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

Autor: Guo Y; Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, 136 Zhong shan Er Road, Yu Zhong District, Chongqing, 400014, China. yiguo_cq@hotmail.com.; Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China. yiguo_cq@hotmail.com., Li J; Chongqing Medical University, Chongqing, 400014, China., Kang Y; Department of Cardiovascular Disease, School of Medicine, Shanghai Jiaotong University, Shanghai, 200030, China., Jiang L; Department of Neurology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, 136 Zhong shan Er Road, Yu Zhong District, Chongqing, 400014, China.; Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China.
Jazyk: angličtina
Zdroj: Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery [Childs Nerv Syst] 2021 Aug; Vol. 37 (8), pp. 2545-2555. Date of Electronic Publication: 2021 Mar 29.
DOI: 10.1007/s00381-021-05146-3
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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