通过敲除双特异性蛋白磷酸酶5增强脑血流动力学和认知功能。

Journal of pharmacy and pharmacology research Pub Date : 2023-01-01 Epub Date: 2023-05-12 DOI:10.26502/fjppr.070
Huawei Zhang, Jane J Border, Xing Fang, Yedan Liu, Chengyun Tang, Wenjun Gao, Shaoxun Wang, Seung Min Shin, Ya Guo, Chao Zhang, Ezekiel Gonzalez-Fernandez, Hongwei Yu, Peng Sun, Richard J Roman, Fan Fan
{"title":"通过敲除双特异性蛋白磷酸酶5增强脑血流动力学和认知功能。","authors":"Huawei Zhang,&nbsp;Jane J Border,&nbsp;Xing Fang,&nbsp;Yedan Liu,&nbsp;Chengyun Tang,&nbsp;Wenjun Gao,&nbsp;Shaoxun Wang,&nbsp;Seung Min Shin,&nbsp;Ya Guo,&nbsp;Chao Zhang,&nbsp;Ezekiel Gonzalez-Fernandez,&nbsp;Hongwei Yu,&nbsp;Peng Sun,&nbsp;Richard J Roman,&nbsp;Fan Fan","doi":"10.26502/fjppr.070","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are neurodegenerative disorders. Recent studies suggest that cerebral hypoperfusion is an early symptom of AD/ADRD. Dual-specificity protein phosphatase 5 (DUSP5) has been implicated in several pathological conditions, including pulmonary hypertension and cancer, but its role in AD/ADRD remains unclear. The present study builds on our previous findings, demonstrating that inhibition of ERK and PKC leads to a dose-dependent dilation of the middle cerebral artery and penetrating arteriole, with a more pronounced effect in <i>Dusp5</i> KO rats. Both ERK and PKC inhibitors resulted in a significant reduction of myogenic tone in vessels from <i>Dusp5</i> KO rats. <i>Dusp5</i> KO rats exhibited stronger autoregulation of the surface but not deep cortical cerebral blood flow. Inhibition of ERK and PKC significantly enhanced the contractile capacity of vascular smooth muscle cells from both strains. Finally, a significant improvement in learning and memory was observed in <i>Dusp5</i> KO rats 24 hours after initial training. Our results suggest that altered vascular reactivity in <i>Dusp5</i> KO rats may involve distinct mechanisms for different vascular beds, and DUSP5 deletion could be a potential therapeutic target for AD/ADRD. Further investigations are necessary to determine the effects of DUSP5 inhibition on capillary stalling, blood-brain barrier permeability, and neurodegeneration in aging and disease models.</p>","PeriodicalId":73897,"journal":{"name":"Journal of pharmacy and pharmacology research","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10430881/pdf/","citationCount":"0","resultStr":"{\"title\":\"Enhanced Cerebral Hemodynamics and Cognitive Function Via Knockout of Dual-Specificity Protein Phosphatase 5.\",\"authors\":\"Huawei Zhang,&nbsp;Jane J Border,&nbsp;Xing Fang,&nbsp;Yedan Liu,&nbsp;Chengyun Tang,&nbsp;Wenjun Gao,&nbsp;Shaoxun Wang,&nbsp;Seung Min Shin,&nbsp;Ya Guo,&nbsp;Chao Zhang,&nbsp;Ezekiel Gonzalez-Fernandez,&nbsp;Hongwei Yu,&nbsp;Peng Sun,&nbsp;Richard J Roman,&nbsp;Fan Fan\",\"doi\":\"10.26502/fjppr.070\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are neurodegenerative disorders. Recent studies suggest that cerebral hypoperfusion is an early symptom of AD/ADRD. Dual-specificity protein phosphatase 5 (DUSP5) has been implicated in several pathological conditions, including pulmonary hypertension and cancer, but its role in AD/ADRD remains unclear. The present study builds on our previous findings, demonstrating that inhibition of ERK and PKC leads to a dose-dependent dilation of the middle cerebral artery and penetrating arteriole, with a more pronounced effect in <i>Dusp5</i> KO rats. Both ERK and PKC inhibitors resulted in a significant reduction of myogenic tone in vessels from <i>Dusp5</i> KO rats. <i>Dusp5</i> KO rats exhibited stronger autoregulation of the surface but not deep cortical cerebral blood flow. Inhibition of ERK and PKC significantly enhanced the contractile capacity of vascular smooth muscle cells from both strains. Finally, a significant improvement in learning and memory was observed in <i>Dusp5</i> KO rats 24 hours after initial training. Our results suggest that altered vascular reactivity in <i>Dusp5</i> KO rats may involve distinct mechanisms for different vascular beds, and DUSP5 deletion could be a potential therapeutic target for AD/ADRD. Further investigations are necessary to determine the effects of DUSP5 inhibition on capillary stalling, blood-brain barrier permeability, and neurodegeneration in aging and disease models.</p>\",\"PeriodicalId\":73897,\"journal\":{\"name\":\"Journal of pharmacy and pharmacology research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10430881/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of pharmacy and pharmacology research\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.26502/fjppr.070\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/5/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmacy and pharmacology research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.26502/fjppr.070","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/5/12 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

