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.

• Authors: Tauheed Ishrat, Sahar Soliman, Wael Eldahshan, Bindu Pillai, Adviye Ergul, Susan C Fagan
• Journal: Neurochemical research (Neurochem Res) Vol. 43 Issue 10 Pg. 1869-1878 (Oct 2018) ISSN: 1573-6903 [Electronic] United States
• PMID: 30088238 (Publication Type: Journal Article)

Chemical References

• Benzimidazoles
• Biphenyl Compounds
• Neuroprotective Agents
• Tetrazoles
• Vascular Endothelial Growth Factor B
• candesartan

Topics

• Animals
• Benzimidazoles (pharmacology)
• Biphenyl Compounds
• Brain Ischemia (drug therapy, genetics)
• Disease Models, Animal
• Infarction, Middle Cerebral Artery (drug therapy, genetics)
• Neuroprotective Agents (pharmacology)
• Tetrazoles (pharmacology)
• Vascular Endothelial Growth Factor B (genetics)