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Methods NE-ICS II was prepared by ultrasonic emulsification and its physicochemical properties were characterized. Pharmacokinetic parameters and brain distribution were systematically evaluated. Therapeutic efficacy was assessed in rats subjected to middle cerebral artery occlusion (MCAO) by measuring infarct volume, neurological deficit scores, and oxidative stress and inflammatory markers. RNA sequencing was performed to elucidate the underlying mechanisms. Results NE-ICS II showed a mean particle size of (147.59 ± 0.71) nm and an encapsulation efficiency of (84.85 ± 5.47) %. NE-ICS II increased the oral bioavailability of ICS II by 2.4-fold and significantly enhanced its accumulation in the brain. Therapeutic oral administration of NE-ICS II markedly improved neurological function, reduced infarct volume, and attenuated oxidative stress and inflammatory responses in MCAO rats. RNA sequencing revealed that NE-ICS II may downregulate signaling pathways associated with oxidative stress and inflammation. Conclusion NE-ICS II substantially improves the oral bioavailability of ICS II and enables effective treatment of CIRI at a low dose, providing a promising strategy for efficient brain delivery of ICS II and for the treatment of central nervous system diseases., authors=WU Changjing, CHEN Xingyan, LU Wenchai, LYU Houbo, GAO Jianmei, GONG Qihai, ZHANG Yuandong, authorsList=WU Changjing, CHEN Xingyan, LU Wenchai, LYU Houbo, GAO Jianmei, GONG Qihai, ZHANG Yuandong, authorCompany=null, correspAuthors=null, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1304388196603810274, articleId=1304388194720567777, tenantId=1146029695717560320, journalId=1302319053441957962, language=CN, title=淫羊藿次苷II纳米乳制备及其改善脑缺血再灌注损伤作用, columnId=1304140189132149234, journalTitle=中草药, columnName=药剂与工艺, runingTitle=null, highlight=null, articleAbstract=目的 制备淫羊藿次苷II纳米乳（icariside II nanoemulsion，NE-ICS II），以提升口服生物利用度并增强抗脑缺血再灌注损伤（cerebral ischemia-reperfusion injury，CIRI）的能力。方法 采用超声乳化法制备NE-ICS II，并对其理化性质进行表征；系统评价药动学参数及脑内药物分布；通过在大脑中动脉闭塞（middle cerebral artery occlusion，MCAO）模型大鼠中检测脑梗死体积、神经功能评分、氧化应激及炎症指标评估其疗效；结合RNA测序解析其作用机制。结果 NE-ICS II的平均粒径为（147.59±0.71）nm，包封率为（84.85±5.47）%，可使ICS II的口服生物利用度提高2.4倍，显著增加药物在脑部的蓄积。治疗性口服NE-ICS II明显改善MCAO大鼠的神经功能，缩小脑梗死体积，减轻病灶氧化应激和炎症反应；RNA测序揭示其可能下调氧化应激与炎症相关信号通路。结论 NE-ICS II显著提升了ICS II的口服生物利用度，在低剂量下即可实现对CIRI的有效治疗，为实现ICS II的高效脑递送及中枢神经系统疾病的治疗提供新策略。, authors=吴昌静1, 陈兴艳1, 卢文钗1, 吕厚波1, 高健美1, 龚其海1, 张远冬1, authorsList=吴昌静, 陈兴艳, 卢文钗, 吕厚波, 高健美, 龚其海, 张远冬, authorCompany=1 遵义医科大学药学院,贵州 遵义 563000, correspAuthors=张远冬, authorNote=吴昌静: 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Icariside II attenuates cerebral ischemia/reperfusion-induced blood-brain barrier dysfunction in rats via regulating the balance of MMP9/ TIMP1[J]. Acta Pharmacol Sin, 2020, 41(12): 1547-1556. Cheng T, Zhang Y, Zhang T, et al. Comparative pharmacokinetics study of icariin and icariside II in rats [J]. Molecules, 2015, 20(12): 21274-21286. Hou J, Wang J, Sun E, et al. Preparation and evaluation of