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Current Drug Delivery

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ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

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Research Article

Enhanced Brain Targeting Delivery of Salvianic Acid Using Borneol as a Promoter of Blood/Brain Transport and Regulator of P-gp

Author(s): Ailing Hui*, Zheng Zhang, Jinghe Wang, Li Yang, Shaohuan Deng, Wencheng Zhang, An Zhou and Zeyu Wu

Volume 21, Issue 5, 2024

Published on: 08 February, 2023

Page: [726 - 733] Pages: 8

DOI: 10.2174/1567201820666230119120314

Price: $65

Abstract

Background: Borneol can enhance the blood-brain barrier (BBB) permeability of some drugs and suppress the efflux transport of P-glycoprotein (P-gp), which will contribute to the brain delivery of salvianic acid A (SAA).

Objective: The study aimed to develop an approach to improve the brain targeting delivery of SAA with the aid of borneol.

Materials and Methods: “Borneol” was involved in SAA via esterified prodrug SAA borneol ester (SBE) and combined administration (SAA-borneol, SAA-B). Subsequently, the blood-brain transport of SAA through brain/blood distribution and P-gp regulation via expression and function assay were investigated in rats.

Results: The SBE and SAA-B-treated group received a three-fold brain concentration and longer t1/2 and retention period of active SAA than that of SAA alone (20.18/13.82 min vs. 6.48 min; 18.30/17.42 min vs. 11.46 min). In addition, blood to brain transport of active SAA in SBE was altered in comparison to that of SAA-B, ultimately resulting in a better drug targeting index (9.93 vs. 3.63). Further studies revealed that SBE-induced downregulation of P-gp expression occurred at the later stage of administration (60 min, P < 0.01), but SBE always showed a more powerful drug transport activity across BBB represented by Kp value of rhodamine 123 than SAA-B (30, 60 min, P < 0.05).

Conclusion: The comparative results indicate that SBE exhibits prominent efficiency on SAA's targeting delivery through improved blood/brain metabolic properties and sustained inhibitory effect of “borneol” on P-gp efflux. Therefore, prodrug modification can be applied as a more effective approach for brain delivery of SAA.

Keywords: Borneol, blood-brain barrier, P-glycoprotein (P-gp), salvianic acid A (SAA), brain targeting delivery, prodrug, combined administration, salvianic acid a borneol ester.

