Neurotherapeutics

, Volume 14, Issue 2, pp 463–483 | Cite as

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

  • Syed Zahid Ali Shah
  • Deming Zhao
  • Giulio Taglialatela
  • Sher Hayat Khan
  • Tariq Hussain
  • Haodi Dong
  • Mengyu Lai
  • Xiangmei Zhou
  • Lifeng Yang
Original Article

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 PrPSc) of the normal cellular prion protein (PrPc) in the brain. Proinflammatory cytokines and chemokines released by PrPSc-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.

Keywords

Central nervous system Gliosis Prion protein scrapie Nuclear factor of activated T-cells Phosphorylated mitogen-activated protein kinase p38 Nuclear factor kappa B Phosphorylated cAMP response element-binding protein Phosphorylated Bcl2-associated death promoter 

Supplementary material

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Fig. S1

Prion infection leads of loss of weight and reduced feed and water intake as the disease progress. (A) The data showing weekly weight gain of individual animals in different experimental groups. Weekly weight gain was calculated upto 14th week post infection, the data was analyzed by two way ANOVA followed by Bonferroni post test (P<0.001) Note: FK506 started showing significant difference in weight loss after 8th week while other groups shown significant weight loss after 11th week post infection. (B) The data showing weekly feed consumed by individual animals in different experimental groups upto 14th week post infection, the data was analyzed by two way ANOVA followed by Bonferroni post test (P<0.001) Note: All groups shown significant difference in food consumed after 11th week post infection as compared to No prion-vehicle group. (C) The data showing weekly water consumed by individual animals in different experimental groups upto 13th week post infection, the data was analyzed by two way ANOVA followed by Bonferroni post test (P<0.001) Note: All groups shown significant difference in water consumed after 12 weeks post infection as compared to No prion-Vehicle group. (GIF 190 kb)

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High Resolution Image (TIF 18932 kb)
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Fig. S2

Diagrammatic presentation of different stages of prion infection for possible therapeutic intervention. Note: In our hamster model of prion, we observed early clinical signs from 80±10 days post infection and animals without treatment survived for 3 to 4 weeks after initial signs. (GIF 108 kb)

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Videos S1–S4Clinical signs of prion infection in prion-vehicle, prion–FK506, prion–minocycline, and no prion–vehicle group on day 86 postinfection (WMV 5573 kb)
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Videos S5–S8Novel objects finding exploration in prion-vehicle, prion–FK506, prion–minocycline, and no prion–vehicle group (WMV 13677 kb)
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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  • Syed Zahid Ali Shah
    • 1
  • Deming Zhao
    • 1
  • Giulio Taglialatela
    • 2
  • Sher Hayat Khan
    • 1
  • Tariq Hussain
    • 1
  • Haodi Dong
    • 1
  • Mengyu Lai
    • 1
  • Xiangmei Zhou
    • 1
  • Lifeng Yang
    • 1
  1. 1.National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of AgrobiotechnologyChina Agricultural UniversityBeijingChina
  2. 2.Mitchell Center for Neurodegenerative Diseases, Department of NeurologyUniversity of Texas Medical BranchGalvestonUSA

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