icariside II-loaded binary mixed micelles using Solutol HS15 and Pluronic F127 as carriers [J]. Drug Deliv, 2016, 23(9): 3248-3256. Mallory D P, Freedman A, Kaliszewski M J, et al. Direct quantification of serum protein interactions with PEGylated micelle nanocarriers [J]. Biomacromolecules, 2023, 24(6): 2479-2488. Chatzidaki M D, Mitsou E. Advancements in nanoemulsion-based drug delivery across different administration routes [J]. Pharmaceutics, 2025, 17(3): 337. Lochhead J J, Ronaldson P T, Davis T P. The role of oxidative stress in blood-brain barrier disruption during ischemic stroke: Antioxidants in clinical trials [J]. Biochem Pharmacol, 2024, 228: 116186. Zhang P, Liu N C, Xue M Y, et al. Anti-inflammatory and antioxidant properties of squalene in copper sulfate-induced inflammation in zebrafish (Danio rerio) [J]. Int J Mol Sci, 2023, 24(10): 8518. Zhao S Q, Wang Z Y, Wang X F, et al. Characterization of nanoemulsions stabilized with different emulsifiers and their encapsulation efficiency for oregano essential oil: Tween 80, soybean protein isolate, tea saponin, and soy lecithin [J]. Foods, 2023, 12(17): 3183. Rocchio J, Neilsen J, Everett K, et al. A solvent-free lecithin-Tween 80 system for oil dispersion [J]. Colloids Surf A Physicochem Eng Aspects, 2017, 533: 218-223. Steiner V, Öhlinger K, Corzo C, et al. Cytotoxicity screening of emulsifiers for pulmonary application of lipid nanoparticles [J]. Eur J Pharm Sci, 2019, 136: 104968. Zhang W, Wan L, Han M Q, et al. Nose-to-brain drug delivery by HS15 micelles for brain targeting of insoluble drug [J]. Acta Mater Med, 2024, 3(2): 119-132. Mohite P, Sule S, Pawar A, et al. Development and characterization of a self-nano emulsifying drug delivery system (SNEDDS) for ornidazole to improve solubility and oral bioavailability of BCS class II drugs [J]. Sci Rep, 2024, 14: 27724. Chae G E, Kim D W, Jin H E. Development of squalene-based oil-in-water emulsion adjuvants using a self-emulsifying drug delivery system for enhanced antigen-specific antibody titers [J]. Int J Nanomed, 2022, 17: 6221-6231. Huang T T, Wu C J, Lu W C, et al. Therapeutic delivery of phloretin by mixed emulsifier-stabilized nanoemulsion alleviated cerebral ischemia/reperfusion injury [J]. Pharmaceutics, 2025, 17(12): 1599. Li B H, Hu S Q, Huang B, et al. The design of icariside II oral nanoemulsion dispersed mini-tablets based on nanoparticle dissolution escape mechanism [J]. J Drug Deliv Sci Technol, 2026, 115: 107608. Kang Y C, Sun Y P, Li T T, et al. Garcinol protects against cerebral ischemia-reperfusion injury in vivo and in vitro by inhibiting inflammation and oxidative stress [J]. Mol Cell Probes, 2020, 54: 101672. Li X C, Wang Y Y, Chen Y X, et al. Icariside II alleviates lipopolysaccharide-induced acute lung injury by inhibiting lung epithelial inflammatory and immune responses mediated by neutrophil extracellular traps [J]. Life Sci, 2024, 346: 122648. Ding Z Y, Chen X P, Tang D Y, et al. Comparisons of the bioavailability of icariin, icariside II, and epimedin C in