Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation
Introduction: Cognitive impairment is a common complication and comorbidity of diabetes. However, the underlying mechanisms of diabetes-associated cognitive dysfunction are currently unclear. M1 microglia secretes pro-inflammatory factors and can be marked by CD16, iNOS, Iba1 and TNF-ɑ. The decline...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1145819/full |
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| author | Yun-yun Zhang Yun-yun Zhang Lu Wang Lu Wang Hua Guo Hua Guo Ting-ting Han Ting-ting Han Yan-hua Chang Yan-hua Chang Xiao-chuan Cui Xiao-chuan Cui |
| author_facet | Yun-yun Zhang Yun-yun Zhang Lu Wang Lu Wang Hua Guo Hua Guo Ting-ting Han Ting-ting Han Yan-hua Chang Yan-hua Chang Xiao-chuan Cui Xiao-chuan Cui |
| author_sort | Yun-yun Zhang |
| collection | DOAJ |
| description | Introduction: Cognitive impairment is a common complication and comorbidity of diabetes. However, the underlying mechanisms of diabetes-associated cognitive dysfunction are currently unclear. M1 microglia secretes pro-inflammatory factors and can be marked by CD16, iNOS, Iba1 and TNF-ɑ. The decline of M2 microglia in the diabetic rats indicates that high glucose promotes the differentiation of microglia into the M1 type to trigger neuroinflammatory responses. Moreover, there is a lack of strong evidence for treatments of diabetes-associated cognitive impairment in addition to controlling blood glucose.Methods: Diabetic rats were established by intraperitoneal injection of one dose of streptozotocin (60 mg/kg). Polarization transitions of microglia were induced by high glucose treatment in BV2 cells. Levetiracetam was orally administered to rats 72 h after streptozotocin injection for 12 weeks.Results: In STZ-induced diabetic rats, the results demonstrated that levetiracetam improved rat cognitive function (Morris water maze test) and hippocampus morphology (Hematoxylin-eosin staining), and the effect was more evident in the high-dose levetiracetam group. Microglia activation in the hippocampus was inhibited by levetiracetam treatment for 12 weeks. Serum levels of TNF-α, IL-1β, and IL-6 were reduced in the LEV-L and LEV-H groups, and IL-1β level was obviously reduced in the LEV-H group. In vitro, we found that levetiracetam 50 µM attenuated high-glucose induced microglial polarization by increasing IL-10 level and decreasing IL-1β and TNF-α levels. Moreover, levetiracetam 50 µM increased and decreased the proportion of CD206+/Iba1+ and iNOS+/Iba1+cells, respectively. Western blot analysis illustrated that LEV 50 µM downregulated the expression of MyD88 and TRAF6, and phosphorylation of TAK1, JNK, p38, and NF-κB p65. The effect of levetiracetam on the anti-polarization and expression of p-JNK and p-NF-κB p65 were partly reversed by anisomycin (p38 and JNK activators).Discussion: Together, our data suggest that levetiracetam attenuates streptozotocin-induced cognitive impairment by suppressing microglia activation. The in vitro findings also indicate that the levetiracetam inhibited the polarization of microglia via the JNK/MAPK/NF-κB signaling pathway. |
| first_indexed | 2024-04-09T14:26:09Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-04-09T14:26:09Z |
| publishDate | 2023-05-01 |
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| spelling | doaj.art-7b51cf845b34468eb617ab0f6edbf13a2023-05-04T04:25:02ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-05-011410.3389/fphar.2023.11458191145819Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammationYun-yun Zhang0Yun-yun Zhang1Lu Wang2Lu Wang3Hua Guo4Hua Guo5Ting-ting Han6Ting-ting Han7Yan-hua Chang8Yan-hua Chang9Xiao-chuan Cui10Xiao-chuan Cui11Department of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaWuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaDepartment of General Practice, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, ChinaIntroduction: Cognitive impairment is a common complication and comorbidity of diabetes. However, the underlying mechanisms of diabetes-associated cognitive dysfunction are currently unclear. M1 microglia secretes pro-inflammatory factors and can be marked by CD16, iNOS, Iba1 and TNF-ɑ. The decline of M2 microglia in the diabetic rats indicates that high glucose promotes the differentiation of microglia into the M1 type to trigger neuroinflammatory responses. Moreover, there is a lack of strong evidence for treatments of diabetes-associated cognitive impairment in addition to controlling blood glucose.Methods: Diabetic rats were established by intraperitoneal injection of one dose of streptozotocin (60 mg/kg). Polarization transitions of microglia were induced by high glucose treatment in BV2 cells. Levetiracetam was orally administered to rats 72 h after streptozotocin injection for 12 weeks.Results: In STZ-induced diabetic rats, the results demonstrated that levetiracetam improved rat cognitive function (Morris water maze test) and hippocampus morphology (Hematoxylin-eosin staining), and the effect was more evident in the high-dose levetiracetam group. Microglia activation in the hippocampus was inhibited by levetiracetam treatment for 12 weeks. Serum levels of TNF-α, IL-1β, and IL-6 were reduced in the LEV-L and LEV-H groups, and IL-1β level was obviously reduced in the LEV-H group. In vitro, we found that levetiracetam 50 µM attenuated high-glucose induced microglial polarization by increasing IL-10 level and decreasing IL-1β and TNF-α levels. Moreover, levetiracetam 50 µM increased and decreased the proportion of CD206+/Iba1+ and iNOS+/Iba1+cells, respectively. Western blot analysis illustrated that LEV 50 µM downregulated the expression of MyD88 and TRAF6, and phosphorylation of TAK1, JNK, p38, and NF-κB p65. The effect of levetiracetam on the anti-polarization and expression of p-JNK and p-NF-κB p65 were partly reversed by anisomycin (p38 and JNK activators).Discussion: Together, our data suggest that levetiracetam attenuates streptozotocin-induced cognitive impairment by suppressing microglia activation. The in vitro findings also indicate that the levetiracetam inhibited the polarization of microglia via the JNK/MAPK/NF-κB signaling pathway.https://www.frontiersin.org/articles/10.3389/fphar.2023.1145819/fulldiabeticcognitionlevetiracetammicroglia polarizationJNK/MAPK/ NF-κB |
| spellingShingle | Yun-yun Zhang Yun-yun Zhang Lu Wang Lu Wang Hua Guo Hua Guo Ting-ting Han Ting-ting Han Yan-hua Chang Yan-hua Chang Xiao-chuan Cui Xiao-chuan Cui Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation Frontiers in Pharmacology diabetic cognition levetiracetam microglia polarization JNK/MAPK/ NF-κB |
| title | Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation |
| title_full | Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation |
| title_fullStr | Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation |
| title_full_unstemmed | Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation |
| title_short | Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation |
| title_sort | levetiracetam attenuates diabetes associated cognitive impairment and microglia polarization by suppressing neuroinflammation |
| topic | diabetic cognition levetiracetam microglia polarization JNK/MAPK/ NF-κB |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1145819/full |
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