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[1]
Yang, G.D.; Zhang, H.; Lin, R.; Wang, W.R.; Shi, X.L.; Liu, Y.; Ji, Q.L. Down-regulation of CD40 gene expression and inhibition of apoptosis with Danshensu in endothelial cells. Basic Clin. Pharmacol. Toxicol., 2009, 104(2), 87-92.
[http://dx.doi.org/10.1111/j.1742-7843.2008.00342.x] [PMID: 19067674]
[2]
Guo, C.; Yin, Y.; Duan, J.L.; Zhu, Y.R.; Yan, J.J.; Wei, G.; Guan, Y.; Wu, X.X.; Wang, Y.H.; Xi, M.M.; Wen, A.D. Neuroprotective effect and underlying mechanism of sodium danshensu [3-(3,4-dihydroxyphenyl) lactic acid from Radix and Rhizoma salviae miltiorrhizae = Danshen] against cerebral ischemia and reperfusion injury in rats. Phytomedicine, 2015, 22(2), 283-289.
[http://dx.doi.org/10.1016/j.phymed.2014.12.001] [PMID: 25765834]
[3]
Han, J.Y.; Fan, J.Y.; Horie, Y.; Miura, S.; Cui, D.H.; Ishii, H.; Hibi, T.; Tsuneki, H.; Kimura, I. Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. Pharmacol. Ther., 2008, 117(2), 280-295.
[http://dx.doi.org/10.1016/j.pharmthera.2007.09.008] [PMID: 18048101]
[4]
Bonaccini, L.; Karioti, A.; Bergonzi, M.C.; Bilia, A.R. Effects of Salvia miltiorrhiza on CNS neuronal injury and degeneration: A plausible complementary role of Tanshinones and depsides. Planta Med., 2015, 81(12-13), 1003-1016.
[PMID: 26190397]
[5]
Pan, J.Y.; Zhao, J.Y.; Shao, Q. Pharmacokinetics and bioavailability of Danshensu in rats. Zhongguo Zhongyao Zazhi, 2018, 33, 146-149.
[6]
Yu. P.F.. Wang, W.Y.; Eerdun, G.; Wang, T.; Zhang, L.M.; Li, C.; Fu, F.H. The role of P-glycoprotein in transport of Danshensu across the blood-brain barrier. Evid-Based Compl Alt., 2011, 2011, 713523.
[7]
Löscher, W.; Potschka, H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog. Neurobiol., 2005, 76(1), 22-76.
[http://dx.doi.org/10.1016/j.pneurobio.2005.04.006] [PMID: 16011870]
[8]
Chong, Y.T.; Wang, T.; Wang, W.Y.; Zhang, L.M.; Li, C.; Yu, P.F.; Wang, H.S.; Fu, F.H. Down-regulation of P-glycoprotein expression contributes to an increase in Danshensu accumulation in the cerebral ischemia/reperfusion brain. Mol. Med. Rep., 2012, 5(3), 812-816.
[PMID: 22134431]
[9]
On, N.H.; Miller, D.W. Transporter-based delivery of anticancer drugs to the brain: Improving brain penetration by minimizing drug efflux at the blood-brain barrier. Curr. Pharm. Des., 2014, 20(10), 1499-1509.
[http://dx.doi.org/10.2174/13816128113199990458] [PMID: 23789953]
[10]
Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: Design and clinical applications. Nat. Rev. Drug Discov., 2008, 7(3), 255-270.
[http://dx.doi.org/10.1038/nrd2468] [PMID: 18219308]
[11]
Alaofi, A.; Siahaan, T.J. Prodrug strategies for brain delivery. In: Advances in non-invasive drug delivery to the brain; Egleton, R.D., Ed.; Future Medicine Ltd: London, 2015.
[http://dx.doi.org/10.4155/fseb2013.14.17]
[12]
Ashique, S.; Sandhu, N.K.; Chawla, V.; Chawla, P.A. Targeted drug delivery: Trends and perspectives. Curr. Drug Deliv., 2021, 18(10), 1435-1455.
[http://dx.doi.org/10.2174/1567201818666210609161301] [PMID: 34151759]
[13]
Khatoon, R.; Alam, M.A.; Sharma, P.K. Current approaches and prospective drug targeting to brain. J Drug Del. Sci. Technol., 2020, 57, 102098.
[14]
Li, J.; Li, X.; Hu, S.S.; Yu, Q.L.; Sun, W.J.; Zheng, X.H. Studies on the effects of Baras Camphor on the tissue distribution of Salviamiltirrhiza Bge. In complex Danshen prescription in rabbits. Chin. J. Pharmcent. Anal., 2008, 28, 1612-1615.
[15]
Zhang, Q.; Wu, D.; Wu, J.; Ou, Y.; Mu, C.L.; Han, B.; Zhang, Q.L. Improved blood–brain barrier distribution: Effect of borneol on the brain pharmacokinetics of kaempferol in rats by in vivo microdialysis sampling. J. Ethnopharmacol., 2015, 162, 270-277.
[http://dx.doi.org/10.1016/j.jep.2015.01.003] [PMID: 25582491]
[16]
Zhang, Q.L.; Fu, B.M.; Zhang, Z.J. Borneol, a novel agent that improves central nervous system drug delivery by enhancing blood–brain barrier permeability. Drug Deliv., 2017, 24(1), 1037-1044.
[http://dx.doi.org/10.1080/10717544.2017.1346002] [PMID: 28687052]
[17]
Jia, C.; Han, S.S.; Wei, L.M.; Dang, X.J.; Niu, Q.Q.; Chen, M.Y.; Cao, B.Q.; Liu, Y.T.; Jiao, H.S. Protective effect of compound Danshen (Salvia miltiorrhiza) dripping pills alone and in combination with carbamazepine on kainic acid-induced temporal lobe epilepsy and cognitive impairment in rats. Pharm. Biol., 2018, 56(1), 217-224.
[http://dx.doi.org/10.1080/13880209.2018.1432665] [PMID: 29560767]
[18]
Fan, X. Chai. L.J.; Zhang, H.; Wang, Y.F.; Zhang, B.L.; Gao, X.M. Borneol depresses P-glycoprotein function by a NF-κB signaling mediated mechanism in a blood brain barrier in vitro model. Int. J. Mol. Sci., 2015, 16(11), 27576-27588.
