Effects of Controlled Cortical Impact on the Mouse Brain Vasculome

Guo, Shuzhen; Lok, Josephine; Zhao, Song; Leung, Wendy; Som, Angel T.; Hayakawa, Kazuhide; Wang, Qingzhi; Xing, Chao; Wang, Xiaoying; Ji, Xunming; Zhou, Yiming; Lo, Eng H.

doi:10.1089/neu.2015.4101

Cited by 16 publications

(11 citation statements)

References 151 publications

(136 reference statements)

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“…Brain microvascular was isolated following an established method as we previously described [22]. Briefly, after cardiac perfusion with phosphate-buffered saline (PBS), the hippocampus and cortex were harvested, then homogenized in cold PBS on ice with Knote Dounce glass tissue grinder (Part 885300-0002; Kimble Chase Life Science, Vineland, NJ) and centrifuged at 4 °C, 500 g for 5 min.…”

Section: Methodsmentioning

confidence: 99%

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HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice

Zhao

Zhang

et al. 2019

J Neuroinflammation

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Background Type 2 diabetes mellitus (T2DM) is a chronic metabolic dysfunction characterized by progressive insulin resistance and hyperglycaemia. Increased blood-brain barrier (BBB) permeability is a critical neurovascular complication of T2DM that adversely affects the central nervous system homeostasis and function. Histone deacetylase 3 (HDAC3) has been reported to be elevated in T2DM animals and may promote neuroinflammation; however, its involvement in the BBB permeability of T2DM has not been investigated. In this study, we tested our hypothesis that HDAC3 expression and activity are increased in the T2DM mouse brain. Inhibition of HDAC3 may ameliorate T2DM-induced BBB permeability through Nrf2 activation. Methods T2DM (db/db, leptin receptor-deficient), genetic non-hyperglycemic control (db/+), and wild-type male mice at the age of 16 weeks were used in this study. HDAC3 expression and activity, Nrf2 activation, and BBB permeability and junction protein expression were examined. The effects of HDAC3 activity on BBB permeability were tested using highly selective HDAC3 inhibitor RGFP966. In primary cultured human brain microvascular endothelial cells (HBMEC), hyperglycemia (25 mM glucose) plus interleukin 1 beta (20 ng/ml) (HG-IL1β) served as T2DM insult in vitro. The effects of HDAC3 on transendothelial permeability were investigated by FITC-Dextran leakage and trans-endothelial electrical resistance, and the underlying molecular mechanisms were investigated using Western blot, q-PCR, co-immunoprecipitation, and immunocytochemistry for junction protein expression, miR-200a/Keap1/Nrf2 pathway regulation. Results HDAC3 expression and activity were significantly increased in the hippocampus and cortex of db/db mice. Specific HDAC3 inhibition significantly ameliorated BBB permeability and junction protein downregulation in db/db mice. In cultured HBMEC, HG-IL1β insult significantly increased transendothelial permeability and reduced junction protein expression. HDAC3 inhibition significantly attenuated the transendothelial permeability and junction protein downregulation. Moreover, we demonstrated the underlying mechanism was at least in part attributed by HDAC3 inhibition-mediated miR-200a/Keap1/Nrf2 signaling pathway and downstream targeting junction protein expression in T2DM db/db mice. Conclusions Our experimental results show that HDAC3 might be a new therapeutic target for BBB damage in T2DM. Electronic supplementary material The online version of this article (10.1186/s12974-019-1495-3) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

“…The resulting microvascular on the top of the cell strainer was used directly for RNA extraction. Our previous study has demonstrated these isolated brain microvascular fragments are positive for endothelial CD31 marker immune staining and lack contaminating signals from astrocytic GFAP or smooth muscle/pericyte a-SMA markers [22].…”

Section: Methodsmentioning

confidence: 99%

HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice

Zhao

Zhang

et al. 2019

J Neuroinflammation

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“…Central nervous system (CNS) vascular endothelium actively participates in signaling within the neurovascular unit, supporting neurogenesis, protecting neurons against stress, and mediating homeostasis14. When stimulated by physical stresses, the endothelium produces proinflammatory cytokines and chemokines which act to protect the brain from further damage, however, if this inflammatory response becomes chronic, neuroinflammation is magnified and secondary injury can occur15.…”

