Effects of fibrinogen synthesis inhibition on vascular cognitive impairment during traumatic brain injury in mice.
Effects of fibrinogen synthesis inhibition on vascular cognitive impairment during traumatic brain injury in mice.
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DOI：
10.1016/j.brainres.2020.147208
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发表时间：
2021-01-15
期刊：
影响因子：
2.9
通讯作者：
Lominadze D
中科院分区：
文献类型：
--
作者：
Muradashvili N;Charkviani M;Sulimai N;Tyagi N;Crosby J;Lominadze D
外伤性脑损伤（TBI）与血液纤维蛋白原（Fg）含量增加有关，称为高纤维蛋白原血症（HFg），导致脑血管通透性增强，导致短期记忆（STM）减少。在此之前，我们发现在小鼠轻度至中度脑外伤期间，外渗的Fg沉积在血管-星形胶质细胞界面，并与细胞朊病毒蛋白（PrPC）共定位。这些影响伴随着神经退行性变和STM减少。然而，没有证据表明所描述的影响是脑外伤期间HFg的直接结果。我们现在的数据表明，抑制Fg合成可以改善tbi诱导的脑血管通透性和STM减少。C57BL/6J小鼠皮质挫伤（CCI）。然后用Fg反义寡核苷酸（Fg- aso）或对照aso治疗小鼠两周。用y迷宫试验评价STM后，在皮质小静脉中评估了对荧光结合牛血清白蛋白的脑血管通透性。另外，收集脑样本，通过Western blotting确定PrPC的表达，同时用real-time PCR检测Fg和PrPC的沉积和共定位，以及炎症标志物激活转录因子3 （ATF3）的基因表达。结果表明，Fg- aso抑制Fg合成可减少AFT3过表达，改善脑血管通透性增强，减少PrPC表达和Fg沉积，减少Fg-PrPC复合物在脑内的形成，改善STM。这些数据提供了直接证据，表明cci诱导的炎症介导的HFg可能是一种触发机制，参与了我们之前在轻中度TBI中发现的血管认知障碍。
Traumatic brain injury (TBI) is associated with increased blood content of fibrinogen (Fg), called hyperfibrinogenemia (HFg), which results in enhanced cerebrovascular permeability and leads to short-term memory (STM) reduction. Previously, we showed that extravasated Fg was deposited in the vasculo-astrocyte interface and was co-localized with cellular prion protein (PrPC) during mild-to-moderate TBI in mice. These effects were accompanied by neurodegeneration and STM reduction. However, there was no evidence presented that the described effects were the direct result of the HFg during TBI. We now present data indicating that inhibition of Fg synthesis can ameliorate TBI-induced cerebrovascular permeability and STM reduction. Cortical contusion injury (CCI) was induced in C57BL/6J mice. Then mice were treated with either Fg antisense oligonucleotide (Fg-ASO) or with control-ASO for two weeks. Cerebrovascular permeability to fluorescently conjugated bovine serum albumin was assessed in cortical venules following evaluation of STM with a Y-maze test. Separately, brain samples were collected in order to define the expression of PrPC via Western blotting while deposition and co-localization of Fg and PrPC, as well as gene expression of inflammatory marker activating transcription factor 3 (ATF3), were characterized with real-time PCR. Results showed that inhibition of Fg synthesis with Fg-ASO reduced overexpression of AFT3, ameliorated enhanced cerebrovascular permeability, decreased expression of PrPC and Fg deposition, decreased formation of Fg-PrPC complexes in brain, and improved STM. These data provide direct evidence that a CCI-induced inflammation-mediated HFg could be a triggering mechanism involved in vascular cognitive impairment seen previously in our studies during mild-to-moderate TBI.
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DOI：
10.1523/jneurosci.5103-10.2011
发表时间：
2011-03-30
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Greer JE;McGinn MJ;Povlishock JT
通讯作者：
Povlishock JT
影响因子：
8.3
作者：
del Zoppo GJ;Levy DE;Wasiewski WW;Pancioli AM;Demchuk AM;Trammel J;Demaerschalk BM;Kaste M;Albers GW;Ringelstein EB
通讯作者：
Ringelstein EB
影响因子：
2.5
作者：
Charkviani, Mariam;Muradashvili, Nino;Lominadze, David
通讯作者：
Lominadze, David
影响因子：
2.9
作者：
GORMAN, LK;SHOOK, BL;BECKER, DP
通讯作者：
BECKER, DP
影响因子：
15.9
作者：
MARTINEZ, J;HOLBURN, RR;ERSLEV, AJ
通讯作者：
ERSLEV, AJ