miR-23a-3p is involved in drug resistance by directly targeting the influx drug transporter organic anion-transporting polypeptide 2

作者全名："Guo, Yi; Li, Junzhi; Kang, Yu; Jiang, Li"

作者地址："[Guo, Yi; Jiang, Li] Chongqing Med Univ, Dept Neurol, Childrens Hosp,Key Lab Child Dev & Disorders, Natl Clin Res Ctr Child Hlth & Disorders,Minist E, 136 Zhong Shan Er Rd, Chongqing 400014, Peoples R China; [Guo, Yi; Jiang, Li] Chongqing Key Lab Pediat, Chongqing 400014, Peoples R China; [Li, Junzhi] Chongqing Med Univ, Chongqing 400014, Peoples R China; [Kang, Yu] Shanghai Jiao Tong Univ, Sch Med, Dept Cardiovasc Dis, Shanghai 200030, Peoples R China"

通信作者："Guo, Y (corresponding author), Chongqing Med Univ, Dept Neurol, Childrens Hosp,Key Lab Child Dev & Disorders, Natl Clin Res Ctr Child Hlth & Disorders,Minist E, 136 Zhong Shan Er Rd, Chongqing 400014, Peoples R China.; Guo, Y (corresponding author), Chongqing Key Lab Pediat, Chongqing 400014, Peoples R China."

来源：CHILDS NERVOUS SYSTEM

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000634639400004

JCR分区：Q3

影响因子：1.4

年份：2021

卷号：37

期号：8

开始页：2545

结束页：2555

文献类型：Article

关键词：MicroRNA; miR-23a-3p; Drug transporter; Organic anion-transporting polypeptide 2; Valproate; Drug resistance

摘要："Objective Drug transporters are involved in the drug resistance of individuals with drug-resistant epilepsy by influencing the intracerebral transport of antiepileptic drugs (AEDs). The expression of drug transporters is associated with microRNAs. We previously revealed that miR-23a-3p levels were elevated in the blood of patients with intractable epilepsy. Additionally, the influx drug transporter organic anion-transporting polypeptide 2 (Oatp2) is involved in the intracerebral transport of valproic acid (VPA), the most commonly used AED; repeated seizures lead to decreased expression of Oatp2. However, the role of miR-23a-3p in the expression of Oatp2 and in the development of drug resistance has not been established. Herein, we aimed to determine the potential role of miR-23a-3p in VPA-resistant epilepsy through in vivo and in vitro experiments. Methods Epilepsy was elicited after status epilepticus (SE) was induced by lithium-pilocarpine in adult Sprague-Dawley rats, followed by VPA treatment to select rats with VPA resistance. The expression of miR-23a-3p was detected by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). A miR-23a-3p inhibitor was intracerebrally injected into VPA-resistant rats, and histological staining and Morris water maze tests were performed to evaluate brain damage and learning/memory functions in these rats. Subsequently, a dual-luciferase reporter assay and a VPA uptake assay were performed in brain microvascular endothelial cells (BMECs) to investigate the underlying mechanism of action of miR-23a-3p. Results Our results indicated that compared to that in control rats, miR-23a-3p was elevated in VPA-resistant rats. Intracerebral injection of a miR-23a-3p inhibitor reduced brain damage and the associated deficits in learning and memory functions in rats with VPA resistance. Further investigation indicated that Oatp2 was the direct target of miR-23a-3p, and it was negatively regulated by miR-23a-3p in the brain and BMECs. Furthermore, we demonstrated that miR-23a-3p reduced VPA uptake in BMECs by regulating Oatp2 expression. Conclusions miR-23a-3p is involved in VPA resistance in epilepsy by directly targeting the influx drug transporter Oatp2, indicating that miR-23a-3p could be a potential therapeutic target for intractable epilepsy."

基金机构：National Natural Science Function of China [81701277]; National Health and Family Planning Commission of Chongqing [2016MSXM040]

基金资助正文：This work was supported by a grant from the National Natural Science Function of China (81701277) and National Health and Family Planning Commission of Chongqing (2016MSXM040).