rats after oral administration of total flavonoids of Epimedium brevicornu Maxim. and its three formulations [J]. J Pharm Biomed Anal, 2025, 255: 116631. Gurjar R, Chan C Y S, Curley P, et al. Inhibitory effects of commonly used excipients on P-glycoprotein in vitro [J]. Mol Pharmaceutics, 2018, 15(11): 4835-4842. Yan B Y, Pan C S, Mao X W, et al. Icariside II improves cerebral microcirculatory disturbance and alleviates hippocampal injury in gerbils after ischemia-reperfusion [J]. Brain Res, 2014, 1573: 63-73. Deng Y Y, Xiong D Q, Yin C X, et al. Icariside II protects against cerebral ischemia-reperfusion injury in rats via nuclear factor-κB inhibition and peroxisome proliferator-activated receptor up-regulation [J]. Neurochem Int, 2016, 96: 56-61. He L Z, Deng Y Y, Gao J M, et al. Icariside II ameliorates ibotenic acid-induced cognitive impairment and apoptotic response via modulation of MAPK pathway in rats [J]. Phytomedicine, 2018, 41: 74-81. Jover-Mengual T, Hwang J Y, Byun H R, et al. The role of NF-κB triggered inflammation in cerebral ischemia [J]. Front Cell Neurosci, 2021, 15: 633610. Xie X H, Wang F, Ge W X, et al. Scutellarin attenuates oxidative stress and neuroinflammation in cerebral ischemia/reperfusion injury through PI3K/Akt-mediated Nrf2 signaling pathways [J]. Eur J Pharmacol, 2023, 957: 175979.)
Objective To develop an icariside II nanoemulsion (NE-ICS II) to enhance oral bioavailability and improve efficacy against cerebral ischemia-reperfusion injury (CIRI). Methods NE-ICS II was prepared by ultrasonic emulsification and its physicochemical properties were characterized. Pharmacokinetic parameters and brain distribution were systematically evaluated. Therapeutic efficacy was assessed in rats subjected to middle cerebral artery occlusion (MCAO) by measuring infarct volume, neurological deficit scores, and oxidative stress and inflammatory markers. RNA sequencing was performed to elucidate the underlying mechanisms. Results NE-ICS II showed a mean particle size of (147.59 ± 0.71) nm and an encapsulation efficiency of (84.85 ± 5.47) %. NE-ICS II increased the oral bioavailability of ICS II by 2.4-fold and significantly enhanced its accumulation in the brain. Therapeutic oral administration of NE-ICS II markedly improved neurological function, reduced infarct volume, and attenuated oxidative stress and inflammatory responses in MCAO rats. RNA sequencing revealed that NE-ICS II may downregulate signaling pathways associated with oxidative stress and inflammation. Conclusion NE-ICS II substantially improves the oral bioavailability of ICS II and enables effective treatment of CIRI at a low dose, providing a promising strategy for efficient brain delivery of ICS II and for the treatment of central nervous system diseases.
WU Changjing, CHEN Xingyan, LU Wenchai, LYU Houbo, GAO Jianmei, GONG Qihai, ZHANG Yuandong.
Preparation of an icariside II nanoemulsion and its effect on improving cerebral ischemia-reperfusion injury[J].
Chinese Traditional and Herbal Drugs,
2026
, 57
(12)
: 4609
-4618
.
