:199-207.
[7] Jiang Q, Liu WY, Feng W, et al. Effects of prenatal tetrandrine treatment on the expression of kruppel-like factor 5 and survivin in the lung of congenital diaphragmatic hernia rat model induced by nitrofen[J]. Natl Med J China (中华医学杂志), 2018, 98:539-543.
[8] Thurgur H, Pinteaux E. Microglia in the neurovascular unit:blood-brain barrier-microglia interactions after central nervous system disorders[J]. Neuroscience, 2019, 405:55-67.
[9] Kanazawa T, Kaneko M, Niide T, et al. Enhancement of nose-to-brain delivery of hydrophilic macromolecules with stearate-or polyethylene glycol-modified arginine-rich peptide[J]. Int J Pharm, 2017, 530:195-200.
[10] Lin T, Liu E, He H, et al. Nose-to-brain delivery of macromolecules mediated by cell-penetrating peptides[J]. Acta Pharm Sin B, 2016, 6:352-358.
[11] Sunena Singh S, Mishra D. Nose to brain delivery of galantamine loaded nanoparticles:in-vivo pharmacodynamic and biochemical study in mice[J]. Curr Drug Deliv, 2019, 16:51-58.
[12] Trotta V, Pavan B, Ferraro L, et al. Brain targeting of resveratrol by nasal administration of chitosan-coated lipid microparticles[J]. Eur J Pharm Biopharm, 2018, 127:250-259.
[13] Hao J, Zhao J, Zhang S, et al. Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery[J]. Colloids Surf B Biointerfaces, 2016, 147:376-386.
[14] Soliman M, Elmowafy E, Casettari L, et al. Star-shaped poly(oligoethylene glycol) copolymer-based gels:thermo-responsive behaviour and bioapplicability for risedronate intranasal delivery[J]. Int J Pharm, 2018, 543:224-233.
[15] Kouchak M, Mahmoodzadeh M, Farrahi F. Designing of a pH-triggered carbopol(R)/HPMC in situ gel for ocular delivery of dorzolamide HCl:in vitro, in vivo, and ex vivo evaluation[J]. AAPS PharmSciTech, 2019. DOI:10.1208/s12249-019-1431-y.
[16] Hou W, Zhou Z, Zhang L, et al. Low-voltage-manipulating spin dynamics of flexible Fe3O4 films through ionic gel gating for wearable devices[J]. ACS Appl Mater Interfaces, 2019, 11:21727-21733.
[17] Huang J, Jiang X. Injectable and degradable pH-responsive hydrogels via spontaneous amino-yne click reaction[J]. ACS Appl Mater Interfaces, 2018, 10:361-370.
[18] Ci L, Huang Z, Liu Y, et al. Amino-functionalized poloxamer 407 with both mucoadhesive and thermosensitive properties:preparation, characterization and application in a vaginal drug delivery system[J]. Acta Pharm Sin B, 2017, 7:593-602.
[19] Cheng YK, Guo YW, Shang KX, et al. Selecting solvent and solubilizer for puerarin nasal drops by solubility and irritation[J]. China J Chin Mater Med (中国中药杂志), 2014, 39:4335-4339.
[20] Wan J, Liu D, Zhang J, et al. Single-prolonged stress induce different change in the cell organelle of the hippocampal cells:a study of ultrastructure[J]. Acta Histochem, 2016, 118:10-19.
[21] Alonso-Caraballo Y, Hodgson KJ, Morgan SA, et al. Enhanced anxiety-like behavior emerges with weight gain in male and female obesity-susceptible rats[J]. Behav Brain Res, 2019, 360:81-93.
[22] Brás S, Soares SC, Cruz T, et al. The feasibility of an augment reality system to study the psychophysiological correlates of fear-related responses[J]. Brain Behav, 2018, 8:e01084.
[23] Sanjo N, Nose Y, Shishido-Hara Y, et al. A controlled inflammation and a regulatory immune system are associated with more favorable prognosis of progressive multifocal leukoencephalopathy[J]. J Neurol, 2019, 266:369-377.
[24] Song X, He R, Han W, et al. Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats[J]. J Neurosci Res, 2019, 97:506-519.
[25] Fung C, Koussoulas K, Unterweger P, et al. Cholinergic submucosal neurons display increased excitability following in vivo cholera toxin exposure in mouse ileum[J]. Front Physiol, 2018. DOI:10.3389/fphys.2018.00260.
[26] Zhe X, Liu K, Mu Y, et al. Decreased regional cerebral perfusion at resting state in acute posttraumatic stress disorder resulting from a single, prolonged stress event[J]. Acad Radiol, 2016, 23:1083-1090.
[27] Sabbagh J, Cordova R, Zheng D, et al. Targeting the FKBP51/GR/Hsp90 complex to identify functionally relevant treatments for depression and PTSD[J]. ACS Chem Biol, 2018, 13:2288-2299.
[28] Lima B, Hammadah M, Wilmot K, et al. Posttraumatic stress disorder is associated with enhanced interleukin-6 response to mental stress in subjects with a recent myocardial infarction[J]. Brain Behav Immun, 2019, 75:26-33.
[29] Browne C, Falcon E, Robinson S, et al. Reversal of stress-induced social interaction deficits by buprenorphine[J]. Int J Neuropsychopharmacol, 2018, 21:164-174.
[30] Xu W, Meng K, Tu Y, et al. Tetrandrine potentiates the glucocorticoid pharmacodynamics via inhibiting P-glycoprotein and mitogen-activated protein kinase in mitogen-activated human peripheral blood mononuclear cells[J]. Eur J Pharmacol, 2017, 807:102-108.
[31] Maximino C, van der Staay FJ. Behavioral models in psychopathology:epistemic and semantic considerations[J]. Behav Brain Funct, 2019. DOI:10.1186/s12993-019-0152-4.
[32] Piggott VM,Bosse KE, Lisieski MJ, et al. Single-prolonged stress impairs prefrontal cortex control of amygdala and striatum in rats[J]. Front Behav Neurosci, 2019. DOI:10.3389/fnbeh. 2019.00018.
[33] Abdullahi PR, Vafaei A, Ghanbari A, et al. Time-dependent protective effects of morphine against behavioral and morphological deficits in an animal model of posttraumatic stress disorder[J]. Behav Brain Res, 2019, 364:19-28.