Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats
BackgroundMethamphetamine (MA) is one of the most harmful synthetic drugs, yet the mechanisms underlying its addiction and relapse remain incompletely understood. This study investigates how cardiomyocyte-derived exosomes carrying miRNAs facilitate heart-brain crosstalk and contribute to MA dependen...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-05-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1541442/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849322369297940480 |
|---|---|
| author | Hancheng Li Hancheng Li Hancheng Li Yongen Peng Yangkai Wu Yangkai Wu Yiling Chen Yiling Chen Jieyu Li Jieyu Li Yunbing He Yunbing He Hongwu Wang Hongwu Wang Chaohua Luo Zhixian Mo |
| author_facet | Hancheng Li Hancheng Li Hancheng Li Yongen Peng Yangkai Wu Yangkai Wu Yiling Chen Yiling Chen Jieyu Li Jieyu Li Yunbing He Yunbing He Hongwu Wang Hongwu Wang Chaohua Luo Zhixian Mo |
| author_sort | Hancheng Li |
| collection | DOAJ |
| description | BackgroundMethamphetamine (MA) is one of the most harmful synthetic drugs, yet the mechanisms underlying its addiction and relapse remain incompletely understood. This study investigates how cardiomyocyte-derived exosomes carrying miRNAs facilitate heart-brain crosstalk and contribute to MA dependence.Materials and methodsA conditioned place preference (CPP) model of MA dependence was established in rats. High-throughput sequencing were employed to identify candidate miRNAs in cardiac exosomes and brain tissues. Behavioral assessments, real-time PCR, nanoparticle tracking analysis, in vivo imaging, in vitro uptake assays, network pharmacology, and dual-luciferase reporter assays were used to explore the role of cardiomyocyte-derived exosomes in MA dependence.ResultsMA induced significant CPP in rats. miR-181a-5p was markedly upregulated in cardiac exosomes and brain tissue, with higher levels observed in cardiac exosomes. In vivo biodistribution showed that cardiomyocyte-derived exosomes cross the blood-brain barrier and accumulate in the brain. In vitro uptake assays demonstrated that SH-SY5Y cells internalized these exosomes, leading to increased miR-181a-5p expression. Tail vein injections of miR-181a-5p-enriched exosomes enhanced MA CPP behavior in rats. Network pharmacology revealed 108 potential targets of miR-181a-5p, enriched in processes such as steroid biosynthesis, amide metabolism, and apoptosis, involving pathways related to the endoplasmic reticulum, MAPK signaling, and amyotrophic lateral sclerosis. Molecular docking identified stable interactions between MA and 12 targets, including HSP90B1, TNF, and MAP2K1, with miR-181a-5p binding to the 3′-UTR regions of these targets. Dual-luciferase assays confirmed the negative regulation of six targets by miR-181a-5p.ConclusionThis study reveals that cardiomyocyte-derived exosomes transport miR-181a-5p, facilitating heart-brain crosstalk and exacerbating MA CPP behavior in rats. These effects are mediated through the regulation of key brain targets, including HSP90B1, TNF, and MAP2K1, providing new insights into the molecular mechanisms of MA addiction and potential therapeutic targets. |
| format | Article |
| id | doaj-art-413988d39c4c4e32831b025d54f5a3de |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-413988d39c4c4e32831b025d54f5a3de2025-08-20T03:49:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-05-011610.3389/fphar.2025.15414421541442Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in ratsHancheng Li0Hancheng Li1Hancheng Li2Yongen Peng3Yangkai Wu4Yangkai Wu5Yiling Chen6Yiling Chen7Jieyu Li8Jieyu Li9Yunbing He10Yunbing He11Hongwu Wang12Hongwu Wang13Chaohua Luo14Zhixian Mo15Department of Pharmaceutical Engineering, School of Food and Pharmaceutical Engineering, Zhaoqing University, Zhaoqing, ChinaDepartment of Pharmacology of Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaKey Laboratory for Research and Utilization of Southern Medicine, Zhaoqing University, Zhaoqing, ChinaDepartment of Pharmacology of Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaDepartment of Pharmaceutical Engineering, School of Food and Pharmaceutical Engineering, Zhaoqing University, Zhaoqing, ChinaRisk Assessment Laboratory for Agricultural Product Quality and Safety, Ministry of Agriculture and Rural Development, Zhaoqing University, Zhaoqing, ChinaDepartment of Pharmaceutical Engineering, School of Food and Pharmaceutical Engineering, Zhaoqing University, Zhaoqing, ChinaRisk Assessment Laboratory for Agricultural Product Quality and Safety, Ministry of Agriculture and Rural Development, Zhaoqing University, Zhaoqing, ChinaDepartment of Pharmaceutical Engineering, School of Food and Pharmaceutical Engineering, Zhaoqing University, Zhaoqing, ChinaKey Laboratory for Research and Utilization of Southern Medicine, Zhaoqing University, Zhaoqing, ChinaDepartment of Pharmaceutical Engineering, School of Food and Pharmaceutical Engineering, Zhaoqing University, Zhaoqing, ChinaKey Laboratory for Research and Utilization of Southern Medicine, Zhaoqing University, Zhaoqing, ChinaDepartment of Pharmaceutical