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Celastrol-Based Nanomedicines as Modulators of Neuroinflammation

S. Boridy, E. Hutter, G. Soliman, D. Maysinger
McGill University, CA

Keywords: Celastrol, microglia, neuroinflammation, PAMAM dendrimers, gold nanoparticles

Abstract:

Chronic inflammation plays a pivotal role in promoting disease pathology in the central nervous system (CNS). Microglial cells are the main innate immune effector cells in the CNS and orchestrate these neuroinflammatory reactions that ultimately determine whether the response to injury will be protective or destructive. As such, microglia are ideal targets for anti-inflammatory therapies aimed at reducing inflammation in the CNS. Celastrol, a naturally occurring quinone methide triterpene, is an ideal anti-inflammatory drug candidate, however, its low water solubility and toxicity represent major pitfalls for drug delivery in the clinic. Our group has recently begun investigating nano-delivery systems for celastrol. Poly-(amidomine) (PAMAM) dendrimers and gold nanoparticles (GNPs) have been considered. The HYPOTHESIS of the present study is that PAMAM-celastrol and GNP-celastrol assemblies can be tailored to inhibit microglial activation and reduce neuroinflammaotory responses. Our RESULTS indicate that: (i) GNP-celastrol can modulate microglial activation in vitro, and in vivo and (ii) PAMAM-celastrol exhibits sustained drug release and can inhibit LPS-mediated microglial cytokine and pro-inflammatory signaling. In CONCLUSION, celastrol-based nanomedicines can modulate microglial activation, exhibiting therapeutic potential for further vivo studies.
 
 
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