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Microbial pathogenesis v.112, 2017년, pp.38 - 49   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Inhibition of MEK-ERK1/2-MAP kinase signalling pathway reduces rabies virus induced pathologies in mouse model

Manjunatha, Venkataravanappa (Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India ) ; Singh, Karam Pal (Centre for Animal Disease Research and Diagnosis, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India ) ; Saminathan, Mani (Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India ) ; Singh, Rajendra (Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India ) ; Shivasharanappa, Nayakwadi (Animal Science Section, ICAR-Central Coastal Agricultural Research Institute, Ela, Goa, India ) ; Umeshappa, Channakeshava Sokke (Cancer Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Canada ) ; Dhama, Kuldeep (Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, India ) ; Manjunathareddy, Gundallahalli Bayyappa (ICAR-National Institute of Veterinary Epidemiology and Disease Informatics, Bengaluru, Karnataka, India ) ;
  • 초록  

    Abstract The extracellular signal-regulated kinase (ERK) pathway has been shown to regulate pathogenesis of many viral infections, but its role during rabies virus (RV) infection in vivo is not clear. In the present study, we investigated the potential role of MEK-ERK1/2 signalling pathway in the pathogenesis of rabies in mouse model and its regulatory effects on pro-inflammatory cytokines and other mediators of immunity, and kinetics of immune cells. Mice were infected with 25 LD 50 of challenge virus standard (CVS) strain of RV by intracerebral (i.c.) inoculation and were treated i.c. with U0126 (specific inhibitor of MEK1/2) at 10 μM/mouse at 0, 2, 4 and 6 days post-infection. Treatment with U0126 resulted in delayed disease development and clinical signs, increased survival time with lesser mortality than untreated mice. The better survival of inhibitor-treated and RV infected mice was positively correlated with reduced viral load and reduced viral spread in the brain as quantified by real-time PCR, direct fluorescent antibody test and immunohistochemistry. CVS-infected/mock-treated mice developed severe histopathological lesions with increased Fluoro-Jade B positive degenerating neurons in brain, which were associated with higher levels of serum nitric oxide, iNOS, TNF-α, and CXCL10 mRNA. Also CVS-infected/U0126-treated mice revealed significant decrease in caspase 3 but increase in Bcl-2 mRNA levels and less TUNEL positive apoptotic cells. CVS-infected/U0126-treated group also showed significant increase in CD4 + , CD8 + T lymphocytes and NK cells in blood and spleen possibly due to less apoptosis of these cells. In conclusion, these data suggest that MEK-ERK1/2 signalling pathway play critical role in the pathogenesis of RV infection in vivo and opens up new avenues of therapeutics. Highlights MEK-ERK-1/2 inhibition delayed development of clinical signs and increased survival time in rabies virus infection. CVS-infected/U0126-treated mice developed severe histopathological lesions, higher cytokines levels and viral load. MEK1/2 inhibition reduced apoptosis and increased CD4 + , CD8 + T lymphocytes and NK cells.


  • 주제어

    U0126 .   MEK1/2 inhibitor .   Rabies virus .   Histopathology .   Cytokines .   T lymphocytes.  

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