miR-23a-3p is involved in drug resistance by directly targeting the influx drug transporter organic anion-transporting polypeptide 2.
In: Child's Nervous System, Jg. 37 (2021-08-01), Heft 8, S. 2545-2555
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Zugriff:
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. [ABSTRACT FROM AUTHOR]
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miR-23a-3p is involved in drug resistance by directly targeting the influx drug transporter organic anion-transporting polypeptide 2.
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Autor/in / Beteiligte Person: | Guo, Yi ; Li, Junzhi ; Kang, Yu ; Jiang, Li |
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Zeitschrift: | Child's Nervous System, Jg. 37 (2021-08-01), Heft 8, S. 2545-2555 |
Veröffentlichung: | 2021 |
Medientyp: | academicJournal |
ISSN: | 0256-7040 (print) |
DOI: | 10.1007/s00381-021-05146-3 |
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