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Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway

Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells’ (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, mino...

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Autores principales: Shah, Syed Zahid Ali, Zhao, Deming, Taglialatela, Giulio, Hussain, Tariq, Dong, Haodi, Sabir, Naveed, Mangi, Mazhar Hussain, Wu, Wei, Lai, Mengyu, Zhang, Xixi, Duan, Yuhan, Wang, Lu, Zhou, Xiangmei, Yang, Lifeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429086/
https://www.ncbi.nlm.nih.gov/pubmed/30845718
http://dx.doi.org/10.3390/ijms20051144
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author Shah, Syed Zahid Ali
Zhao, Deming
Taglialatela, Giulio
Hussain, Tariq
Dong, Haodi
Sabir, Naveed
Mangi, Mazhar Hussain
Wu, Wei
Lai, Mengyu
Zhang, Xixi
Duan, Yuhan
Wang, Lu
Zhou, Xiangmei
Yang, Lifeng
author_facet Shah, Syed Zahid Ali
Zhao, Deming
Taglialatela, Giulio
Hussain, Tariq
Dong, Haodi
Sabir, Naveed
Mangi, Mazhar Hussain
Wu, Wei
Lai, Mengyu
Zhang, Xixi
Duan, Yuhan
Wang, Lu
Zhou, Xiangmei
Yang, Lifeng
author_sort Shah, Syed Zahid Ali
collection PubMed
description Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells’ (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor–erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease.
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spelling pubmed-64290862019-04-10 Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway Shah, Syed Zahid Ali Zhao, Deming Taglialatela, Giulio Hussain, Tariq Dong, Haodi Sabir, Naveed Mangi, Mazhar Hussain Wu, Wei Lai, Mengyu Zhang, Xixi Duan, Yuhan Wang, Lu Zhou, Xiangmei Yang, Lifeng Int J Mol Sci Article Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells’ (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor–erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease. MDPI 2019-03-06 /pmc/articles/PMC6429086/ /pubmed/30845718 http://dx.doi.org/10.3390/ijms20051144 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shah, Syed Zahid Ali
Zhao, Deming
Taglialatela, Giulio
Hussain, Tariq
Dong, Haodi
Sabir, Naveed
Mangi, Mazhar Hussain
Wu, Wei
Lai, Mengyu
Zhang, Xixi
Duan, Yuhan
Wang, Lu
Zhou, Xiangmei
Yang, Lifeng
Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway
title Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway
title_full Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway
title_fullStr Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway
title_full_unstemmed Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway
title_short Combinatory FK506 and Minocycline Treatment Alleviates Prion-Induced Neurodegenerative Events via Caspase-Mediated MAPK-NRF2 Pathway
title_sort combinatory fk506 and minocycline treatment alleviates prion-induced neurodegenerative events via caspase-mediated mapk-nrf2 pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429086/
https://www.ncbi.nlm.nih.gov/pubmed/30845718
http://dx.doi.org/10.3390/ijms20051144
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