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Published on: June 10, 2013
MicroRNA-155 modulates methotrexate-induced spatial memory impairment by disruption of the blood-brain barrier
Yu-Chieh Chen1, Li-Tung Huang2, Hong-Ren Yu3
1Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Department of Traditional Medicine, Chang Gung University, Taoyuan, Taiwan; School of Medicine, College of Medicine, National SunYat-sen University, Kaohsiung, Taiwan.
Aim:
Methotrexate (MTX) is a commonly used chemotherapy drug, yet its late neurotoxic side effects are gaining attention. The aim of the study was to evaluate the role of miR-155 in the pathogenesis of MTX-induced cognitive impairment, mainly focused on the interplay of blood-brain barrier (BBB) integrity and MTX toxicity.
Main Methods:
We use young rat model mimicking children leukemia treatment protocol, focusing on the systemic MTX effect on the central nervous system by intraperitoneal (IP) MTX injection. The cognitive function was evaluated by Morris Water Maze test and the BBB integrity was accessed by cortex permeability test. Tight junction proteins expression were also examined. Finally, we tested whether anti-miR155 pretreatment can reversed the MTX effect.
Key Findings:
We found increased plasma miR-155 expression at 24 hr after IP MTX treatment. Besides, IP MTX resulted in impaired learning acquisition, which can be reversed by anti-miR155 treatment. Furthermore, brain cortex permeability and tight junction proteins were changed by IP MTX. miR-155 revealed its protective role in the current study for the development of MTX-induced cognitive impairment.
Significance:
IP MTX can induce significant cognitive impairment, which is related to the disruption of BBB integrity. miR-155 plays a vital role in the regulation of MTX-induced cognitive impairment, mainly through the maintenance of BBB integrity.
Insights
Methotrexate chemotherapy can cause cognitive impairment by damaging the blood-brain barrier. MicroRNA-155 (miR-155) protects against this, maintaining barrier integrity and reversing cognitive deficits.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Methotrexate (MTX) is a vital chemotherapy agent.
- Late-onset neurotoxicity, including cognitive impairment, is a significant concern with MTX treatment.
- The precise mechanisms underlying MTX-induced neurotoxicity require further elucidation.
Purpose of the Study:
- To investigate the role of microRNA-155 (miR-155) in the development of MTX-induced cognitive impairment.
- To explore the relationship between blood-brain barrier (BBB) integrity and MTX neurotoxicity.
- To determine if modulating miR-155 can mitigate MTX-induced cognitive deficits.
Main Methods:
- A young rat model was utilized, mimicking pediatric leukemia treatment protocols.
- Intraperitoneal (IP) MTX injections were administered to assess systemic effects on the central nervous system.
- Cognitive function was evaluated using the Morris Water Maze test, and BBB integrity was assessed via cortex permeability and tight junction protein analysis.
- The therapeutic potential of anti-miR155 pretreatment was examined.
Main Results:
- Plasma miR-155 levels increased 24 hours post-IP MTX administration.
- IP MTX treatment led to impaired learning acquisition, which was reversed by anti-miR155 pretreatment.
- MTX treatment altered brain cortex permeability and tight junction protein expression, indicating BBB disruption.
- miR-155 demonstrated a protective role against MTX-induced cognitive impairment.
Conclusions:
- Systemic administration of MTX induces cognitive impairment linked to blood-brain barrier disruption.
- miR-155 plays a critical role in regulating MTX-induced cognitive impairment, primarily by maintaining BBB integrity.
- Targeting miR-155 presents a potential therapeutic strategy to counteract MTX neurotoxicity.
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