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.

Nanoformulation of Brain‐Derived Neurotrophic Factor with Target Receptor‐Triggered‐Release in the Central Nervous System

“…In the present study, the indication of the neuroprotective effect of Nano-BDNF in the brain has been provided using an LPS-induced acute neuroinflammation model. Taken together, our data represent a compelling rationale for advancing the evaluation of Nano-BDNF for treatment for CNS disorders such as stroke, [35] Rett syndrome, [36] and Alzheimer’s disease. [37] …”

Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke

“…Given that loss of P2X4R leads to a reduction in BDNF, which is linked to depression (Harris et al, 2016), we performed tests for depressive-like behaviors (anhedonia and lack of motivation). At baseline, male and female MS P2X4R KO mice showed no difference in anhedonia (based on the SCT) compared to WT littermates (Fig.…”

“…We and several other laboratories have correlated the chronic loss of BDNF with poor behavioral recovery and depressive behaviors at chronic time points after ischemic injury (Verma et al, 2016; Harris et al, 2016; Chen et al, 2015; Qin et al, 2014). Furthermore, infarct size measurements alone can be misleading (Verma et al, 2016; Bouet et al, 2007; Mergenthaler and Meisel, 2012) and P2X4Rs may also modulate social behavioral responses (Wyatt et al, 2013).…”

“…We performed the TST as described previously (Harris et al, 2016). Briefly, we placed mice in the behavioral room for one hour prior to testing to allow acclimatization.…”

Neurotrophin biology at NGF 2016: From fundamental science to clinical applications

“…Alexander Kabanov (University of North Carolina, Chapel Hill, NC) discussed strategies and ongoing work aimed at delivering compounds to the brain, with particular emphasis on BDNF. One method utilizes a polyion complex termed “nano‐BDNF” (Harris et al, 2016). This compound has several benefits.…”