Advertisement

Regulation of P-glycoprotein efflux activity by Z-guggulsterone of Commiphora mukul at the blood-brain barrier

Published:February 20, 2016DOI:https://doi.org/10.1016/j.jns.2016.02.046

      Highlights

      • P-glycoprotein restricts numerous therapeutic drugs across blood-brain barrier.
      • P-glycoprotein inhibitors increase brain accumulation of therapeutic drugs.
      • P-glycoprotein inhibitors have been disappointing because of side effects.
      • Z-guggulsterone might regulate P-glycoprotein expression at blood-brain barrier.

      Abstract

      The present study was to investigate whether Z-guggulsterone had the regulatory effect on the activity and expression of P-glycoprotein in rat brain microvessel endothelial cells (rBMECs) and in rat brain. Inorganic phosphate liberation assay, high performance liquid chromatography, and western blot analysis were performed to assess the P-glycoprotein ATPase activity, the accumulation of NaF and rhodamine 123, and P-glycoprotein and MRP1 expression. The results showed that Z-guggulsterone (0–100 μM) significantly enhanced basal P-glycoprotein ATPase activity in a concentration-dependent manner. Tetrandrine (0.1, 0.3, 1 μM) or cyclosporine A (0.1, 0.3, 1 μM) had non-competitively inhibitory manner on Z-guggulsterone-stimulated P-glycoprotein ATPase activity, suggesting that Z-guggulsterone might have unique binding site or regulating site on P-glycoprotein. However, Z-guggulsterone (30, 100 μM) had almost no influence on MRP1 expression in rBMECs. Further results revealed that Z-guggulsterone (50 mg/kg) significantly increased the accumulation of rhodamine 123 by down-regulating P-glycoprotein expression in rat brain, as compared with control (P < 0.05). Our studies suggested that Z-guggulsterone potentially inhibited the activity and expression of P-glycoprotein in rBMECs and in rat brain.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Miller D.S.
        Regulation of P-glycoprotein and other ABC drug transports at the blood–brain barrier.
        Trends Pharmacol. Sci. 2010; 31: 246-254
        • Watchko J.F.
        P-glycoprotein in the developing human blood brain barrier.
        Pediatr. Res. 2016 Jan 12; (in press)https://doi.org/10.1038/pr.2016.5
        • Kemper E.M.
        • van Zandbergen A.E.
        • Cleypool C.
        • Mos H.A.
        • Boogerd W.
        • Beijnen J.H.
        • et al.
        Increased penetration of paclitaxel into the brain by inhibition of P-glycoprotein.
        Clin. Cancer Res. 2003; 9: 2849-2855
        • Kemper E.M.
        • Verheij M.
        • Boogerd W.
        • Beijnen J.H.
        • van Tellingen O.
        Improved penetration of docetaxel into the brain by co-administration of inhibitors of P-glycoprotein.
        Eur. J. Cancer. 2004; 40: 1269-1274
        • Breedveld P.
        • Beijnen J.H.
        • Schellens J.H.
        Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs.
        Trends Pharmacol. Sci. 2006; 27: 17-24
        • de Vries N.A.
        • Zhao J.
        • Kroon E.
        • Buckle T.
        • Beijnen J.H.
        • van Tellingen O.
        P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan.
        Clin. Cancer Res. 2007; 13: 6440-6449
        • Leggas M.
        • Adachi M.
        • Scheffer G.L.
        • Sun D.
        • Wielinga P.
        • Du G.
        • et al.
        Mrp4 confers resistance to topotecan and protects the brain from chemotherapy.
        Mol. Cell. Biol. 2004; 24: 7612-7621
        • Bundgaard C.
        • Eneberg E.
        • Sanchez C.
        P-glycoprotein differentially affects escitalopram, levomilnacipran, vilazodone and vortioxetine transport at the mouse blood–brain barrier in vivo.
        Neuropharmacology. 2016; 103: 104-111
        • Shishodia S.
        • Azu N.
        • Rosenzweig J.A.
        • Jackson D.A.
        Guggulsterone for chemoprevention of cancer.
        Curr. Pharm. Des. 2016; 22: 294-306
        • Agrawal H.
        • Kaul N.
        • Paradkar A.R.
        • Mahadik K.R.
        HPTLC method for guggulsterone. I. Quantitative determination of E- and Z-guggulsterone in herbal extract and pharmaceutical dosage form.
        J. Pharm. Biomed. Anal. 2004; 36: 33-41
        • Xu H.B.
        • Li L.
        • Liu G.Q.
        Reversal of P-glycoprotein-mediated multidrug resistance by guggulsterone in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells.
        Pharmazie. 2009; 64: 660-665
        • Xu H.B.
        • Li L.
        • Liu G.Q.
        Reversal of multidrug resistance by guggulsterone in drug-resistant MCF-7 cell lines.
        Chemotherapy. 2011; 57: 62-70
        • Xu H.B.
        • Xu L.Z.
        • Li L.
        • Fu J.
        • Mao X.P.
        Reversion of P-glycoprotein-mediated multidrug resistance by guggulsterone in multidrug-resistant human cancer cell lines.
        Eur. J. Pharmacol. 2012; 694: 39-44
