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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome

Authors: Elizabeth Nance, Siva P. Kambhampati, Elizabeth S. Smith, Zhi Zhang, Fan Zhang, Sarabdeep Singh, Michael V. Johnston, Rangaramanujam M. Kannan, Mary E. Blue, Sujatha Kannan

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome.

Methods

To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc−) is upregulated in Mecp2-null glia when compared to WT, the role of Xc− in the uptake of NAC and l-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan.

Results

We demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc− was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc− for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival.

Conclusions

These results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT.
Appendix
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Metadata
Title
Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome
Authors
Elizabeth Nance
Siva P. Kambhampati
Elizabeth S. Smith
Zhi Zhang
Fan Zhang
Sarabdeep Singh
Michael V. Johnston
Rangaramanujam M. Kannan
Mary E. Blue
Sujatha Kannan
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1004-5

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