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Synthesis, characterization and in vivo evaluation of honokiol bisphosphate prodrugs protects against rats' brain ischemia-reperfusion injury.

ABSTRACT: Honokiol (HK) usage is greatly restricted by its poor aqueous solubility and limited oral bioavailability. We synthesized and characterized a novel phosphate prodrug of honokiol (HKP) for in vitro and in vivo use. HKP greatly enhanced the aqueous solubility of HK (127.54?±?15.53?mg/ml) and the stability in buffer solution was sufficient for intravenous administration. The enzymatic hydrolysis of HKP to HK was extremely rapid in vitro (T1/ 2 ?=?8.9?±?2.11?s). Pharmacokinetics studies demonstrated that after intravenous administration of HKP (32?mg/kg), HKP was converted rapidly to HK with a time to reach the maximum plasma concentration of ?5?min. The prodrug HKP achieved an improved T1/2 (7.97?±?1.30?h) and terminal volume of distribution (26.02?±?6.04?ml/kg) compared with direct injection of the equimolar parent drug (0.66?±?0.01?h) and (2.90?±?0.342?ml/kg), respectively. Furthermore, oral administration of HKP showed rapid and improved absorption compared with the parent drug. HKP was confirmed to maintain the bioactivity of the parent drug for ameliorating ischemia-reperfusion injury by decreasing brain infarction and improving neurologic function. Taken together, HKP is a potentially useful aqueous-soluble prodrug with improved pharmacokinetic properties which may merit further development as a potential drug candidate.

SUBMITTER: Xu G

PROVIDER: S-EPMC7032162 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Synthesis, characterization and in vivo evaluation of honokiol bisphosphate prodrugs protects against rats' brain ischemia-reperfusion injury.

Xu Gaojie G Dong Renghan R Liu Jin J Zhao Li L Zeng Yan Y Xiao Xiaofan X An Jinglin J Huang Sheng S Zhong Yueling Y Guang Bing B Yang Tai T

Asian journal of pharmaceutical sciences 20181215 6

Honokiol (HK) usage is greatly restricted by its poor aqueous solubility and limited oral bioavailability. We synthesized and characterized a novel phosphate prodrug of honokiol (HKP) for in vitro and in vivo use. HKP greatly enhanced the aqueous solubility of HK (127.54 ± 15.53 mg/ml) and the stability in buffer solution was sufficient for intravenous administration. The enzymatic hydrolysis of HKP to HK was extremely rapid in vitro (T1/ 2 ...[more]

PMID: 32104490

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Project description:Search for new cardioprotective therapies is of great importance since no cardioprotective drugs are available on the market. In line with this need, several natural biomolecules have been extensively tested for their potential cardioprotective effects. Previously, we have shown that biglycan, a member of a diverse group of small leucine-rich proteoglycans, enhanced the expression of cardioprotective genes and decreased ischemia/reperfusion-induced cardiomyocyte death via a TLR-4 dependent mechanism. Therefore, in the present study we aimed to test whether decorin, a small leucine-rich proteoglycan closely related to biglycan, could exert cardiocytoprotection and to reveal possible downstream signaling pathways. Methods: Primary cardiomyocytes isolated from neonatal and adult rat hearts were treated with 0 (Vehicle), 1, 3, 10, 30 and 100 nM decorin as 20 h pretreatment and maintained throughout simulated ischemia and reperfusion (SI/R). In separate experiments, to test the mechanism of decorin-induced cardio protection, 3 nM decorin was applied in combination with inhibitors of known survival pathways, that is, the NOS inhibitor L-NAME, the PKG inhibitor KT-5823 and the TLR-4 inhibitor TAK-242, respectively. mRNA expression changes were measured after SI/R injury. Results: Cell viability of both neonatal and adult cardiomyocytes was significantly decreased due to SI/R injury. Decorin at 1, 3 and 10 nM concentrations significantly increased the survival of both neonatal and adult myocytes after SI/R. At 3nM (the most pronounced protective concentration), it had no effect on apoptotic rate of neonatal cardiac myocytes. No one of the inhibitors of survival pathways (L-NAME, KT-5823, TAK-242) influenced the cardiocytoprotective effect of decorin. MYND-type containing 19 (Zmynd19) and eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1) were significantly upregulated due to the decorin treatment. In conclusion, this is the first demonstration that decorin exerts a direct cardiocytoprotective effect possibly independent of NO-cGMP-PKG and TLR-4 dependent survival signaling.

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Synthesis, characterization and in vivo evaluation of honokiol bisphosphate prodrugs protects against rats' brain ischemia-reperfusion injury.

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Synthesis, characterization and <i>in vivo</i> evaluation of honokiol bisphosphate prodrugs protects against rats' brain ischemia-reperfusion injury.

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