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

All Science Journal Classification (ASJC) codes

  • 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{acea88050a774c88ab7ff306a52ea62b,
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.",
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.

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

C2 - 30088238

AN - SCOPUS:85051275500

VL - 43

SP - 1869

EP - 1878

JO - Neurochemical Research

JF - Neurochemical Research

SN - 0364-3190

IS - 10

ER -