Abstract W P108: Pharmacological Evaluation of a BDNF Nano-Particle Formulation after Experimental Stroke

Abstract

Backgrounds: Brain Derived Neurotrophic factor (BDNF) is a well-recognized neuro-protective and neuro-restorative protein of the neurotrophin family. Unfortunately, systemically administered native BDNF has minimal therapeutic effects due to poor blood brain barrier permeability and short half-life. Therefore, the aim of this study was to utilize a novel nano-particle formulation of BDNF for enhanced delivery to the brain in mice after middle cerebral artery occlusion (MCAO). Methods: Male C57BL/6J (8-10 weeks) mice were randomly assigned to saline or BDNF nano (Exp group 1, n=6/group) or saline vs. BDNF native vs. BDNF nano (Exp group 2, n=8/group) and subjected to 60min of MCAO. The mice in Exp. group 1 were treated twice with either saline or BDNF Nanoparticles (250μg/kg i.v) 3 and 24 hrs after the onset of MCAO. Exp group2 was also treated twice with saline vs. BDNF native vs. BDNF nano (250μg/kg i.v) but treatment was delayed until 12 hrs after MCAO with a second dose at 24 hrs. Mice were tested weekly on several behavioral tests and were sacrificed on day 15 and brains used for histological analysis. Results: Treatment with BDNF nanoparticles 3 hours after MCAo (Exp group 1) led to a significant (p<0.0062) reduction in tissue loss (42.33±2.24 vs 31.02± 4.02) and earlier behavioral recovery. When we delayed treatment to 12 hrs after MCAO, neither native nor BDNF nanoparticles reduced tissue loss compared to saline. Neurological deficit scores were similar between groups. However, treatment with BDNF nanoparticles led to early improvements in memory/cognitive performance (Day 7) in the Novel Object Recognition Test (NORT) and reduced immobility (p< 0.05, 155.2± 18.56 Saline vs 162.8± 15.55 BDNF native vs.117.0±25.44 in BDNF nano) in the tail suspension test suggestive of a reduced depressive phenotype in BDNF nano treated mice. Conclusions: This study reveals that BDNF nanoparticle formulation is neuroprotective when given within three hours of stroke, and enhances neuronal repair and behavioral recovery beyond that seen with native BDNF even in the absence of decreased infarct size when treatment is delayed.