Nano-particle Delivery of Brain Derived Neurotrophic Factor after Focal Cerebral Ischemia Reduces Tissue Injury and Enhances Behavioral Recovery

Abstract

Background

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.

Methods

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

Results

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.

Conclusions

The results indicate that administration of a novel nano-particle formulation of BDNF leads to both neuroprotective and neuro-restorative effects after stroke.