Epimedium flavonoids improve cognitive impairment and white matter lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/NRG1/PI3K pathway in rats
Copyright © 2020 Elsevier B.V. All rights reserved..
Chronic cerebral hypoperfusion is a common cause of cerebral small vascular disease (CSVD). White matter (WM) lesions are the typical pathological manifestation of CSVD and contribute to cognitive decline. Epimedium flavonoids (EF) are the main component in Epimedium brevicornu Maxim., which is commonly used in traditional Chinese medicine. The purpose of this study was to investigate the effects of EF on cognitive impairment and the underlying mechanisms in a CSVD rat model induced with chronic cerebral hypoperfusion. The model was established by permanent bilateral common carotid artery occlusion (2VO) in rats. EF (50, 100, and 200 mg/kg) was intragastrically administered once a day for 12 weeks starting 2 weeks after 2VO surgery. The learning and memory capacity of the rats were measured using the Morris water maze and step-through tests. WM lesions were observed by MRI-diffusion tensor imaging, transmission electron microscopy, and LFB staining. Oligodendrocytes were detected by immunohistochemistry. Western blotting assay was used to determine the level of protein expression. The results showed that EF significantly improved learning and memory impairment, alleviated WM nerve fiber injuries and demyelination, and increased the number of mature oligodendrocytes in the corpus callosum, subcortical WM, and periventricular WM in 2VO rats. Mechanistically, EF reduced the expression of Lingo-1 and ROCK2 and increased the levels of phosphorylated (p-) Fyn, brain-derived neurotrophic factor (BDNF), TrkB, neuregulin-1 (NRG-1), p-ErbB4, PI3K p85 and p110α, p-Akt, and p-CREB in the corpus callosum of 2VO rats. These results suggest that EF may improve cognitive impairment and WM lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/TrkB, NRG-1/ErbB4, and the downstream PI3K/Akt/CREB pathways in WM. Thus, EF can be used as a potential neuroprotective agent in CSVD therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1743 |
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| Enthalten in: |
Brain research - 1743(2020) vom: 15. Sept., Seite 146902 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Niu, Hong-Mei [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.10.2021 Date Revised 04.10.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.brainres.2020.146902 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM310291275 |
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| 100 | 1 | |a Niu, Hong-Mei |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Epimedium flavonoids improve cognitive impairment and white matter lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/NRG1/PI3K pathway in rats |
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| 500 | |a Date Revised 04.10.2021 | ||
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| 520 | |a Copyright © 2020 Elsevier B.V. All rights reserved. | ||
| 520 | |a Chronic cerebral hypoperfusion is a common cause of cerebral small vascular disease (CSVD). White matter (WM) lesions are the typical pathological manifestation of CSVD and contribute to cognitive decline. Epimedium flavonoids (EF) are the main component in Epimedium brevicornu Maxim., which is commonly used in traditional Chinese medicine. The purpose of this study was to investigate the effects of EF on cognitive impairment and the underlying mechanisms in a CSVD rat model induced with chronic cerebral hypoperfusion. The model was established by permanent bilateral common carotid artery occlusion (2VO) in rats. EF (50, 100, and 200 mg/kg) was intragastrically administered once a day for 12 weeks starting 2 weeks after 2VO surgery. The learning and memory capacity of the rats were measured using the Morris water maze and step-through tests. WM lesions were observed by MRI-diffusion tensor imaging, transmission electron microscopy, and LFB staining. Oligodendrocytes were detected by immunohistochemistry. Western blotting assay was used to determine the level of protein expression. The results showed that EF significantly improved learning and memory impairment, alleviated WM nerve fiber injuries and demyelination, and increased the number of mature oligodendrocytes in the corpus callosum, subcortical WM, and periventricular WM in 2VO rats. Mechanistically, EF reduced the expression of Lingo-1 and ROCK2 and increased the levels of phosphorylated (p-) Fyn, brain-derived neurotrophic factor (BDNF), TrkB, neuregulin-1 (NRG-1), p-ErbB4, PI3K p85 and p110α, p-Akt, and p-CREB in the corpus callosum of 2VO rats. These results suggest that EF may improve cognitive impairment and WM lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/TrkB, NRG-1/ErbB4, and the downstream PI3K/Akt/CREB pathways in WM. Thus, EF can be used as a potential neuroprotective agent in CSVD therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a BDNF/NRG-1/PI3K pathway | |
| 650 | 4 | |a Cerebral small vascular disease | |
| 650 | 4 | |a Chronic cerebral hypoperfusion | |
| 650 | 4 | |a Cognitive impairment | |
| 650 | 4 | |a Epimedium flavonoids | |
| 650 | 4 | |a Lingo-1/Fyn/ROCK pathway | |
| 650 | 4 | |a White matter lesion | |
| 650 | 7 | |a Bdnf protein, rat |2 NLM | |
| 650 | 7 | |a Brain-Derived Neurotrophic Factor |2 NLM | |
| 650 | 7 | |a Drugs, Chinese Herbal |2 NLM | |
| 650 | 7 | |a Flavonoids |2 NLM | |
| 650 | 7 | |a LINGO1 protein, rat |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Nerve Tissue Proteins |2 NLM | |
| 650 | 7 | |a Neuregulin-1 |2 NLM | |
| 650 | 7 | |a Nrg1 protein, rat |2 NLM | |
| 650 | 7 | |a Fyn protein, rat |2 NLM | |
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| 650 | 7 | |a Proto-Oncogene Proteins c-fyn |2 NLM | |
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| 650 | 7 | |a rho-Associated Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Wang, Ming-Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Deng-Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xiao-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ya-Li |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Lin |e verfasserin |4 aut | |
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