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

Syed Zahid Ali Shah, Deming Zhao, Giulio Taglialatela, Tariq Hussain, Haodi Dong, Naveed Sabir, Mazhar Hussain Mangi, Wei Wu, Mengyu Lai, Xixi Zhang, Yuhan Duan, Lu Wang, Xiangmei Zhou, Lifeng Yang

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Abstract

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.

Original languageEnglish (US)
JournalInternational journal of molecular sciences
Volume20
Issue number5
DOIs
StatePublished - Mar 6 2019

Fingerprint

Minocycline
Prions
Tacrolimus
Caspases
Mitogen-Activated Protein Kinases
proteins
Proteins
infectious diseases
death
markers
activation
Prion Diseases
interleukins
phosphorylation
Chemical activation
hamsters
antibiotics
necrosis
impairment
apoptosis

Keywords

  • astrogliosis
  • heme oxygenase 1 (HO-1)
  • nuclear factor kappa-b (NF-kB)
  • nuclear factor of activated T-cells (NFAT)
  • nuclear factor–erythroid2-related factor-2 (NRF2)
  • phosphorylated Bcl2-associated death promoter (pBAD)
  • phosphorylated cAMP response element-binding protein (pCREB)
  • phosphorylated mitogen-activated protein kinase (MAPK) p38
  • transcription factors

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

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.

In: International journal of molecular sciences, Vol. 20, No. 5, 06.03.2019.

Research output: Contribution to journalArticle

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. In: International journal of molecular sciences. 2019 ; Vol. 20, No. 5.
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abstract = "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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AU - Zhao, Deming

AU - Taglialatela, Giulio

AU - Hussain, Tariq

AU - Dong, Haodi

AU - Sabir, Naveed

AU - Mangi, Mazhar Hussain

AU - Wu, Wei

AU - Lai, Mengyu

AU - Zhang, Xixi

AU - Duan, Yuhan

AU - Wang, Lu

AU - Zhou, Xiangmei

AU - Yang, Lifeng

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