Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia

Tauheed Ishrat, Sahar Soliman, Wael Eldahshan, Bindu Pillai, Adviye Ergul, Susan C. Fagan

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The pro-survival effect of VEGF-B has been documented in different in vivo and in vitro models. We have previously shown an enhanced VEGF-B expression in response to candesartan treatment after focal cerebral ischemia. In this study, we aimed to silence VEGF-B expression to assess its contribution to candesartan’s benefit on stroke outcome. Silencing VEGF-B expression was achieved by bilateral intracerebroventricular injections of lentiviral particles containing short hairpin RNA (shRNA) against VEGF-B. Two weeks after lentiviral injections, rats were subjected to either 90 min or 3 h of middle cerebral artery occlusion (MCAO) and randomized to intravenous candesartan (1 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 or 72 h and brains were collected and analyzed for hemoglobin (Hb) excess and infarct size, respectively. Functional outcome at 24, 48 and 72 h was assessed blindly. Candesartan treatment improved neurobehavioral and motor function, and decreased infarct size and Hb. While silencing VEGF-B expression diminished candesartan’s neuroprotective effect, candesartan-mediated vascular protection was maintained even in the absence of VEGF-B suggesting that this growth factor is not the mediator of candesartan’s vascular protective effects. However, VEGF-B is a mediator of neuroprotection achieved by candesartan and represents a potential drug target to improve stroke outcome. Further studies are needed to elucidate the underlying molecular mechanisms of VEGF-B in neuroprotection and recovery after ischemic stroke.

Original languageEnglish (US)
Pages (from-to)1869-1878
Number of pages10
JournalNeurochemical Research
Volume43
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Vascular Endothelial Growth Factor B
Neuroprotective Agents
Brain Ischemia
Therapeutics
Stroke
Blood Vessels
Hemoglobins
candesartan
Injections
Middle Cerebral Artery Infarction
Small Interfering RNA
Reperfusion
Rats
Brain
Intercellular Signaling Peptides and Proteins
Animals

Keywords

  • Angiotensin II type-1 receptor blocker (ARB)
  • Candesartan
  • Neuroprotection
  • Stroke
  • Vascular endothelial growth factor-B (VEGF-B)

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia. / Ishrat, Tauheed; Soliman, Sahar; Eldahshan, Wael; Pillai, Bindu; Ergul, Adviye; Fagan, Susan C.

In: Neurochemical Research, Vol. 43, No. 10, 01.10.2018, p. 1869-1878.

Research output: Contribution to journalArticle

Ishrat, Tauheed ; Soliman, Sahar ; Eldahshan, Wael ; Pillai, Bindu ; Ergul, Adviye ; Fagan, Susan C. / Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia. In: Neurochemical Research. 2018 ; Vol. 43, No. 10. pp. 1869-1878.
@article{f6736bcb1ad9487aae1d0e41ce62cbb3,
title = "Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia",
abstract = "The pro-survival effect of VEGF-B has been documented in different in vivo and in vitro models. We have previously shown an enhanced VEGF-B expression in response to candesartan treatment after focal cerebral ischemia. In this study, we aimed to silence VEGF-B expression to assess its contribution to candesartan’s benefit on stroke outcome. Silencing VEGF-B expression was achieved by bilateral intracerebroventricular injections of lentiviral particles containing short hairpin RNA (shRNA) against VEGF-B. Two weeks after lentiviral injections, rats were subjected to either 90 min or 3 h of middle cerebral artery occlusion (MCAO) and randomized to intravenous candesartan (1 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 or 72 h and brains were collected and analyzed for hemoglobin (Hb) excess and infarct size, respectively. Functional outcome at 24, 48 and 72 h was assessed blindly. Candesartan treatment improved neurobehavioral and motor function, and decreased infarct size and Hb. While silencing VEGF-B expression diminished candesartan’s neuroprotective effect, candesartan-mediated vascular protection was maintained even in the absence of VEGF-B suggesting that this growth factor is not the mediator of candesartan’s vascular protective effects. However, VEGF-B is a mediator of neuroprotection achieved by candesartan and represents a potential drug target to improve stroke outcome. Further studies are needed to elucidate the underlying molecular mechanisms of VEGF-B in neuroprotection and recovery after ischemic stroke.",
keywords = "Angiotensin II type-1 receptor blocker (ARB), Candesartan, Neuroprotection, Stroke, Vascular endothelial growth factor-B (VEGF-B)",
author = "Tauheed Ishrat and Sahar Soliman and Wael Eldahshan and Bindu Pillai and Adviye Ergul and Fagan, {Susan C.}",
year = "2018",
month = "10",
day = "1",
doi = "10.1007/s11064-018-2604-x",
language = "English (US)",
volume = "43",
pages = "1869--1878",
journal = "Neurochemical Research",
issn = "0364-3190",
publisher = "Springer New York",
number = "10",

