RETRACTED ARTICLE: Early Minocycline and Late FK506 Treatment Improves Survival and Alleviates Neuroinflammation, Neurodegeneration, and Behavioral Deficits in Prion-Infected Hamsters

Abstract

Prion infections of the central nervous system (CNS) are characterized by initial reactive gliosis followed by overt neuronal death. Gliosis is likely to be caused initially by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrP) of the normal cellular prion protein (PrP) in the brain. Proinflammatory cytokines and chemokines released by PrP-activated glia and stressed neurons may also contribute directly or indirectly to the disease development by enhancing gliosis and inducing neurotoxicity. Recent studies have illustrated that early neuroinflammation activates nuclear factor of activated T cells (NFAT) in the calcineurin signaling cascade, resulting in nuclear translocation of nuclear factor kappa B (NF-κB) to promote apoptosis. Hence, useful therapeutic approaches to slow down the course of prion disease development should control early inflammatory responses to suppress NFAT signaling. Here we used a hamster model of prion diseases to test, for the first time, the neuroprotective and NFAT-suppressive effect of a second-generation semisynthetic tetracycline derivative, minocycline, versus a calcineurin inhibitor, FK506, with known NFAT suppressive activity. Our results indicate that prolonged treatment with minocycline, starting from the presymptomatic stage of prion disease was more effective than FK506 given either during the presymptomatic or symptomatic stage of prion disease. Specifically, minocycline treatment reduced the expression of the astrocyte activation marker glial fibrillary acidic protein and of the microglial activation marker ionized calcium-binding adapter molecule-1, subsequently reducing the level of proinflammatory cytokines interleukin 1β and tumor necrosis factor-α. We further found that minocycline and FK506 treatment inhibited mitogen-activated protein kinase p38 phosphorylation and NF-κB nuclear translocation in a caspase-dependent manner, and enhanced phosphorylated cyclic adenosine monophosphate response element-binding protein and phosphorylated Bcl2-associated death promoter levels to reduce cognitive impairment and apoptosis. Taken together, our results indicate that minocycline is a better choice for prolonged use in prion diseases and encourage its further clinical development as a possible treatment for this disease.

MicroRNA 27a-3p Regulates Antimicrobial Responses of Murine Macrophages Infected by Mycobacterium avium subspecies paratuberculosis by Targeting Interleukin-10 and TGF-β-Activated Protein Kinase 1 Binding Protein 2

“…Afterward, samples were sonicated for 20 s and then centrifuged at 12,000 × g for 20 min at 4°C. The resulting supernatants were collected and boiled for 10 min after the addition of loading buffer (250 nM Tris HCl 6.8 pH, 10% sodium dodecyl sulfate, 0.5% bromophenol blue, 50% glycerol, and 0.5 M dithiothreitol) ( 52 ). Equal amounts of protein were separated by 12% or 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred onto polyvinylidene difluoride membranes (Millipore, Billerica, MA, USA).…”

p62-Keap1-NRF2-ARE Pathway: A Contentious Player for Selective Targeting of Autophagy, Oxidative Stress and Mitochondrial Dysfunction in Prion Diseases

“…Animal prion diseases are bovine spongiform encephalopathies (BSE) in cattle, scrapie disease in sheep and goats, and chronic wasting disease in elk and wild deer. Human prion diseases include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS) and Fatal Familial Insomnia (FFI; Nakagaki et al, 2013 ; Puig et al, 2016 ; Shah et al, 2017d ). An important event in prion diseases is the continuous and constant conversion of normal cellular alpha-helical prion protein (PrP c ) into an abnormal beta-sheet rich, protease-resistant, misfolded, and aggregated isoform termed prion protein scrapie (PrP Sc ; Pan et al, 1993 ).…”

Modulation of Mitochondrial Dynamics in Neurodegenerative Diseases: An Insight Into Prion Diseases

“…These diseases all share the same pathological characteristics of spongiform degeneration, neuronal death and astrocytic and microglial proliferation (Zhu et al, 2014 ; Ji et al, 2017 ; Shah et al, 2017a ).The underlying cause of prion disease is the conformational conversion of a cellular prion protein (PrP C ) to a misfolded isoform (PrP Sc ), which has a higher proportion of beta-sheets in place of the normal alpha-helices in PrP C and is protease-resistant (Prusiner, 1998 ; Wang et al, 2015 ). All prion diseases are associated with the accumulation and aggregation of misfolded PrP Sc in the central nervous system (CNS), which leads to neuroinflammation and neurodegeneration (Prusiner, 2001 ; White et al, 2003 ; Shah et al, 2017b ).…”