The behavioral and biochemical effects of BDNF containing polymers implanted in the hippocampus of rats.
Brain-derived neurotrophic factor (BDNF) is closely linked with neuronal survival and plasticity in psychiatric disorders. In this work, we engineered degradable, injectable alginate microspheres and non-degradable, implantable poly(ethylene vinyl acetate) matrices to continuously deliver BDNF to the dorsal hippocampus of rats for two days or more than a week, respectively. The antidepressant-like behavioral effects of BDNF delivery were examined in the Porsolt forced swim test. Rats were sacrificed 10days after surgery and tissue samples were analyzed by western blot. A small dose of BDNF delivered in a single infusion, or from a two-day sustained-release alginate implant, produced an antidepressant-like behavior, whereas the same dose delivered over a longer period of time to a larger tissue region did not produce antidepressant-like effects. Prolonged delivery of BDNF resulted in a dysregulation of plasticity-related functions: increased dose and duration of BDNF delivery produced increased levels of TrkB, ERK, CREB, and phosphorylated ERK, while also producing decreased phosphorylated CREB. It is evident from this work that both duration and magnitude of BDNF dosing are of critical importance in achieving functional outcome.
Sirianni
Rachael W
RW
Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
Olausson
Peter
P
Chiu
Amy S
AS
Taylor
Jane R
JR
Saltzman
W Mark
WM
D000464:Alginates / Q000008:administration & dosage; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects; D001672:Biocompatible Materials / Q000008:administration & dosage; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage*; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects; D003863:Depression / Q000517:prevention & control*; D004337:Drug Carriers / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D020723:Glucuronic Acid / Q000008:administration & dosage; D006603:Hexuronic Acids / Q000008:administration & dosage; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D008863:Microspheres; D009473:Neuronal Plasticity / Q000187:drug effects; D011145:Polyvinyls / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000187:drug effects / Q000378:metabolism; D013315:Stress, Psychological / Q000517:prevention & control
D000464:Alginates; D000928:Antidepressive Agents; D001672:Biocompatible Materials; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004337:Drug Carriers; D006603:Hexuronic Acids; D011145:Polyvinyls; C016438:ethylenevinylacetate copolymer; D020723:Glucuronic Acid; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases