title: 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 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.
authors.affiliation: 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 Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
authors.forename: Syed Zahid Ali
authors.initials: SZA
authors.lastname: Shah
authors.affiliation: 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 Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
authors.forename: Deming
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch, Galveston, TX, 77555-1044, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Taglialatela
authors.affiliation: 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 Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
authors.forename: Sher Hayat
authors.initials: SH
authors.lastname: Khan
authors.affiliation: 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 Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
authors.forename: Tariq
authors.initials: T
authors.lastname: Hussain
authors.affiliation: 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 Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
authors.forename: Haodi
authors.initials: H
authors.lastname: Dong
authors.affiliation: 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 Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Lai
authors.affiliation: 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 Agrobiotechnology, China Agricultural University, Beijing, 100193, China.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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 Agrobiotechnology, China Agricultural University, Beijing, 100193, China. yanglf@cau.edu.cn.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism; D006224:Cricetinae; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism* / Q000517:prevention & control; D005911:Gliosis / Q000473:pathology / Q000517:prevention & control; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008647:Mesocricetus; D008911:Minocycline / Q000008:administration & dosage*; D009043:Motor Activity / Q000187:drug effects; D009425:Nesting Behavior / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017096:Prion Diseases / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D016019:Survival Analysis; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage*; D051996:Transcription Factor RelA / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051996:Transcription Factor RelA; D051025:bcl-Associated Death Protein; D019703:Calcineurin; D008911:Minocycline; D016559:Tacrolimus
keywords: Central nervous system; Gliosis; Nuclear factor kappa B; Nuclear factor of activated T-cells; Phosphorylated Bcl2-associated death promoter; Phosphorylated cAMP response element-binding protein; Phosphorylated mitogen-activated protein kinase p38; Prion protein scrapie