DOI: 10.7501/j.issn.0253-2670.2026.12.009
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The role of oxidative stress in blood-brain barrier disruption during ischemic stroke: Antioxidants in clinical trials [J]. Biochem Pharmacol, 2024, 228: 116186. Zhang P, Liu N C, Xue M Y, et al. Anti-inflammatory and antioxidant properties of squalene in copper sulfate-induced inflammation in zebrafish (Danio rerio) [J]. Int J Mol Sci, 2023, 24(10): 8518. Zhao S Q, Wang Z Y, Wang X F, et al. Characterization of nanoemulsions stabilized with different emulsifiers and their encapsulation efficiency for oregano essential oil: Tween 80, soybean protein isolate, tea saponin, and soy lecithin [J]. Foods, 2023, 12(17): 3183. Rocchio J, Neilsen J, Everett K, et al. A solvent-free lecithin-Tween 80 system for oil dispersion [J]. Colloids Surf A Physicochem Eng Aspects, 2017, 533: 218-223. Steiner V, Öhlinger K, Corzo C, et al. Cytotoxicity screening of emulsifiers for pulmonary application of lipid nanoparticles [J]. Eur J Pharm Sci, 2019, 136: 104968. Zhang W, Wan L, Han M Q, et al. Nose-to-brain drug delivery by HS15 micelles for brain targeting of insoluble drug [J]. Acta Mater Med, 2024, 3(2): 119-132. Mohite P, Sule S, Pawar A, et al. Development and characterization of a self-nano emulsifying drug delivery system (SNEDDS) for ornidazole to improve solubility and oral bioavailability of BCS class II drugs [J]. Sci Rep, 2024, 14: 27724. Chae G E, Kim D W, Jin H E. Development of squalene-based oil-in-water emulsion adjuvants using a self-emulsifying drug delivery system for enhanced antigen-specific antibody titers [J]. Int J Nanomed, 2022, 17: 6221-6231. Huang T T, Wu C J, Lu W C, et al. Therapeutic delivery of phloretin by mixed emulsifier-stabilized nanoemulsion alleviated cerebral ischemia/reperfusion injury [J]. Pharmaceutics, 2025, 17(12): 1599. Li B H, Hu S Q, Huang B, et al. The design of icariside II oral nanoemulsion dispersed mini-tablets based on nanoparticle dissolution escape mechanism [J]. J Drug Deliv Sci Technol, 2026, 115: 107608. Kang Y C, Sun Y P, Li T T, et al. Garcinol protects against cerebral ischemia-reperfusion injury in vivo and in vitro by inhibiting inflammation and oxidative stress [J]. Mol Cell Probes, 2020, 54: 101672. Li X C, Wang Y Y, Chen Y X, et al. Icariside II alleviates lipopolysaccharide-induced acute lung injury by inhibiting lung epithelial inflammatory and immune responses mediated by neutrophil extracellular traps [J]. Life Sci, 2024, 346: 122648. Ding Z Y, Chen X P, Tang D Y, et al. Comparisons of the bioavailability of icariin, icariside II, and epimedin C in rats after oral administration of total flavonoids of Epimedium brevicornu Maxim. and its three formulations [J]. J Pharm Biomed Anal, 2025, 255: 116631. Gurjar R, Chan C Y S, Curley P, et al. Inhibitory effects of commonly used excipients on P-glycoprotein in vitro [J]. Mol Pharmaceutics, 2018, 15(11): 4835-4842. Yan B Y, Pan C S, Mao X W, et al. Icariside II improves cerebral microcirculatory disturbance and alleviates hippocampal injury in gerbils after ischemia-reperfusion [J]. Brain Res, 2014, 1573: 63-73. Deng Y Y, Xiong D Q, Yin C X, et al. Icariside II protects against cerebral ischemia-reperfusion injury in rats via nuclear factor-κB inhibition and peroxisome proliferator-activated receptor up-regulation [J]. Neurochem Int, 2016, 96: 56-61. He L Z, Deng Y Y, Gao J M, et al. Icariside II ameliorates ibotenic acid-induced cognitive impairment and apoptotic response via modulation of MAPK pathway in rats [J]. Phytomedicine, 2018, 41: 74-81. Jover-Mengual T, Hwang J Y, Byun H R, et al. The role of NF-κB triggered inflammation in cerebral ischemia [J]. Front Cell Neurosci, 2021, 15: 633610. Xie X H, Wang F, Ge W X, et al. Scutellarin attenuates oxidative stress and neuroinflammation in cerebral ischemia/reperfusion injury through PI3K/Akt-mediated Nrf2 signaling pathways [J]. Eur J Pharmacol, 2023, 957: 175979.
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