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

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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“…Besides, NF-κB could also increase the survival ability in endothelial cells and cardiomyocytes under LPS stimulation [23]. Previous study also indicated that the translation of NF-κB could be activated by rutin treatment via increasing the phosphorylation of p38-MAPK signaling pathway [24,25]. NO in endothelial cells were synthesized by eNOS, and the expression and activity of eNOS is largely related to the function of endothelial function.…”

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“…The octadecyl chain can attach to and remain on activated macrophage/microglial cell membranes for a long time, while the short peptide sequence can be specifically cleaved by MMP9 for responsive and controlled drug release. [37,38] Because short peptides have free amino groups and GOQDs have many carboxyl groups on their surfaces, covalent coupling of C18P to GOQDs via amide bonds can be achieved using EDC/NHS chemical crosslinking methods.…”

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FKBP11 improves the malignant property of osteosarcoma cells and acts as a prognostic factor of osteosarcoma

“…Consistently, the expression of the apoptotic marker caspase 3 markedly increased (Figure 4B). It was reported previously that the FK506 binding proteinmediated MAPK pathway can alleviate prion-induced neurodegeneration [12]. The role of the MAPK pathway regulated by FKBP52 in polycystic ovary syndrome (PCOS) has also been reported [13].…”