[http://dx.doi.org/10.3390/ijms161126051] [PMID: 26593909]
[19]
Zhu, S.J.; Yuan, Y.; Yin, H.Y.; Hui, A.L.; Zhou, A.; Pan, J. On the brain-targeting of Ginkgolide B prodrug. Chin. Pharmacol. Bull., 2015, 31, 542-549.
[20]
Zuo, Z.L. Synthesis optimal design of Danshensu borneol ester. Xi'an: Northwest University. 2012.
[21]
Zhang, Z.; Yang, L.; Zhu, K.L.; Zhou, A.; Hui, A.L.; Zhang, W.C.; Wu, Z.Y. Effect of Danshensu borneol ester on P-glycoprotein expression level in rat brain. Chin Pharmacol. Bull., 2017, 33, 1114-1119.
[22]
Hui, A.L.; Yin, H.Y.; Zhang, Z.; Zhou, A.; Chen, J.C.; Yang, L.; Wu, Z.Y.; Zhang, W.C. Enhancement of brain-targeting delivery of danshensu in rat through conjugation with pyrazine moiety to form danshensu-pyrazine ester. Drug Deliv. Transl. Res., 2018, 8(3), 787-796.
[http://dx.doi.org/10.1007/s13346-018-0501-0] [PMID: 29524164]
[23]
Lu, Y.M.; Pan, J.; Zhang, W.N.; Hui, A.L.; Guo, W.Q.; Huang, L.; Zhu, Q.J.; Chen, Y. Synthesis, in silico and in vivo blood brain barrier permeability of ginkgolide B cinnamate. Fitoterapia, 2015, 106, 110-114.
[http://dx.doi.org/10.1016/j.fitote.2015.08.012] [PMID: 26327588]
[24]
Hui, A.L.; Zhu, S.J.; Yin, H.Y.; Yang, L.; Zhang, Z.; Zhou, A.; Pan, J.; Zhang, W.C. Novel ginkgolide B derivative attenuated the function and expression of P-glycoprotein at the blood–brain barrier, presenting brain-targeting ability. RSC Advances, 2016, 6(37), 31101-31106.
[http://dx.doi.org/10.1039/C5RA25248B]
[25]
Yang, L.M. Inhibitory effection of “Liang” DBZ on activation responses of BV-2 microglial and exploration research for designation and synthesis of QXs. Xi'an: Northwest University. 2017.
[26]
Liu, S.J. Study on structural characterization, quality control and pharmacokinetic of DBZ. Xi'an: Northwest University. 2009.
[27]
Zhang, Y. Protective effect of DBZ on cerebral ischemia injure in rats. Beijing: Beijing University of Chinese Medicine. 2012.
[28]
Liao, S.; Fan, T.P.; Zhao, X.F.; Choi, R.; Zheng, X.H. DBZ, a novel synthetic compound inspired by Compound Danshen Dripping Pills, promotes angiogenesis in vitro through activating Akt and MAPK signalling pathways. Eur. J. Integr. Med., 2014, 6(6), 688-688.
[http://dx.doi.org/10.1016/j.eujim.2014.09.007]
[29]
Jia, P.; Wang, S.X.; Xiao, C.N.; Yang, L.M.; Chen, Y.Y.; Jiang, W.; Zheng, X.P.; Zhao, G.F.; Zang, W.J.; Zheng, X.H. The anti-atherosclerotic effect of tanshinol borneol ester using fecal metabolomics based on liquid chromatography-mass spectrometry. Analyst, 2016, 141(3), 1112-1120.
[http://dx.doi.org/10.1039/C5AN01970B] [PMID: 26689835]
[30]
Wang, J.; Xu, P.F.; Xie, X.N.; Li, J.; Zhang, J.; Wang, J.L.; Hong, F.; Li, J.; Zhang, Y.Y.; Song, Y.; Zheng, X.H.; Zhai, Y.G. DBZ (Danshensu Bingpian Zhi), a novel natural compound derivative, attenuates atherosclerosis in apolipoprotein E-deficient mice. J. Am. Heart Assoc., 2017, 6(10), e006297.
[http://dx.doi.org/10.1161/JAHA.117.006297] [PMID: 28971954]
[31]
Liu, D.; Zheng, X.H.; Tang, Y.T.; Zi, J.; Nan, Y.F.; Wang, S.X.; Xiao, C.N.; Zhu, J.L.; Chen, C. Metabolism of tanshinol borneol ester in rat and human liver microsomes. Drug Metab. Dispos., 2010, 38(9), 1464-1470.
[http://dx.doi.org/10.1124/dmd.110.033381] [PMID: 20522662]
[32]
Yuan, X.Y.; Fei, F.H.; Sun, H.M.; Xiao, C.N.; Zhao, X.F.; Zhang, Y.J.; Zheng, X.H. Tanshinol borneol ester on nanostructured lipid carriers has longer brain and systemic effector retention and better antioxidant activity in vivo. Int. J. Nanomedicine, 2018, 13, 2265-2274.
[http://dx.doi.org/10.2147/IJN.S159789] [PMID: 29695905]
[33]
Ghaleb, H.; Li, H.L.; Kairuki, M.; Qiu, Q.Q.; Bi, X.Z.; Liu, C.X.; Liao, C.; Li, J.M.; Hezam, K.; Huang, W.L.; Qian, H. Design, synthesis and evaluation of a novel series of inhibitors reversing P-glycoprotein-mediated multidrug resistance. Chem. Biol. Drug Des., 2018, 92(3), 1708-1716.
[http://dx.doi.org/10.1111/cbdd.13338] [PMID: 29786944]
[34]
Junyaprasert, V.B.; Soonthornchareonnon, N.; Thongpraditchote, S.; Murakami, T.; Takano, M. Inhibitory effect of Thai plant extracts on P-glycoprotein mediated efflux. Phytother. Res., 2006, 20(1), 79-81.
[http://dx.doi.org/10.1002/ptr.1785] [PMID: 16397849]
[35]
Li, N.; Wang, D.D.; Ge, G.B.; Wang, X.L.; Liu, Y.; Yang, L. Ginsenoside metabolites inhibit P-glycoprotein in vitro and in situ using three absorption models. Planta Med., 2014, 80(4), 290-296.
[http://dx.doi.org/10.1055/s-0033-1360334] [PMID: 24493631]

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