Engineering, School of Food and Pharmaceutical Engineering, Zhaoqing University, Zhaoqing, ChinaRisk Assessment Laboratory for Agricultural Product Quality and Safety, Ministry of Agriculture and Rural Development, Zhaoqing University, Zhaoqing, ChinaDepartment of Pharmacology of Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaDepartment of Pharmacology of Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaBackgroundMethamphetamine (MA) is one of the most harmful synthetic drugs, yet the mechanisms underlying its addiction and relapse remain incompletely understood. This study investigates how cardiomyocyte-derived exosomes carrying miRNAs facilitate heart-brain crosstalk and contribute to MA dependence.Materials and methodsA conditioned place preference (CPP) model of MA dependence was established in rats. High-throughput sequencing were employed to identify candidate miRNAs in cardiac exosomes and brain tissues. Behavioral assessments, real-time PCR, nanoparticle tracking analysis, in vivo imaging, in vitro uptake assays, network pharmacology, and dual-luciferase reporter assays were used to explore the role of cardiomyocyte-derived exosomes in MA dependence.ResultsMA induced significant CPP in rats. miR-181a-5p was markedly upregulated in cardiac exosomes and brain tissue, with higher levels observed in cardiac exosomes. In vivo biodistribution showed that cardiomyocyte-derived exosomes cross the blood-brain barrier and accumulate in the brain. In vitro uptake assays demonstrated that SH-SY5Y cells internalized these exosomes, leading to increased miR-181a-5p expression. Tail vein injections of miR-181a-5p-enriched exosomes enhanced MA CPP behavior in rats. Network pharmacology revealed 108 potential targets of miR-181a-5p, enriched in processes such as steroid biosynthesis, amide metabolism, and apoptosis, involving pathways related to the endoplasmic reticulum, MAPK signaling, and amyotrophic lateral sclerosis. Molecular docking identified stable interactions between MA and 12 targets, including HSP90B1, TNF, and MAP2K1, with miR-181a-5p binding to the 3′-UTR regions of these targets. Dual-luciferase assays confirmed the negative regulation of six targets by miR-181a-5p.ConclusionThis study reveals that cardiomyocyte-derived exosomes transport miR-181a-5p, facilitating heart-brain crosstalk and exacerbating MA CPP behavior in rats. These effects are mediated through the regulation of key brain targets, including HSP90B1, TNF, and MAP2K1, providing new insights into the molecular mechanisms of MA addiction and potential therapeutic targets.https://www.frontiersin.org/articles/10.3389/fphar.2025.1541442/fullmethamphetamine dependencecardiomyocyte-derived exosomesconditioned place preferenceheart-brain crosstalkmiR-181a-5p |
| spellingShingle | Hancheng Li Hancheng Li Hancheng Li Yongen Peng Yangkai Wu Yangkai Wu Yiling Chen Yiling Chen Jieyu Li Jieyu Li Yunbing He Yunbing He Hongwu Wang Hongwu Wang Chaohua Luo Zhixian Mo Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats Frontiers in Pharmacology methamphetamine dependence cardiomyocyte-derived exosomes conditioned place preference heart-brain crosstalk miR-181a-5p |
| title | Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats |
| title_full | Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats |
| title_fullStr | Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats |
| title_full_unstemmed | Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats |
| title_short | Cardiomyocyte-derived exosomes carrying miR-181a-5p facilitate heart-brain crosstalk and exacerbate methamphetamine dependence in rats |
| title_sort | cardiomyocyte derived exosomes carrying mir 181a 5p facilitate heart brain crosstalk and exacerbate methamphetamine dependence in rats |
| topic | methamphetamine dependence cardiomyocyte-derived exosomes conditioned place preference heart-brain crosstalk miR-181a-5p |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1541442/full |
| work_keys_str_mv | AT hanchengli cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT hanchengli cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT hanchengli cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT yongenpeng cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT yangkaiwu cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT yangkaiwu cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT yilingchen cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT yilingchen cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT jieyuli cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT jieyuli cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT yunbinghe cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT yunbinghe cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT hongwuwang cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT hongwuwang cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT chaohualuo cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats AT zhixianmo cardiomyocytederivedexosomescarryingmir181a5pfacilitateheartbraincrosstalkandexacerbatemethamphetaminedependenceinrats |