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.
Highlights
Prion diseases are a group of transmissible spongiform encephalopathies (TSEs), which are fatal neurodegenerative disorders affecting both humans and animals [1,2,3]
To evaluate the effect of FK506+minocycline treatment on microglia-induced neuroinflammation, we evaluated the levels of proinflammatory cytokines interleukin-1 beta (IL-1b) and tumor necrosis factor-alpha (TNF-a), and anti-inflammatory cytokines IL-10 and IL-27 in the brain homogenates of prion infected hamsters
Heeanrclye ntheeurreoiisnfsluafmfimcieantitocnonasnednsluastetrhantetuhreomdeogset neeffiractiieonnt tmhearkaepseuitticcostmraptleigcaytefodr ptoriodnevdeisloepaseasnweofufilcdiebnet tbhaesreadpoynfoarcpormiobnindaistoearyseasp[p43ro].aHchentocestthopertehies csounffviceiresniot ncoonfsneonrsmusatlhcaetlltuhlearmPorsPtceifnfitcoietnhtetnheeurarpoetouxtiicc strategy for prion diseases would be based on a combinatory approach to stop the conversion of normal cellular PrPc into the neurotoxic and misfolded PrPSc whilst rescuing neurons from initial synaptic dysfunction and neuroinflammation to later neurodegeneration and cell death
Summary
Prion diseases are a group of transmissible spongiform encephalopathies (TSEs), which are fatal neurodegenerative disorders affecting both humans and animals [1,2,3]. Prion diseases have a typical long asymptomatic phase of up to several years [5]. The most common feature of all these diseases is the presence of an abnormal, protease-resistant misfolded isoform of the normal cellular prion protein (PrPc), termed PrPSc [4,6]. PrPSc is highly pathogenic and neurotoxic due to its β-sheet rich conformation, as compared to predominantly α-helical structure of the normal cellular PrPc [7,8]. The long presymptomatic phase and lack of diagnostic facilities are great challenges for the scientists working on prion diseases [10]
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