Enhancing effect of borneol and muscone on geniposide transport across the human nasal epithelial cell monolayer.

Zhenzhen Chen,Xin Gong,Pengyue Li,Shouying Du,Yang Lu,Huichao Wu,Jie Bai,Zhihui Yang,Brahim Nait-Oumesmar

doi:10.1371/journal.pone.0101414

Zhenzhen Chen, Xin Gong + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0101414

Copy DOI

Abstract

Geniposide is widely used in the treatment of cerebral ischemic stroke and cerebrovascular diseases for its anti-thrombotic and anti-inflammatory effects. Recent studies demonstrated that geniposide could be absorbed promptly and thoroughly by intranasal administration in mice and basically transported into the brain. Here, we explored its transport mechanism and the effect of borneol and muscone on its transport by human nasal epithelial cell (HNEC) monolayer. The cytotoxicity of geniposide, borneol, muscone and their combinations on HNECs was evaluated by the MTT assay. Transcellular transport of geniposide and the influence of borneol and muscone were studied using the HNEC monolayer. Immunostaining and transepithelial electrical resistance were measured to assess the integrity of the monolayer. The membrane fluidity of HNEC was evaluated by fluorescence recovery after photobleaching. Geniposide showed relatively poor absorption in the HNEC monolayer and it was not a P-gp substrate. Geniposide transport in both directions significantly increased when co-administrated with increasing concentrations of borneol and muscone. The enhancing effect of borneol and muscone on geniposide transport across the HNEC may be attributed to the significant enhancement on cell membrane fluidity, disassembly effect on tight junction integrity and the process was reversible. These results indicated that intranasal administration has good potential to treat cerebrovascular diseases.

Highlights

Geniposide, an iridoid glycoside isolated from Gardenia, is one of the main active ingredients in ‘‘Xing Nao Jing’’, an herbal injection extracted from a traditional Chinese herbal medicine recipe ‘‘An Gong Niu Huang Wan’’ that has been used clinically in stroke treatment for hundreds of years
The intranasal pathway has been proposed as a non-invasive alternative route to deliver therapeutics to the brain
Since the nasal epithelium plays an important role in defense against mucosal infections [25,26], it is important to evaluate the toxicity of compounds in nasal epithelial cells when studying nasal drug formulations

Summary

Introduction

Geniposide, an iridoid glycoside isolated from Gardenia, is one of the main active ingredients in ‘‘Xing Nao Jing’’, an herbal injection extracted from a traditional Chinese herbal medicine recipe ‘‘An Gong Niu Huang Wan’’ that has been used clinically in stroke treatment for hundreds of years. Our previous studies have shown that the brain/blood drug ratio of geniposide via intravenous administration in mice was only about 10% [2]. Intranasal administration has been studied as a potential strategy for enhancing the delivery of drugs to the brain [3,4]. This route of administration is relatively more patient compliant and noninvasive than injection, allowing for more frequent administration. Since drugs could be directly delivered into CNS bypassing the blood-brain barrier via intranasal administration, this route was considered to be an attractive alternative to traditional injection therapy for CNS disorders. Previous studies have shown that borneol could enhance drug permeation through skin [11], gastrointestinal mucous membrane [12], nasal mucosa and cornea [13,14]

Objectives

Methods

Results

Conclusion