title: Brain-Derived Neurotrophic Factor Knockdown Blocks the Angiogenic and Protective Effects of Angiotensin Modulation After Experimental Stroke.
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.
authors.affiliation: Charlie Norwood VA Medical Center and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA.
authors.forename: Abdelrahman Y
authors.initials: AY
authors.lastname: Fouda
authors.affiliation: Jordan University of Science and Technology, College of Pharmacy, Irbid, Jordan.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alhusban
authors.affiliation: Charlie Norwood VA Medical Center and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA.
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.affiliation: Charlie Norwood VA Medical Center and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Pillai
authors.affiliation: Charlie Norwood VA Medical Center and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA.
authors.forename: Wael
authors.initials: W
authors.lastname: Eldahshan
authors.affiliation: Department of Biostatistics, Augusta University, Augusta, GA, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Waller
authors.affiliation: Charlie Norwood VA Medical Center and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA.|Department of Physiology, Augusta University, Augusta, GA, USA.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
authors.affiliation: Charlie Norwood VA Medical Center and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA. sfagan@gru.edu.|Department of Neurology, Augusta University, Augusta, GA, USA. sfagan@gru.edu.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Fagan
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000809:Angiotensins / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D007276:Injections, Intraventricular; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D043925:Angiogenesis Inducing Agents; D047228:Angiotensin II Type 1 Receptor Blockers; D000809:Angiotensins; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C081643:candesartan
keywords: Angiogenesis; Angiotensin type 1 receptor blockade; Behavioral recovery; Brain-derived neurotrophic factor; Stroke