Local delivery of AdipoRon from self-assembled microparticles to inhibit myelin lipid uptake and to promote lipid efflux from rat macrophages

Abstract

Abstract Objective. Abundant lipid-laden macrophages are found at the injury site after spinal cord injury (SCI). These cells have been suggested to be pro-inflammatory and neurotoxic. AdipoRon, an adiponectin receptor agonist, has been shown to promote myelin lipid efflux from mouse macrophage foam cells. While it is an attractive therapeutic strategy, systemic administration of AdipoRon is likely to exert off-target effects. In addition, the pathophysiology after SCI in mice is different from that in humans, whereas rat and human SCI share similar functional and histological outcomes. In this study, we evaluated the effects of AdipoRon on rat macrophage foam cells and developed a drug delivery system capable of providing sustained local release of AdipoRon to the injured spinal cord. Approach. Rat macrophages were treated with myelin debris to generate an in vitro model of SCI foam cells, and the effects of AdipoRon treatment on myelin uptake and efflux were studied. AdipoRon was then loaded into and released from microparticles made from dextran sulfate and fibrinogen for sustained release. Main results. AdipoRon treatment not only significantly promotes efflux of metabolized myelin lipids, but also inhibits uptake of myelin debris. Myelin debris alone does not appear to be inflammatory, but myelin debris treatment potentiates inflammation when administered along with pro-inflammatory lipopolysaccharide (LPS) and interferon-γ. AdipoRon significantly attenuated myelin lipid-induced potentiation of inflammation. Bioactive AdipoRon can be released in therapeutic doses from microparticles. Significance. These data suggest that AdipoRon is a promising therapeutic capable of reducing lipid accumulation via targeting both myelin lipid uptake and efflux, which potentially addresses chronic inflammation following SCI. Furthermore, we developed microparticle-based drug delivery systems for local delivery of AdipoRon to avoid deleterious side effects. This is the first study to release AdipoRon from drug delivery systems designed to reduce lipid accumulation and inflammation in reactive macrophages after SCI.