Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke

Abdelrahman Y. Fouda, Ahmed Alhusban, Tauheed Ishrat, Bindu Pillai, Wael Eldahshan, Jennifer L Waller, Adviye Ergul, Susan C. Fagan

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Angiotensin type 1 receptor blockers (ARBs) have been shown to be neuroprotective and neurorestorative in experimental stroke. The mechanisms proposed include anti-inflammatory, antiapoptotic effects, as well as stimulation of endogenous trophic factors leading to angiogenesis and neuroplasticity. We aimed to investigate the involvement of the neurotrophin, brain-derived neurotrophic factor (BDNF), in ARB-mediated functional recovery after stroke. To achieve this aim, Wistar rats received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles or nontargeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-min middle cerebral artery occlusion (MCAO) and received the ARB, candesartan, 1 mg/kg, or saline IV at reperfusion (one dose), then followed for another 14 days using a battery of behavioral tests. BDNF protein expression was successfully reduced by about 70 % in both hemispheres at 14 days after bilateral shRNA lentiviral particle injection. The NTC group that received candesartan showed better functional outcome as well as increased vascular density and synaptogenesis as compared to saline treatment. BDNF knockdown abrogated the beneficial effects of candesartan on neurobehavioral outcome, vascular density, and synaptogenesis. In conclusion, BDNF is directly involved in candesartan-mediated functional recovery, angiogenesis, and synaptogenesis.

Original languageEnglish (US)
Pages (from-to)661-670
Number of pages10
JournalMolecular Neurobiology
Volume54
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Brain-Derived Neurotrophic Factor
Angiotensins
Angiotensin II Type 1 Receptor Blockers
Stroke
Nerve Growth Factors
Small Interfering RNA
Blood Vessels
Injections
Neuronal Plasticity
Middle Cerebral Artery Infarction
Reperfusion
Wistar Rats
Anti-Inflammatory Agents
Control Groups
candesartan

Keywords

  • Angiogenesis
  • Angiotensin type 1 receptor blockade
  • Behavioral recovery
  • Brain-derived neurotrophic factor
  • Stroke

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke. / Fouda, Abdelrahman Y.; Alhusban, Ahmed; Ishrat, Tauheed; Pillai, Bindu; Eldahshan, Wael; Waller, Jennifer L; Ergul, Adviye; Fagan, Susan C.

In: Molecular Neurobiology, Vol. 54, No. 1, 01.01.2017, p. 661-670.

Research output: Contribution to journalArticle

Fouda, Abdelrahman Y. ; Alhusban, Ahmed ; Ishrat, Tauheed ; Pillai, Bindu ; Eldahshan, Wael ; Waller, Jennifer L ; Ergul, Adviye ; Fagan, Susan C. / Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke. In: Molecular Neurobiology. 2017 ; Vol. 54, No. 1. pp. 661-670.
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AB - Angiotensin type 1 receptor blockers (ARBs) have been shown to be neuroprotective and neurorestorative in experimental stroke. The mechanisms proposed include anti-inflammatory, antiapoptotic effects, as well as stimulation of endogenous trophic factors leading to angiogenesis and neuroplasticity. We aimed to investigate the involvement of the neurotrophin, brain-derived neurotrophic factor (BDNF), in ARB-mediated functional recovery after stroke. To achieve this aim, Wistar rats received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles or nontargeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-min middle cerebral artery occlusion (MCAO) and received the ARB, candesartan, 1 mg/kg, or saline IV at reperfusion (one dose), then followed for another 14 days using a battery of behavioral tests. BDNF protein expression was successfully reduced by about 70 % in both hemispheres at 14 days after bilateral shRNA lentiviral particle injection. The NTC group that received candesartan showed better functional outcome as well as increased vascular density and synaptogenesis as compared to saline treatment. BDNF knockdown abrogated the beneficial effects of candesartan on neurobehavioral outcome, vascular density, and synaptogenesis. In conclusion, BDNF is directly involved in candesartan-mediated functional recovery, angiogenesis, and synaptogenesis.

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