A proton-coupled organic cation antiporter is involved in the blood-brain barrier transport of Aconitum alkaloids

doi:10.1016/j.jep.2020.112581

	A proton-coupled organic cation antiporter is involved in the blood-brain barrier transport of Aconitum alkaloids
	Cong, Jiaojiao 1,2; Ruan, Yiling 1,2; Lyu, Qinglin 2; Qin, Xiaohui 1,2; Qi, Xinming 3; Liu, Wenyuan 1,2; Kang, Lifeng 4; Zhang, Junying 2; Wu, Chunyong 1,2
刊名	JOURNAL OF ETHNOPHARMACOLOGY
	2020-04-24
卷号	252 页码:9
关键词	Aconitum alkaloids Blood-brain barrier Proton-coupled organic cation antiporter hCMEC/D3 cells Drug transport
ISSN号	0378-8741
DOI	10.1016/j.jep.2020.112581
通讯作者	Zhang, Junying(cpuzjy@cpu.edu.cn) ; Wu, Chunyong(cywu@cpu.edu.cn)
英文摘要	Ethnopharmacological relevance: The herbs of Aconitum are the essential Traditional Chinese medicine and have played an indispensable role in many Asian countries for thousands of years to treat critical illnesses, and chronic, stubborn diseases. However, Aconitum may induce severe neurotoxicity and even death. So far the mechanism of Aconitum penetrating the blood -brain barrier (BBB) is still unclear. Aim of the study: To determine whether influx transporters contribute to the brain uptake of the highly toxic alkaloids in Aconitum including aconitine (AC), mesaconitine (MA) and hypaconitine (HA). Materials and methods: The uptake of AC, MA and HA was characterized using in vitro hCMEC/D3 model and in situ mouse brain perfusion. In hCMEC/D3 cells, the effect of incubation temperature, time, initial drug concentration, energy (NaN3), extracellular and intracellular pH (FCCP and NH4Cl), the prototypical substrates/inhibitors of known organic cation transporting carriers and trans-stimulation (pre-incubating with pyrilamine and diphenhydramine) on the cellular uptake were studied. In addition, the effect of silencing OCTN1, OCTN2 and PMAT by specific siRNA was investigated. In mice, the contribution of the proton-coupled antiporter on the brain uptake of Aconitum was investigated by chemical inhibition. Results: In hCMEC/D3 cells, AC, MA and HA were each taken up in a temperature-, time- and concentration dependent manner, which were reduced by NaN3 and FCCP. Regulation of extracellular and intracellular pH as well as trans-stimulation studies showed that AC, MA and HA were transported by a proton-coupled antiporter expressed at the plasma membrane that could also transport pyrilamine and diphenhydramine. Each uptake was markedly inhibited by various cationic drugs, but insensitive to the prototypical substrates/inhibitors of identified organic cation transporting carriers, such as OCTs, PMAT, MATEs and OCTNs. In addition, silence of OCTN1, OCTN2 and PMAT had no significant inhibitory effect on the uptake of AC, MA and HA. In mice, the brain uptake of each alkaloid measured by in situ brain perfusion was suppressed by diphenhydramine when the transport capacity of P-gp/Bcrp at the BBB was chemically inhibited. Conclusions: A novel proton-coupled organic cation antiporter plays a predominant role in the blood to brain influx of AC, MA and HA at the BBB, and thus affect the safety of Aconitum species.
资助项目	National Natural Science Foundation of China[81673681] ; National Natural Science Foundation of China[81473357] ; National Natural Science Foundation of China[CPU2018GY34] ; Priority Academic Program Development of Jiangsu Higher Education Institutions
WOS关键词	CELL LINE HCMEC/D3 ; IN-VITRO ; FUNCTIONAL EXPRESSION ; H+/OC ANTIPORTER ; P-GLYCOPROTEIN ; TOXICITY ; EFFLUX ; MULTIDRUG ; PROTEINS ; CACO-2
WOS研究方向	Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine
语种	英语
出版者	ELSEVIER IRELAND LTD
WOS记录号	WOS:000518870800027
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281125]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Junying; Wu, Chunyong
作者单位	1.China Pharmaceut Univ, Minist Educ, Key Lab Drug Qual Control & Pharmacovigilance, 24 Tongjia Rd, Nanjing 210009, Peoples R China 2.China Pharmaceut Univ, 24 Tongjia Rd, Nanjing 210009, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 4.Univ Sydney, Sch Pharm, Pharm & Bank Bldg A15, Sydney, NSW 2006, Australia
推荐引用方式 GB/T 7714	Cong, Jiaojiao,Ruan, Yiling,Lyu, Qinglin,et al. A proton-coupled organic cation antiporter is involved in the blood-brain barrier transport of Aconitum alkaloids[J]. JOURNAL OF ETHNOPHARMACOLOGY,2020,252:9.
APA	Cong, Jiaojiao.,Ruan, Yiling.,Lyu, Qinglin.,Qin, Xiaohui.,Qi, Xinming.,...&Wu, Chunyong.(2020).A proton-coupled organic cation antiporter is involved in the blood-brain barrier transport of Aconitum alkaloids.JOURNAL OF ETHNOPHARMACOLOGY,252,9.
MLA	Cong, Jiaojiao,et al."A proton-coupled organic cation antiporter is involved in the blood-brain barrier transport of Aconitum alkaloids".JOURNAL OF ETHNOPHARMACOLOGY 252(2020):9.