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      Brain derived neurotrophic factor knockdown blocks the angiogenic and protective effects of angiotensin modulation after experimental stroke

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          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 non-targeting control (NTC) vector, to knock down BDNF in both hemispheres. After 14 days, rats were subjected to 90-minute 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 particles 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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          Author and article information

          Journal
          8900963
          1466
          Mol Neurobiol
          Mol. Neurobiol.
          Molecular neurobiology
          0893-7648
          1559-1182
          14 January 2016
          12 January 2016
          January 2017
          01 January 2018
          : 54
          : 1
          : 661-670
          Affiliations
          [1 ]Charlie Norwood VA Medical Center, and Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA
          [2 ] Department of Physiology, Augusta University, Augusta, GA
          [3 ]Department of Neurology, Augusta University, Augusta, GA
          [4 ]Department of Biostatistics, Augusta University, Augusta, GA
          [5 ]Jordan University of Science and Technology, College of Pharmacy, Irbid, Jordan
          Author notes
          Correspondence: Susan C Fagan, Pharm.D., FAHA, University of Georgia, College of Pharmacy, HM 1200; 1120 15 th St., Augusta, GA 30912, sfagan@ 123456gru.edu , Voice: 706-721-0130, Fax: 706-721-3994
          Article
          PMC4940333 PMC4940333 4940333 nihpa751330
          10.1007/s12035-015-9675-3
          4940333
          26758277
          ab9e291a-bbad-4c8c-a231-b552be0d8cd9
          Categories
          Article

          angiogenesis,Stroke,angiotensin type 1 receptor blockade,behavioral recovery,brain derived neurotrophic factor

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