Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury
Cognitive dysfunction has become the second leading cause of death among the diabetic patients. In pre-diabetic stage, blood-brain barrier (BBB) injury occurs and induced the microvascular complications of diabetes, especially, diabetes-associated cognitive dysfunction (DACD). Endothelial cells are...
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Elsevier
2025-02-01
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| Series: | Brain Research Bulletin |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0361923025000231 |
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| author | Fuxing Xu Juan Hu Xuying Li Lan Yang Shiqiu Jiang Tao Jiang Bo Cheng Hailiang Du Ruiduo Wang Yingying Deng Wei Gao Yansong Li Yaomin Zhu |
| author_facet | Fuxing Xu Juan Hu Xuying Li Lan Yang Shiqiu Jiang Tao Jiang Bo Cheng Hailiang Du Ruiduo Wang Yingying Deng Wei Gao Yansong Li Yaomin Zhu |
| author_sort | Fuxing Xu |
| collection | DOAJ |
| description | Cognitive dysfunction has become the second leading cause of death among the diabetic patients. In pre-diabetic stage, blood-brain barrier (BBB) injury occurs and induced the microvascular complications of diabetes, especially, diabetes-associated cognitive dysfunction (DACD). Endothelial cells are the major component of BBB, on which the increased expression of CD40 could mediate BBB dysfunction in diabetics. Since platelets play an important role in regulating endothelial cell barrier function and over 95 % of the circulating soluble CD40 ligand (sCD40L) is derived from activated platelets, we speculated that the release of CD40L from activated platelets induced by diabetes was the key mechanism that aggravated BBB injury and leaded to DACD. We performed inhibition of platelet activation on diabetic and non-diabetic mice, with or without cilostazol treatment, and then compared cognitive function, platelet activation, BBB structure and permeability. In vitro, mouse brain microvascular endothelial cell line (b.End3) were exposed to CD40L for 24 h at 5.5 mM or 30 mM glucose media after silencing CD40 and HIF1α or not to investigate the effects of CD40 on BBB disruption and the underlying molecular pathways. Inhibition of platelet activation improved cognitive behaviors in diabetic mice, accompanied with reduced BBB permeability, increased tight junction proteins, balanced Aβ transporters, as well as attenuated Aβ deposition and hippocampal neurons damage. In vitro, CD40L increased HIF1α, diminished tight junction proteins and dysregulated Aβ transporters in b.End3 cells, which could be restored by CD40 siRNA and HIF1α siRNA. Hence, inhibition of platelet activation ameliorates DACD via alleviating BBB injury, which involving the regulation of CD40L-CD40-HIF1α signaling pathway. Our study may demonstrate a potential therapeutic target for the treatment of DACD. |
| format | Article |
| id | doaj-art-4db2b249b36941bf8060aa00c4a31330 |
| institution | Kabale University |
| issn | 1873-2747 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Brain Research Bulletin |
| spelling | doaj-art-4db2b249b36941bf8060aa00c4a313302025-02-07T04:46:44ZengElsevierBrain Research Bulletin1873-27472025-02-01221111211Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injuryFuxing Xu0Juan Hu1Xuying Li2Lan Yang3Shiqiu Jiang4Tao Jiang5Bo Cheng6Hailiang Du7Ruiduo Wang8Yingying Deng9Wei Gao10Yansong Li11Yaomin Zhu12Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China; Department of Anesthesiology, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi 030013, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China; Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712021, ChinaDepartment of Anesthesiology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570100, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China; Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi 710004, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, ChinaState Key Laboratory of Transient Optics and Photonics, Xi’an Institute of Optics and Precision Mechanics, Chinese Academy of Sciences, Xi’an 710119, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, ChinaDepartment of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China; Correspondence to: Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi province 710061, China.Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China; Correspondence to: Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi province 710061, China.Cognitive dysfunction has become the second leading cause of death among the diabetic patients. In pre-diabetic stage, blood-brain barrier (BBB) injury occurs and induced the microvascular complications of diabetes, especially, diabetes-associated cognitive dysfunction (DACD). Endothelial cells are the major component of BBB, on which the increased expression of CD40 could mediate BBB dysfunction in diabetics. Since platelets play an important role in regulating endothelial cell barrier function and over 95 % of the circulating soluble CD40 ligand (sCD40L) is derived from activated platelets, we speculated that the release of CD40L from activated platelets induced by diabetes was the key mechanism that aggravated BBB injury and leaded to DACD. We performed inhibition of platelet activation on diabetic and non-diabetic mice, with or without cilostazol treatment, and then compared cognitive function, platelet activation, BBB structure and permeability. In vitro, mouse brain microvascular endothelial cell line (b.End3) were exposed to CD40L for 24 h at 5.5 mM or 30 mM glucose media after silencing CD40 and HIF1α or not to investigate the effects of CD40 on BBB disruption and the underlying molecular pathways. Inhibition of platelet activation improved cognitive behaviors in diabetic mice, accompanied with reduced BBB permeability, increased tight junction proteins, balanced Aβ transporters, as well as attenuated Aβ deposition and hippocampal neurons damage. In vitro, CD40L increased HIF1α, diminished tight junction proteins and dysregulated Aβ transporters in b.End3 cells, which could be restored by CD40 siRNA and HIF1α siRNA. Hence, inhibition of platelet activation ameliorates DACD via alleviating BBB injury, which involving the regulation of CD40L-CD40-HIF1α signaling pathway. Our study may demonstrate a potential therapeutic target for the treatment of DACD.http://www.sciencedirect.com/science/article/pii/S0361923025000231Platelet activationCD40CD40LHIF1αBlood-brain barrier injuryDiabetic associated cognitive dysfunction |
| spellingShingle | Fuxing Xu Juan Hu Xuying Li Lan Yang Shiqiu Jiang Tao Jiang Bo Cheng Hailiang Du Ruiduo Wang Yingying Deng Wei Gao Yansong Li Yaomin Zhu Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury Brain Research Bulletin Platelet activation CD40 CD40L HIF1α Blood-brain barrier injury Diabetic associated cognitive dysfunction |
| title | Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury |
| title_full | Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury |
| title_fullStr | Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury |
| title_full_unstemmed | Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury |
| title_short | Inhibition of platelet activation alleviates diabetes-associated cognitive dysfunction via attenuating blood-brain barrier injury |
| title_sort | inhibition of platelet activation alleviates diabetes associated cognitive dysfunction via attenuating blood brain barrier injury |
| topic | Platelet activation CD40 CD40L HIF1α Blood-brain barrier injury Diabetic associated cognitive dysfunction |
| url | http://www.sciencedirect.com/science/article/pii/S0361923025000231 |
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