Nano-particle delivery of brain derived neurotrophic factor after focal cerebral ischemia reduces tissue injury and enhances behavioral recovery.
Low levels of brain-derived neurotrophic factor (BDNF) are linked to delayed neurological recovery, depression, and cognitive impairment following stroke. Supplementation with BDNF reverses these effects. Unfortunately, systemically administered BDNF in its native form has minimal therapeutic value due to its poor blood brain barrier permeability and short serum half-life. In this study, a novel nano-particle polyion complex formulation of BDNF (nano-BDNF) was administered to mice after experimental ischemic stroke.



Male C57BL/6J (8-10weeks) mice were randomly assigned to receive nano-BDNF, native-BDNF, or saline treatment after being subjected to 60min of reversible middle cerebral artery occlusion (MCAo). Mice received the first dose at 3 (early treatment), 6 (intermediate treatment), or 12h (delayed treatment) following stroke onset; a second dose was given in all cohorts at 24h after stroke onset. Post-stroke outcome was evaluated by behavioral, histological, and molecular analysis for 15days after stroke.



Early and intermediate nano-BDNF treatment led to a significant reduction in cerebral tissue loss. Delayed treatment led to improved memory/cognition, reduced post-stroke depressive phenotypes, and maintained myelin basic protein and brain BDNF levels, but had no effect on tissue atrophy.



The results indicate that administration of a novel nano-particle formulation of BDNF leads to both neuroprotective and neuro-restorative effects after stroke.
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA.
Nia M
NM
Harris
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA.
Rodney
R
Ritzel
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA.
Nickolas S
NS
Mancini
Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill,, Chapel Hill, NC 27599-7362, USA.
Yuhang
Y
Jiang
Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill,, Chapel Hill, NC 27599-7362, USA.
Xiang
X
Yi
Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill,, Chapel Hill, NC 27599-7362, USA.
Devika S
DS
Manickam
Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98108, USA.
William A
WA
Banks
Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill,, Chapel Hill, NC 27599-7362, USA.
Alexander V
AV
Kabanov
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA; Department of Neurology, University of Texas Health Science Center, Houston, TX 77030, USA.
Louise D
LD
McCullough
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA. Electronic address: raverma@uchc.edu.
Rajkumar
R
Verma
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage*; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis; D003863:Depression / Q000188:drug therapy; D004339:Drug Compounding; D016503:Drug Delivery Systems; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage*
D019208:Brain-Derived Neurotrophic Factor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein
BDNF; Depressive behavior; Neuro-restorative; Neuroprotection; Stroke