Nose-to-brain co-delivery of repurposed simvastatin and BDNF synergistically attenuates LPS-induced neuroinflammation
Microglia; Nanoparticles; Drug repurposing; Polymersomes; Intranasal delivery
A therapeutic strategy that can combat the multifaceted nature of neuroinflammation pathology was investigated. Thus, we fabricated PEG-PdLLA polymersomes and evaluated the efficacy in co-delivery of simvastatin (Sim, as a repurposed anti-inflammatory agent) with brain derived neurotrophic factor (BDNF, as an exogeneous trophic factor supplementation). Using LPS model of neuroinflammation, intranasal administration of combination drug-loaded polymersomes (containing both Sim and BDNF; Sim-BDNF-Ps) markedly down-regulated brain levels of cytokines compared to free drug and single-drug-loaded polymersomes. Further, Sim-BDNF-Ps effectively replenished brain level of BDNF that was depleted following neuroinflammation, resulting in a 2-fold BDNF increase versus untreated LPS control group. We found out that the efficiency of the combination drug-loaded polymersomes to suppress microglia activation in brain regions followed the order: frontal cortex > striatum > hippocampus. Our findings indicated that Sim-BDNF-Ps could effectively inhibit microglial-mediated inflammation as well as potentially resolve the neurotoxic microenvironment that is often associated with neuroinflammation.
Manickavasagam Dharani; Lin Li; Oyewumi Moses O
Nanomedicine: Nanotechnology, Biology, And Medicine
2019
2019-10-23
Journal Article
<a href="http://doi.org/10.1016/j.nano.2019.102107" target="_blank" rel="noreferrer noopener">10.1016/j.nano.2019.102107</a>
PMID: 31655202
Internalization of particulate delivery systems by activated microglia influenced the therapeutic efficacy of simvastatin repurposing for neuroinflammation
Brain; Drug delivery; Drug repurposing; PEG-PdLLA; Polymersomes
October 2019 Update
We recently evaluated the suitability of polymersome delivery systems in simvastatin repurposing for treating neuroinflammation. The goal of the current study is to elucidate the therapeutic impact of particulate internalization by activated microglia on the resultant anti-inflammatory properties. Thus, we investigated the endocytic mechanism(s) involved in uptake and transport of simvastatin-loaded polymersomes by BV2 microglia cells coupled with delineation of the intracellular pathway(s) involved in regulating anti-inflammatory effects. Our data indicated that internalization of polymersome delivery systems by activated microglial BV2 cells was important in the suppression of nitric oxide (NO), TNF-α and IL-6 production. Further, we observed that the lipid raft/caveolae pathway had the most influential effect on polymersome internalization by microglia cells while clathrin-mediated endocytosis did not play a major role. Enhancement of anti-inflammatory effects of simvastatin could be attributed to inhibition of ERK1/2, JNK and AKT signaling pathways and internalization of polymersome delivery systems in activated microglia. Taken together, our data provided insights into how the intracellular trafficking of delivery systems by microglial could be a useful tool in modulating the desired anti-inflammatory effects of drugs.
Manickavasagam Dharani; Oyewumi Moses O
International Journal of Pharmaceutics
2019
2019-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ijpharm.2019.118690" target="_blank" rel="noreferrer noopener">10.1016/j.ijpharm.2019.118690</a>