Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation

Haiying Zhang, Joon Ha Park, Sony Maharjan, Jeong Ae Park, Kyu Sung Choi, Hyojin Park, Yoonjeong Jeong, Ji Hyeon Ahn, In Hye Kim, Jae Chul Lee, Jeong Hwi Cho, In Kyu Lee, Choong Hyun Lee, In Koo Hwang, Young Myeong Kim, Young Ger Suh, Moo Ho Won, Young Guen Kwon

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: Blood-brain barrier (BBB) breakdown and inflammation are critical events in ischemic stroke, contributing to aggravated brain damage. The BBB mainly consists of microvascular endothelial cells sealed by tight junctions to protect the brain from blood-borne substances. Thus, the maintenance of BBB integrity may be a potential target for neuroprotection. Sac-1004, a pseudo-sugar derivative of cholesterol, enhances the endothelial barrier by the stabilization of the cortical actin ring. Results: Here, we report on the protective effects of Sac-1004 on cerebral ischemia-reperfusion (I/R) injury. Treatment with Sac-1004 significantly blocked the interleukin-1β-induced monolayer hyperpermeability of human brain microvascular endothelial cells (HBMECs), loss of tight junctions, and formation of actin stress fiber. Sac-1004 suppressed the expression of adhesion molecules, adhesion of U937 cells, and activation of nuclear factor-ΚB in HBMECs. Using a rat model of transient focal cerebral ischemia, it was shown that Sac-1004 effectively ameliorated neurological deficits and ischemic damage. In addition, Sac-1004 decreased BBB leakage and rescued tight junction-related proteins. Moreover, the staining of CD11b and glial fibrillary acidic protein showed that Sac-1004 inhibited glial activation. Conclusions: Taken together, these results demonstrate that Sac-1004 has neuroprotective activities through maintaining BBB integrity, suggesting that it is a great therapeutic candidate for stroke.

Original languageEnglish
Article number122
JournalJournal of Neuroinflammation
Volume14
Issue number1
DOIs
Publication statusPublished - 2017 Jun 23

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Reperfusion Injury
Brain Ischemia
Blood-Brain Barrier
Blood Vessels
Inflammation
Endothelial Cells
Tight Junctions
Brain
Actins
Stroke
Tight Junction Proteins
Stress Fibers
U937 Cells
Sac-1004
Glial Fibrillary Acidic Protein
Transient Ischemic Attack
Interleukin-1
Neuroglia
Cholesterol
Maintenance

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Zhang, Haiying ; Park, Joon Ha ; Maharjan, Sony ; Park, Jeong Ae ; Choi, Kyu Sung ; Park, Hyojin ; Jeong, Yoonjeong ; Ahn, Ji Hyeon ; Kim, In Hye ; Lee, Jae Chul ; Cho, Jeong Hwi ; Lee, In Kyu ; Lee, Choong Hyun ; Hwang, In Koo ; Kim, Young Myeong ; Suh, Young Ger ; Won, Moo Ho ; Kwon, Young Guen. / Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation. In: Journal of Neuroinflammation. 2017 ; Vol. 14, No. 1.
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title = "Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation",
abstract = "Background: Blood-brain barrier (BBB) breakdown and inflammation are critical events in ischemic stroke, contributing to aggravated brain damage. The BBB mainly consists of microvascular endothelial cells sealed by tight junctions to protect the brain from blood-borne substances. Thus, the maintenance of BBB integrity may be a potential target for neuroprotection. Sac-1004, a pseudo-sugar derivative of cholesterol, enhances the endothelial barrier by the stabilization of the cortical actin ring. Results: Here, we report on the protective effects of Sac-1004 on cerebral ischemia-reperfusion (I/R) injury. Treatment with Sac-1004 significantly blocked the interleukin-1β-induced monolayer hyperpermeability of human brain microvascular endothelial cells (HBMECs), loss of tight junctions, and formation of actin stress fiber. Sac-1004 suppressed the expression of adhesion molecules, adhesion of U937 cells, and activation of nuclear factor-ΚB in HBMECs. Using a rat model of transient focal cerebral ischemia, it was shown that Sac-1004 effectively ameliorated neurological deficits and ischemic damage. In addition, Sac-1004 decreased BBB leakage and rescued tight junction-related proteins. Moreover, the staining of CD11b and glial fibrillary acidic protein showed that Sac-1004 inhibited glial activation. Conclusions: Taken together, these results demonstrate that Sac-1004 has neuroprotective activities through maintaining BBB integrity, suggesting that it is a great therapeutic candidate for stroke.",
author = "Haiying Zhang and Park, {Joon Ha} and Sony Maharjan and Park, {Jeong Ae} and Choi, {Kyu Sung} and Hyojin Park and Yoonjeong Jeong and Ahn, {Ji Hyeon} and Kim, {In Hye} and Lee, {Jae Chul} and Cho, {Jeong Hwi} and Lee, {In Kyu} and Lee, {Choong Hyun} and Hwang, {In Koo} and Kim, {Young Myeong} and Suh, {Young Ger} and Won, {Moo Ho} and Kwon, {Young Guen}",
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Zhang, H, Park, JH, Maharjan, S, Park, JA, Choi, KS, Park, H, Jeong, Y, Ahn, JH, Kim, IH, Lee, JC, Cho, JH, Lee, IK, Lee, CH, Hwang, IK, Kim, YM, Suh, YG, Won, MH & Kwon, YG 2017, 'Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation', Journal of Neuroinflammation, vol. 14, no. 1, 122. https://doi.org/10.1186/s12974-017-0897-3

Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation. / Zhang, Haiying; Park, Joon Ha; Maharjan, Sony; Park, Jeong Ae; Choi, Kyu Sung; Park, Hyojin; Jeong, Yoonjeong; Ahn, Ji Hyeon; Kim, In Hye; Lee, Jae Chul; Cho, Jeong Hwi; Lee, In Kyu; Lee, Choong Hyun; Hwang, In Koo; Kim, Young Myeong; Suh, Young Ger; Won, Moo Ho; Kwon, Young Guen.

In: Journal of Neuroinflammation, Vol. 14, No. 1, 122, 23.06.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation

AU - Zhang, Haiying

AU - Park, Joon Ha

AU - Maharjan, Sony

AU - Park, Jeong Ae

AU - Choi, Kyu Sung

AU - Park, Hyojin

AU - Jeong, Yoonjeong

AU - Ahn, Ji Hyeon

AU - Kim, In Hye

AU - Lee, Jae Chul

AU - Cho, Jeong Hwi

AU - Lee, In Kyu

AU - Lee, Choong Hyun

AU - Hwang, In Koo

AU - Kim, Young Myeong

AU - Suh, Young Ger

AU - Won, Moo Ho

AU - Kwon, Young Guen

PY - 2017/6/23

Y1 - 2017/6/23

N2 - Background: Blood-brain barrier (BBB) breakdown and inflammation are critical events in ischemic stroke, contributing to aggravated brain damage. The BBB mainly consists of microvascular endothelial cells sealed by tight junctions to protect the brain from blood-borne substances. Thus, the maintenance of BBB integrity may be a potential target for neuroprotection. Sac-1004, a pseudo-sugar derivative of cholesterol, enhances the endothelial barrier by the stabilization of the cortical actin ring. Results: Here, we report on the protective effects of Sac-1004 on cerebral ischemia-reperfusion (I/R) injury. Treatment with Sac-1004 significantly blocked the interleukin-1β-induced monolayer hyperpermeability of human brain microvascular endothelial cells (HBMECs), loss of tight junctions, and formation of actin stress fiber. Sac-1004 suppressed the expression of adhesion molecules, adhesion of U937 cells, and activation of nuclear factor-ΚB in HBMECs. Using a rat model of transient focal cerebral ischemia, it was shown that Sac-1004 effectively ameliorated neurological deficits and ischemic damage. In addition, Sac-1004 decreased BBB leakage and rescued tight junction-related proteins. Moreover, the staining of CD11b and glial fibrillary acidic protein showed that Sac-1004 inhibited glial activation. Conclusions: Taken together, these results demonstrate that Sac-1004 has neuroprotective activities through maintaining BBB integrity, suggesting that it is a great therapeutic candidate for stroke.

AB - Background: Blood-brain barrier (BBB) breakdown and inflammation are critical events in ischemic stroke, contributing to aggravated brain damage. The BBB mainly consists of microvascular endothelial cells sealed by tight junctions to protect the brain from blood-borne substances. Thus, the maintenance of BBB integrity may be a potential target for neuroprotection. Sac-1004, a pseudo-sugar derivative of cholesterol, enhances the endothelial barrier by the stabilization of the cortical actin ring. Results: Here, we report on the protective effects of Sac-1004 on cerebral ischemia-reperfusion (I/R) injury. Treatment with Sac-1004 significantly blocked the interleukin-1β-induced monolayer hyperpermeability of human brain microvascular endothelial cells (HBMECs), loss of tight junctions, and formation of actin stress fiber. Sac-1004 suppressed the expression of adhesion molecules, adhesion of U937 cells, and activation of nuclear factor-ΚB in HBMECs. Using a rat model of transient focal cerebral ischemia, it was shown that Sac-1004 effectively ameliorated neurological deficits and ischemic damage. In addition, Sac-1004 decreased BBB leakage and rescued tight junction-related proteins. Moreover, the staining of CD11b and glial fibrillary acidic protein showed that Sac-1004 inhibited glial activation. Conclusions: Taken together, these results demonstrate that Sac-1004 has neuroprotective activities through maintaining BBB integrity, suggesting that it is a great therapeutic candidate for stroke.

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