阿尔茨海默病(AD)和阿尔茨海默病相关痴呆症(ADRD)是神经退行性疾病。最近的研究表明,脑灌注不足是AD/ARD的早期症状。双特异性蛋白磷酸酶5(DUSP5)与多种病理状况有关,包括肺动脉高压和癌症,但其在AD/ADD中的作用尚不清楚。本研究建立在我们之前的研究结果的基础上,证明ERK和PKC的抑制导致大脑中动脉和穿透小动脉的剂量依赖性扩张,在Dusp5 KO大鼠中具有更显著的作用。ERK和PKC抑制剂均导致Dusp5 KO大鼠血管中肌源性张力的显著降低。Dusp5-KO大鼠表现出更强的皮层表面而非深层脑血流的自动调节。ERK和PKC的抑制显著增强了两种菌株血管平滑肌细胞的收缩能力。最后,在初次训练后24小时,在Dusp5 KO大鼠中观察到学习和记忆的显著改善。我们的研究结果表明,Dusp5 KO大鼠血管反应性的改变可能涉及不同血管床的不同机制,Dusp5缺失可能是AD/ADD的潜在治疗靶点。需要进一步研究DUSP5抑制对衰老和疾病模型中毛细血管停滞、血脑屏障通透性和神经退行性变的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

摘要图片

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Enhanced Cerebral Hemodynamics and Cognitive Function Via Knockout of Dual-Specificity Protein Phosphatase 5.

Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are neurodegenerative disorders. Recent studies suggest that cerebral hypoperfusion is an early symptom of AD/ADRD. Dual-specificity protein phosphatase 5 (DUSP5) has been implicated in several pathological conditions, including pulmonary hypertension and cancer, but its role in AD/ADRD remains unclear. The present study builds on our previous findings, demonstrating that inhibition of ERK and PKC leads to a dose-dependent dilation of the middle cerebral artery and penetrating arteriole, with a more pronounced effect in Dusp5 KO rats. Both ERK and PKC inhibitors resulted in a significant reduction of myogenic tone in vessels from Dusp5 KO rats. Dusp5 KO rats exhibited stronger autoregulation of the surface but not deep cortical cerebral blood flow. Inhibition of ERK and PKC significantly enhanced the contractile capacity of vascular smooth muscle cells from both strains. Finally, a significant improvement in learning and memory was observed in Dusp5 KO rats 24 hours after initial training. Our results suggest that altered vascular reactivity in Dusp5 KO rats may involve distinct mechanisms for different vascular beds, and DUSP5 deletion could be a potential therapeutic target for AD/ADRD. Further investigations are necessary to determine the effects of DUSP5 inhibition on capillary stalling, blood-brain barrier permeability, and neurodegeneration in aging and disease models.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
A CXCR3-Activating Peptide Increases Tear Break Up Time and Corrects Corneal haze in a Rabbit Model of Environmental Dry Eye. Enhanced Cerebral Hemodynamics and Cognitive Function Via Knockout of Dual-Specificity Protein Phosphatase 5. Impact of Early Palliative Care on End of life in patients with Advanced Biliary Tract Cancer Effects of Fruits of Aqueous Extract of Sarcocephalus Latifolius B. on Gentamicin-Induced Nephrotoxicity in Rats Analgesic, Anti-inflammatory, and Antioxidant potential of S-adenosyl L-Methionine on Nitroglycerine induced Migraine in mice Models
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1