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Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia
The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famous Chinese herbal prescription used for post-stroke treatment in Taiwan; however, little is known about its biological effects and mechanisms of action. Herein, we implemented a murine...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taiwan Food and Drug Administration
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931010/ https://www.ncbi.nlm.nih.gov/pubmed/35649147 http://dx.doi.org/10.38212/2224-6614.3377 |
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author | Chern, Chang-Ming Lu, Chung-Kuang Liou, Kuo-Tong Wang, Yea-Hwey Tsai, Keng-Chang Chang, Chia-Lin Chang, Chia-Che Shen, Yuh-Chiang |
author_facet | Chern, Chang-Ming Lu, Chung-Kuang Liou, Kuo-Tong Wang, Yea-Hwey Tsai, Keng-Chang Chang, Chia-Lin Chang, Chia-Che Shen, Yuh-Chiang |
author_sort | Chern, Chang-Ming |
collection | PubMed |
description | The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famous Chinese herbal prescription used for post-stroke treatment in Taiwan; however, little is known about its biological effects and mechanisms of action. Herein, we implemented a murine model of cerebral ischemic/reperfusional injury-related stroke to elucidate medicarpin’s neuroprotective effect. In male ICR mice 24 h after stroke induction, treatment with medicarpin (0.5 and 1.0 mg/kg, i.v.) markedly enhanced the survival rates, improved moving distance and walking area coverage, reduced brain infarction, and preserved the blood–brain barrier, supporting medicarpin’s protective effect on stroke-induced injury. Immunohistochemistry analysis further revealed that medicarpin treatment decreased the expression/activation of p65NF-κB and caspase 3, especially near the infarct cortex, while promoting the expression of neurogenesis-associated proteins, including doublecortin (DCX), brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB). These changes of expression levels were accompanied by GSK-3 inactivation and β-catenin upregulation. Notably, pretreatment with LY294002, a PI3K inhibitor, abolished the aforementioned beneficial effects of medicarpin, illustrating an essential role of PI3K/Akt activation in medicarpin’s neuroprotective and reparative activities. In vitro studies revealed that medicarpin displayed strong anti-inflammatory activity by reducing nitric oxide (NO) production in lipopolysaccharide-stimulated microglial cells (BV2) with an IC(50) around 5 ±1 (μM) and anti-apoptotic activity in neuronal cells (N2A) subjected to oxygen-glucose deprivation with an IC(50) around 13 ± 2 (μM). Collectively, this is the first report to demonstrate that medicarpin, isolated from Radix Hedysari, ameliorates ischemic brain injury through its anti-inflammatory microglia/NO), anti-apoptotic (neuronal cells/OGD) and neuroprotective effects by activating the PI3K/Akt-dependent GSK-3 inactivation for upregulating β-catenin, which in turn decreases the expression/activation of p65NF-κB and caspase 3 and promotes the expression of neurogenic (DCX, BDNF, TrkB) and neuroprotective (Bcl2) factors in the brain. |
format | Online Article Text |
id | pubmed-9931010 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Taiwan Food and Drug Administration |
record_format | MEDLINE/PubMed |
spelling | pubmed-99310102023-02-16 Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia Chern, Chang-Ming Lu, Chung-Kuang Liou, Kuo-Tong Wang, Yea-Hwey Tsai, Keng-Chang Chang, Chia-Lin Chang, Chia-Che Shen, Yuh-Chiang J Food Drug Anal Original Article The development of effective post-stroke therapy is highly demanded. Medicarpin is a key active component of a famous Chinese herbal prescription used for post-stroke treatment in Taiwan; however, little is known about its biological effects and mechanisms of action. Herein, we implemented a murine model of cerebral ischemic/reperfusional injury-related stroke to elucidate medicarpin’s neuroprotective effect. In male ICR mice 24 h after stroke induction, treatment with medicarpin (0.5 and 1.0 mg/kg, i.v.) markedly enhanced the survival rates, improved moving distance and walking area coverage, reduced brain infarction, and preserved the blood–brain barrier, supporting medicarpin’s protective effect on stroke-induced injury. Immunohistochemistry analysis further revealed that medicarpin treatment decreased the expression/activation of p65NF-κB and caspase 3, especially near the infarct cortex, while promoting the expression of neurogenesis-associated proteins, including doublecortin (DCX), brain-derived neurotrophic factor (BDNF), and tyrosine receptor kinase B (TrkB). These changes of expression levels were accompanied by GSK-3 inactivation and β-catenin upregulation. Notably, pretreatment with LY294002, a PI3K inhibitor, abolished the aforementioned beneficial effects of medicarpin, illustrating an essential role of PI3K/Akt activation in medicarpin’s neuroprotective and reparative activities. In vitro studies revealed that medicarpin displayed strong anti-inflammatory activity by reducing nitric oxide (NO) production in lipopolysaccharide-stimulated microglial cells (BV2) with an IC(50) around 5 ±1 (μM) and anti-apoptotic activity in neuronal cells (N2A) subjected to oxygen-glucose deprivation with an IC(50) around 13 ± 2 (μM). Collectively, this is the first report to demonstrate that medicarpin, isolated from Radix Hedysari, ameliorates ischemic brain injury through its anti-inflammatory microglia/NO), anti-apoptotic (neuronal cells/OGD) and neuroprotective effects by activating the PI3K/Akt-dependent GSK-3 inactivation for upregulating β-catenin, which in turn decreases the expression/activation of p65NF-κB and caspase 3 and promotes the expression of neurogenic (DCX, BDNF, TrkB) and neuroprotective (Bcl2) factors in the brain. Taiwan Food and Drug Administration 2021-12-15 /pmc/articles/PMC9931010/ /pubmed/35649147 http://dx.doi.org/10.38212/2224-6614.3377 Text en © 2021 Taiwan Food and Drug Administration https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Original Article Chern, Chang-Ming Lu, Chung-Kuang Liou, Kuo-Tong Wang, Yea-Hwey Tsai, Keng-Chang Chang, Chia-Lin Chang, Chia-Che Shen, Yuh-Chiang Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia |
title | Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia |
title_full | Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia |
title_fullStr | Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia |
title_full_unstemmed | Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia |
title_short | Medicarpin isolated from Radix Hedysari ameliorates brain injury in a murine model of cerebral ischemia |
title_sort | medicarpin isolated from radix hedysari ameliorates brain injury in a murine model of cerebral ischemia |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9931010/ https://www.ncbi.nlm.nih.gov/pubmed/35649147 http://dx.doi.org/10.38212/2224-6614.3377 |
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