TY - JOUR
T1 - Combinatory FK506 and minocycline treatment alleviates prion-induced neurodegenerative events via caspase-mediated MAPK-NRF2 pathway
AU - Shah, Syed Zahid Ali
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
N1 - Funding Information:
Funding: This work was supported by National Key R&D Program of China (2017YFC1200500, 2017YFD0501600), Natural Science Foundation of China (Project No. 31472166), Ministry of Agriculture of China, 948 projects (2014-S9) and Chinese Universities Scientific Fund (Project No.2017DY003).
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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-1_) and tumor necrosis factor alpha (TNF-_), 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.
AB - 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-1_) and tumor necrosis factor alpha (TNF-_), 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.
KW - Astrogliosis
KW - Heme oxygenase 1 (HO-1)
KW - Nuclear factor kappa-b (NF-kB)
KW - Nuclear factor of activated T-cells (NFAT)
KW - Nuclear factor–erythroid2-related factor-2 (NRF2)
KW - Phosphorylated Bcl2-associated death promoter (pBAD)
KW - Phosphorylated cAMP response element-binding protein (pCREB)
KW - Phosphorylated mitogen-activated protein kinase (MAPK) p38
KW - Transcription factors
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U2 - 10.3390/ijms20051144
DO - 10.3390/ijms20051144
M3 - Article
C2 - 30845718
AN - SCOPUS:85062605792
SN - 1661-6596
VL - 20
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 5
M1 - 1144
ER -