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confidence: 99%

Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome

McMahon

Bendayan

Hynynen

2017

Sci Rep

118

110

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Therapeutic treatment options for central nervous system diseases are greatly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), in conjunction with circulating microbubbles, can be used to induce a targeted and transient increase in BBB permeability, providing a unique approach for the delivery of drugs from the systemic circulation into the brain. While preclinical research has demonstrated the utility of FUS, there remains a large gap in our knowledge regarding the impact of sonication on BBB gene expression. This work is focused on investigating the transcriptional changes in dorsal hippocampal rat microvessels in the acute stages following sonication. Microarray analysis of microvessels was performed at 6 and 24 hrs post-FUS. Expression changes in individual genes and bioinformatic analysis suggests that FUS may induce a transient inflammatory response in microvessels. Increased transcription of proinflammatory cytokine genes appears to be short-lived, largely returning to baseline by 24 hrs. This observation may help to explain some previously observed bioeffects of FUS and may also be a driving force for the angiogenic processes and reduced drug efflux suggested by this work. While further studies are necessary, these results open up intriguing possibilities for novel FUS applications and suggest possible routes for pharmacologically modifying the technique.

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“…Brain microvessels were obtained as we described previously [ 22 ]. Briefly, mice were sacrificed at 24 h after TBI and perfused transcardially with ice-cold PBS.…”

Section: Methodsmentioning

confidence: 99%

Recombinant annexin A2 inhibits peripheral leukocyte activation and brain infiltration after traumatic brain injury

Liu

Han

et al. 2021

J Neuroinflammation

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Background Traumatic brain injury (TBI) is a significant cause of death and disability worldwide. The TLR4-NFκB signaling cascade is the critical pro-inflammatory activation pathway of leukocytes after TBI, and modulating this signaling cascade may be an effective therapeutic target for treating TBI. Previous studies indicate that recombinant annexin A2 (rA2) might be an interactive molecule modulating the TLR4-NFκB signaling; however, the role of rA2 in regulating this signaling pathway in leukocytes after TBI and its subsequent effects have not been investigated. Methods C57BL/6 mice were subjected to TBI and randomly divided into groups that received intraperitoneal rA2 or vehicle at 2 h after TBI. The peripheral leukocyte activation and infiltrating immune cells were examined by flow cytometry, RT-qPCR, and immunostaining. The neutrophilic TLR4 expression on the cell membrane was examined by flow cytometry and confocal microscope, and the interaction of annexin A2 with TLR4 was assessed by co-immunoprecipitation coupled with Western blotting. Neuroinflammation was measured via cytokine proteome profiler array and RT-qPCR. Neurodegeneration was determined by Western blotting and immunostaining. Neurobehavioral assessments were used to monitor motor and cognitive function. Brain tissue loss was assessed via MAP2 staining. Results rA2 administration given at 2 h after TBI significantly attenuates neutrophil activation and brain infiltration at 24 h of TBI. In vivo and in vitro data show that rA2 binds to and reduces TLR4 expression on the neutrophil surface and suppresses TLR4/NFκB signaling pathway in neutrophils at 12 h after TBI. Furthermore, rA2 administration also reduces pro-inflammation of brain tissues within 24 h and neurodegeneration at 48 h after TBI. Lastly, rA2 improves long-term sensorimotor ability and cognitive function, and reduces brain tissue loss at 28 days after TBI. Conclusions Systematic rA2 administration at 2 h after TBI significantly inhibits activation and brain infiltration of peripheral leukocytes, especially neutrophils at the acute phase. Consequently, rA2 reduces the detrimental brain pro-inflammation-associated neurodegeneration and ultimately ameliorates neurological deficits after TBI. The underlying molecular mechanism might be at least in part attributed to rA2 bindings to pro-inflammatory receptor TLR4 in peripheral leukocytes, thereby blocking NFκB signaling activation pathways following TBI.

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Effects of Controlled Cortical Impact on the Mouse Brain Vasculome

Cited by 16 publications

References 151 publications

HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice

HDAC3 inhibition prevents blood-brain barrier permeability through Nrf2 activation in type 2 diabetes male mice

Acute effects of focused ultrasound-induced increases in blood-brain barrier permeability on rat microvascular transcriptome

Recombinant annexin A2 inhibits peripheral leukocyte activation and brain infiltration after traumatic brain injury

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