Key Lab of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang, 330004, China.
J Ethnopharmacol. 2022 Nov 15;298:115646. doi: 10.1016/j.jep.2022.115646. Epub 2022 Aug 27.
The existence of the blood-brain barrier/blood tumor barrier (BBB/BTB) severely restricts the effectiveness of anti-tumor drugs, thus glioma is still an incurable disease with a high fatality rate. Chuanxiong (Ligusticum chuanxiong Hort., Umbelliferae) was used as a messenger drug to increase the distribution of drugs in brain tissue, and its application in Chinese herbal formula for treating glioma was also the highest.
Our previous researches showed that essential oil (EO) of chuanxiong could promote temozolomide (TMZ) entry into glioma cells in vitro and enhance TMZ-induced anticancer efficiency in vivo, and therefore, the aim of this study was to investigate whether EO could increase the concentration accumulation of TMZ in brain or tumor of C6 glioma rats and the related mechanisms.
The pharmacokinetics were conducted in C6 glioma rats by administering either TMZ alone or combined with EO through oral routes. TMZ concentration in blood, brain and tumor was detected using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and then pharmacokinetic parameters were calculated. The changed expressions of P-gp protein, tight junction occludin, claudin-5 and zonula occludens-1 (ZO-1) in brain of glioma rats were studied by Western blot to clarify the mechanism. Finally, the chemical composition of EO was analyzed by gas chromatography-massspectrometry (GC-MS).
The results showed that EO significantly affected the pharmacokinetic parameters such as T, C and CL (p < 0.01), but did not significantly change the AUC of TMZ in blood (p > 0.05). However, EO markedly improved the AUCof TMZ in brain and tumor (p < 0.01). The calculate drug targeting index was greater than 1, indicating that EO could promote the distribution of TMZ to the brain and tumor. Western blot analysis showed that EO significantly inhibited the expression of P-gp, tight junction protein claudin-5, occludin and ZO-1. And meanwhile, the expressions of P-gp, claudin-5 and occludin also markedly down-regulated in EO-TMZ co-administration treatment. GC-MS analysis of the TIC component of EO was (E)-Ligustilide (36.93%), Terpinolene (7.245%), gamma-terpinene (7.225%) etc. CONCLUSION: EO could promote the distribution of TMZ in the brain and tumor of C6 glioma rats, which may attribute to down-regulate the expression of P-gp, claudin-5 and occludin.
血脑屏障/血肿瘤屏障（BBB/BTB）的存在严重限制了抗肿瘤药物的疗效，因此胶质瘤仍然是一种无法治愈且死亡率高的疾病。川芎（Ligusticum chuanxiong Hort.，伞形科）被用作信使药物，以增加药物在脑组织中的分布，其在治疗胶质瘤的中药方剂中的应用也最高。
我们之前的研究表明，川芎精油（EO）可促进替莫唑胺（TMZ）进入体外胶质瘤细胞，并增强 TMZ 诱导的体内抗癌效率，因此，本研究旨在探讨 EO 是否可以增加 C6 胶质瘤大鼠脑或肿瘤中 TMZ 的浓度积累，以及相关机制。
通过口服途径单独给予 TMZ 或联合 EO，在 C6 胶质瘤大鼠中进行药代动力学研究。采用液相色谱-质谱/质谱联用（LC-MS/MS）检测血、脑和肿瘤中 TMZ 的浓度，计算药代动力学参数。通过 Western blot 研究了 EO 对脑胶质瘤大鼠 P-gp 蛋白、紧密连接 occludin、claudin-5 和 zonula occludens-1（ZO-1）表达的变化，以阐明其机制。最后，采用气相色谱-质谱联用（GC-MS）分析 EO 的化学成分。
结果表明，EO 显著影响 T、C 和 CL 等药代动力学参数（p<0.01），但对血中 TMZ 的 AUC 无显著影响（p>0.05）。然而，EO 显著增加了脑和肿瘤中 TMZ 的 AUC（p<0.01）。计算的药物靶向指数大于 1，表明 EO 可以促进 TMZ 向脑和肿瘤的分布。Western blot 分析表明，EO 显著抑制了 P-gp、紧密连接蛋白 claudin-5、occludin 和 ZO-1 的表达。同时，EO-TMZ 联合给药组 P-gp、claudin-5 和 occludin 的表达也明显下调。EO 的 TIC 成分的 GC-MS 分析为（E）-藁本内酯（36.93%）、萜品烯醇（7.245%）、γ-萜品烯（7.225%）等。
EO 可促进 TMZ 在 C6 胶质瘤大鼠脑和肿瘤中的分布，这可能归因于下调 P-gp、claudin-5 和 occludin 的表达。