}

TY - JOUR

T1 - Silencing VEGF-B Diminishes the Neuroprotective Effect of Candesartan Treatment After Experimental Focal Cerebral Ischemia

AU - Ishrat, Tauheed

AU - Soliman, Sahar

AU - Eldahshan, Wael

AU - Pillai, Bindu

AU - Ergul, Adviye

AU - Fagan, Susan C.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - The pro-survival effect of VEGF-B has been documented in different in vivo and in vitro models. We have previously shown an enhanced VEGF-B expression in response to candesartan treatment after focal cerebral ischemia. In this study, we aimed to silence VEGF-B expression to assess its contribution to candesartan’s benefit on stroke outcome. Silencing VEGF-B expression was achieved by bilateral intracerebroventricular injections of lentiviral particles containing short hairpin RNA (shRNA) against VEGF-B. Two weeks after lentiviral injections, rats were subjected to either 90 min or 3 h of middle cerebral artery occlusion (MCAO) and randomized to intravenous candesartan (1 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 or 72 h and brains were collected and analyzed for hemoglobin (Hb) excess and infarct size, respectively. Functional outcome at 24, 48 and 72 h was assessed blindly. Candesartan treatment improved neurobehavioral and motor function, and decreased infarct size and Hb. While silencing VEGF-B expression diminished candesartan’s neuroprotective effect, candesartan-mediated vascular protection was maintained even in the absence of VEGF-B suggesting that this growth factor is not the mediator of candesartan’s vascular protective effects. However, VEGF-B is a mediator of neuroprotection achieved by candesartan and represents a potential drug target to improve stroke outcome. Further studies are needed to elucidate the underlying molecular mechanisms of VEGF-B in neuroprotection and recovery after ischemic stroke.

AB - The pro-survival effect of VEGF-B has been documented in different in vivo and in vitro models. We have previously shown an enhanced VEGF-B expression in response to candesartan treatment after focal cerebral ischemia. In this study, we aimed to silence VEGF-B expression to assess its contribution to candesartan’s benefit on stroke outcome. Silencing VEGF-B expression was achieved by bilateral intracerebroventricular injections of lentiviral particles containing short hairpin RNA (shRNA) against VEGF-B. Two weeks after lentiviral injections, rats were subjected to either 90 min or 3 h of middle cerebral artery occlusion (MCAO) and randomized to intravenous candesartan (1 mg/kg) or saline at reperfusion. Animals were sacrificed at 24 or 72 h and brains were collected and analyzed for hemoglobin (Hb) excess and infarct size, respectively. Functional outcome at 24, 48 and 72 h was assessed blindly. Candesartan treatment improved neurobehavioral and motor function, and decreased infarct size and Hb. While silencing VEGF-B expression diminished candesartan’s neuroprotective effect, candesartan-mediated vascular protection was maintained even in the absence of VEGF-B suggesting that this growth factor is not the mediator of candesartan’s vascular protective effects. However, VEGF-B is a mediator of neuroprotection achieved by candesartan and represents a potential drug target to improve stroke outcome. Further studies are needed to elucidate the underlying molecular mechanisms of VEGF-B in neuroprotection and recovery after ischemic stroke.

KW - Angiotensin II type-1 receptor blocker (ARB)

KW - Candesartan

KW - Neuroprotection

KW - Stroke

KW - Vascular endothelial growth factor-B (VEGF-B)

UR - http://www.scopus.com/inward/record.url?scp=85051275500&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051275500&partnerID=8YFLogxK

U2 - 10.1007/s11064-018-2604-x

DO - 10.1007/s11064-018-2604-x

M3 - Article

AN - SCOPUS:85051275500

VL - 43

SP - 1869

EP - 1878

JO - Neurochemical Research

JF - Neurochemical Research

SN - 0364-3190

IS - 10

ER -