        • Xu H.B.
        • Shen Z.L.
        • Fu J.
        • Xu L.Z.
        Reversal of doxorubicin resistance by guggulsterone of Commiphora mukul in vivo.
        Phytomedicine. 2014; 21: 1221-1229
        • Chen X.Z.
        • Xu H.B.
        • Xu L.Z.
        • Mao X.P.
        • Li L.
        Guggulsterone regulates the function and expression of P-glycoprotein in rat brain microvessel endothelial cells.
        Eur. J. Pharmacol. 2013; 718: 24-29
        • Zaja R.
        • Loncar J.
        • Popovic M.
        • Smital T.
        First characterization of fish P-glycoprotein (abcb1) substrate specificity using determinations of its ATPase activity and calcein-AM assay with PLHC-1/dox cell line.
        Aquat. Toxicol. 2011; 103: 53-62
        • Abbott N.J.
        • Hughes C.C.
        • Revest P.A.
        • Greenwood J.
        Development and characterization of a rat brain capillary endothelial culture: towards an in vitro blood–brain barrier.
        J. Cell Sci. 1992; 103: 23-37
        • Garrigos M.
        • Mir L.M.
        • Orlowski S.
        Competitive and non-competitive inhibition of the multidrug-resistance-associated P-glycoprotein ATPase further experimental evidence for a multisite model.
        Eur. J. Biochem. 1997; 244: 664-673
        • Sarkadi B.
        • Szasz I.
        • Gerloczy A.
        • Gardos G.
        Transport parameters and stoichiometry of active calcium ion extrusion in intact human red cells.
        Biochim. Biophys. Acta. 1977; 464: 93-107
        • Watanabe T.
        • Kokubu N.
        • Charnick S.B.
        • Naito M.
        • Tsuruo T.
        • Cohen D.
        Interaction of cyclosporin derivatives with the ATPase activity of human P-glycoprotein.
        Br. J. Pharmacol. 1997; 122: 241-248
        • Cen J.
        • Qi Y.
        • Tao Y.F.
        • Deng Y.
        • Fang W.R.
        • Li Y.M.
        • et al.
        HZ08, a great regulator to reverse multidrug resistance via cycle arrest and apoptosis sensitization in MCF-7/ADM.
        Eur. J. Pharmacol. 2010; 647: 21-30
        • Liu X.
        • Jing X.Y.
        • Jin S.
        • Li Y.
        • Liu L.
        • Yu Y.L.
        • et al.
        Insulin suppresses the expression and function of breast cancer resistance protein in primary cultures of rat brain microvessel endothelial cells.
        Pharmacol. Rep. 2011; 63: 487-493
        • Ghosh A.
        • Birngruber T.
        • Sattler W.
        • Kroath T.
        • Ratzer M.
        • Sinner F.
        • et al.
        Assessment of blood–brain barrier function and the neuroinflammatory response in the rat brain by using cerebral open flow microperfusion (cOFM).
        PLoS One. 2014; 9: e98143
        • An M.J.
        • Cheon J.H.
        • Kim S.W.
        • Kim E.S.
        • Kim T.I.
        • Kim W.H.
        Guggulsterone induces apoptosis in colon cancer cells and inhibits tumor growth in murine colorectal cancer xenografts.
        Cancer Lett. 2009; 279: 93-100
        • Nabekura T.
        • Yamaki T.
        • Ueno K.
        • Kitagawa S.
        Effects of plant sterols on human multidrug transporters ABCB1 and ABCC1.
        Biochem. Bioph. Res. Co. 2008; 369: 363-368
        • Zhang C.
        • Kwan P.
        • Zuo Z.
        • Baum L.
        The transport of antiepileptic drugs by P-glycoprotein.
        Adv. Drug Deliv. Rev. 2012; 64: 930-942
        • Seeland S.
        • Treiber A.
        • Hafner M.
        • Huwyler J.
        Online identification of P-glycoprotein substrates by monitoring of extracellular acidification and respiration rates in living cells.
        Biochim. Biophys. Acta. 2011; 1808: 1827-1831
        • Twentyman P.R.
        • Fox N.E.
        • White D.J.
        Cyclosporin A and its analogues as modifiers of adriamycin and vincristine resistance in a multi-drug resistant human lung cancer cell line.
        Br. J. Cancer. 1987; 56: 55-57
        • Ambudkar S.V.
        • Dey S.
        • Hrycyna C.A.
        • Ramachandra M.
        • Pastan I.
        • Gottesman M.M.
        Biochemical, cellular, and pharmacological aspects of the multidrug transporter.
        Annu. Rev. Pharmacol. Toxicol. 1999; 39: 361-398
        • He S.M.
        • Li R.
        • Kanwar J.R.
        • Zhou S.F.
        Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1).
        Curr. Med. Chem. 2011; 18: 439-481
        • Regina A.
        • Koman A.
        • Piciotti M.
        • Hafny B.E.I.
        • Center M.S.
        • Bergmann R.
        • et al.
        Mrp1 multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells.
        J. Neurochem. 1998; 71: 705-715
        • Cen J.
        • Liu L.
        • He L.
        • Wang L.J.
        • Liu Y.Q.
        • Liu M.
        • et al.
        Alteration in P-glycoprotein at the blood-brain barrier in the early period of MCAO in rats.
        J. Pharm. Pharmacol. 2013; 65: 665-672