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Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity
BACKGROUND: HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879748/ https://www.ncbi.nlm.nih.gov/pubmed/27220536 http://dx.doi.org/10.1186/s12974-016-0585-8 |
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author | Fields, Jerel A. Overk, Cassia Adame, Anthony Florio, Jazmin Mante, Michael Pineda, Andrea Desplats, Paula Rockenstein, Edward Achim, Cristian Masliah, Eliezer |
author_facet | Fields, Jerel A. Overk, Cassia Adame, Anthony Florio, Jazmin Mante, Michael Pineda, Andrea Desplats, Paula Rockenstein, Edward Achim, Cristian Masliah, Eliezer |
author_sort | Fields, Jerel A. |
collection | PubMed |
description | BACKGROUND: HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity. METHODS: GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy. RESULTS: We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field. CONCLUSIONS: Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations. |
format | Online Article Text |
id | pubmed-4879748 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-48797482016-05-26 Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity Fields, Jerel A. Overk, Cassia Adame, Anthony Florio, Jazmin Mante, Michael Pineda, Andrea Desplats, Paula Rockenstein, Edward Achim, Cristian Masliah, Eliezer J Neuroinflammation Research BACKGROUND: HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity. METHODS: GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy. RESULTS: We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field. CONCLUSIONS: Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations. BioMed Central 2016-05-24 /pmc/articles/PMC4879748/ /pubmed/27220536 http://dx.doi.org/10.1186/s12974-016-0585-8 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Fields, Jerel A. Overk, Cassia Adame, Anthony Florio, Jazmin Mante, Michael Pineda, Andrea Desplats, Paula Rockenstein, Edward Achim, Cristian Masliah, Eliezer Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity |
title | Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity |
title_full | Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity |
title_fullStr | Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity |
title_full_unstemmed | Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity |
title_short | Neuroprotective effects of the immunomodulatory drug FK506 in a model of HIV1-gp120 neurotoxicity |
title_sort | neuroprotective effects of the immunomodulatory drug fk506 in a model of hiv1-gp120 neurotoxicity |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879748/ https://www.ncbi.nlm.nih.gov/pubmed/27220536 http://dx.doi.org/10.1186/s12974-016-0585-8 |
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