Synthesis of Paeonol-Ozagrel Conjugate: Structure Characterization and In Vivo Anti-Ischemic Stroke potential

Jing Zhang,Ziyu Zhang,Can Peng,Lan Han,Miaomiao Jiang,Weidong Chen,Jianqing Wang,Yu Jin,Hui Zhao

doi:10.3389/fphar.2020.608221

Abstract

Ischemic stroke is a common neurological disease that can lead to mortality and disability. The current curative effect remains unsatisfactory because drug accumulation in the diseased areas is insufficient as a result of the unique blood–brain barrier. Therefore, much attention has been paid to develop a novel therapeutic compound, paeonol-ozagrel conjugate (POC), for ischemic stroke. Then, POC was successfully synthesized by conjugating of paeonol and ozagrel as mutual prodrug. A series of in vitro characterizations and evaluations, including high - resolution mass spectroscopy, nuclear magnetic resonance spectroscopy, partition coefficient, and assessment of cytotoxicity against PC12 cells, were performed. Pharmacokinetic study demonstrated POC is eliminated quickly (t1/2 = 53.46 ± 19.64 min), which supported a short dosing interval. The neurological score, infarct volume, histopathological changes, oxidative stress, inflammatory cytokines levels, and TXA2 levels also were evaluated in vivo in middle cerebral artery occlusion (MCAO) rats. All results showed that POC had a significant curative and therapeutic effect on ischemic stroke, as evaluated by the middle cerebral artery occlusion. Overall, POC can be expected to become a new drug candidate for the treatment of ischemic stroke.

Highlights

Ischemic stroke is one of the most common and potentially lethal cerebrovascular disease in adults worldwide, with substantial morbidity and mortality (Sheng et al, 2015; Su et al, 2017)
The design of a mutual prodrug has improved and even overcome the undesirable properties related to the drugs by changing the structure of drugs; the changes resulted in reduced side effects and increased activity
TNF–α excutes its neurotoxic function by promoting the production of oxygen free radicals and excitatory amino acids, which results in neuronal cell death

Summary

Introduction

Ischemic stroke is one of the most common and potentially lethal cerebrovascular disease in adults worldwide, with substantial morbidity and mortality (Sheng et al, 2015; Su et al, 2017). It has attracted more and more attention in the field of drug discovery (Yu et al, 2017). The unique blood–brain barrier (BBB) in the central nervous system (CNS) hinders the treatment of ischemic stroke because of the poor efficiency of drug delivery (Yue et al, 2014). A thromboxane A2 (TXA2) synthase inhibitor, is used in several countries to treat ischemic stroke (Ishitsuka et al, 2009; Park et al, 2015).

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