The Brain Targeting Effect Of Danshensu Borneol Ester And Its Influence On P-glycoprotein Located On Blood Brain Barrier

Danshensu(DSS)has the pharmacological activity in treatment of ischemic cardiovascular and cerebrovascular diseases,but it is easily oxidized in air and characterized by chemical instability,short half-life in vivo.In addition,its brain targeting effect will need to be strengthened.The increasement of blood-brain barrier(BBB)permeability and inhibition of P-glycoprotein(P-gp)efflux will contribute to the improvement of drug brain targeting ability.It had been reported that the combination use of Salvia miltiorrhiza-borneol improved the brain distribution of DSS.Therefore,borneol was introduced into the structure of DSS as the carrier because of its dual effect on BBB penetration and P-gp efflux inhibition in this paper.A series of DSS-borneol ester derivatives have been designed and the corresponding parameters related to brain targeting were predicted.The desired molecule was determined and its brain targeting effect was evaluated.At the same time,the combination use of DSS-borneol was also studied.The results were as follows:(1)After screening the molecular parameters of DSS-borneol ester derivatives via the calculation software,Danshensu borneol ester(DBE)was selected as the potential brain-targeting candidate.Among the six designed Danshensu-borneol ester derivatives(DB1-DB6),lipid-hydro partition coefficient(logP),the cerebral blood concentration ratio(BB)and the affinity of P-gp were predicted.The above predicted results and the synthetic analysis were considering and DB1(DBE)was choosed as the target molecule for the subsequent targeting evaluation in vivo.(2)The prodrug of DBE and the combination use of Danshensu sodium-borneol(SDSS-B)were characterized by brain-targeting ability.The therapeutic availability(TA)and brain targeting index(DTI)of DBE was better than that of SDSS-B.The HPLC method for quantitative detection of DSS in rat plasma and brain homogenate was established.Subsequently,the pharmacokinetics of SDSS,DBE and SDSS-B in rat via tail vein had been studied according to the estabilished method.The pharmacokinetics parameters of DBE in rat plasma had been improved at some extend.Compared with SDSS,the t1/2,MRT0-? of DSS decomposd by DBE had increased by 1.76,1.71 times.At the same time,the uptake of DSS in rat brainshowed a significant increasement when DBE and SDSS-B were administrated to the rats;their MRT0-? were 2.71 times and 1.42 times that of SDSS,respectively.If a comparison was made between SDSS-B and DBE,DBE should demonstrate a better slow release property.TA and DTI were made as indexes to evaluate the brain targeting effect of DBE and SDSS-B.Their TA were 4.15 and 3.39,DTI were 3.63 and 9.93 respectively.(3)The brain targeting of DBE was stronger than that of SDSS-B,which was related to its effective inhibition of P-gp expression and efflux transport function.The Western blotting results of P-gp in rat brain tissue showed that SDSS only inhibited P-gp expression at 30 min compared with control group;DBE and SDSS-B could significantly reduce the expression of P-gp in hippocampus of rats at the other administration intervals except 5 min(P <0.01);and at 45 min after administration,the expression of P-gp in DBE and SDSS-B groups was the lowest with 47.58% and46.54% respectively.Once the administration time was extended to 60 min,the inhibitory effect on P-gp expression of DBE was stronger than that of SDSS-B(85.04% vs.95.29%).The P-gp efflux transportion of SDSS,DBE and SDSS-B were also investigated in rats via Rhodamine 123(Rho123)as the substrate.Compared with SDSS group,the Rho123 concentration of SDSS-B and DBE prodrug showed an increasing trend;the corresponding Kp value had increased to 1.26~4 times and 1.38~5.4 times,respectively.Both SDSS-B and DBE could inhibit P-gp efflux function in rat brain in four administration intervals,and the inhibition of DBE was stronger than that of SDSS-B.