Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection

Neha Sehgal,Kanhaiya Lal Kumawat,Anirban Basu,Vijayalakshmi Ravindranath,Nancy M Sawtell

doi:10.1371/journal.pone.0035427

Abstract

BackgroundJapanese encephalitis (JE), the most common form of viral encephalitis occurs periodically in endemic areas leading to high mortality and neurological deficits in survivors. It is caused by a flavivirus, Japanese encephalitis virus (JEV), which is transmitted to humans through mosquitoes. No effective cure exists for reducing mortality and morbidity caused by JEV infection, which is primarily due to excessive inflammatory response. Fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) agonist is known to resolve inflammation by repressing nuclear factor-κB (NF-κB) and enhancing transcription of anti-oxidant and anti-inflammatory genes. In addition, fenofibrate also up-regulates a class of proteins, cytochrome P4504Fs (Cyp4fs), which are involved in detoxification of the potent pro-inflammatory eicosanoid, leukotriene B4 (LTB4) to 20-hydroxy LTB4.Methodology/Principal FindingsThe neuroprotective effect of fenofibrate was examined using in vitro (BV-2 microglial cell line) and in vivo (BALB/c mice) models of JEV infection. Mice were treated with fenofibrate for 2 or 4 days prior to JEV exposure. Pretreatment with fenofibrate for 4 but not 2 days reduced mortality by 80% and brain LTB4 levels decreased concomitantly with the induction of Cyp4f15 and 4f18, which catalyze detoxification of LTB4 through hydroxylation. Expression of cytokines and chemokine decreased significantly as did microglial activation and replication of the JEV virus.Conclusions/SignificanceFenofibrate confers neuroprotection against Japanese encephalitis, in vivo, in mouse model of JEV infection. Thus, fenofibrate, a PPARα agonist that is commonly used as a hypolipidemic drug could potentially be used for prophylaxis during JE epidemics to reduce mortality and morbidity.

Highlights

Japanese encephalitis virus (JEV), a flavivirus causes acute encephalopathy in children [1,2,3]
In order to assess the role of cytochrome P4504Fs (Cyp4fs) in attenuating the massive inflammatory response induced by JEV infection, we first used a cell culture approach
Induction of Cyp4fs by fenofibrate attenuates inflammatory response In order to ascertain whether the protective effect conferred by fenofibrate is through the induction of Cyp4fs, we quantitated the levels of Cyp4fs in BV-2 cells

Summary

Introduction

A large geographical area including India, China, Japan and most of South East Asia are afflicted by Japanese encephalopathy (JE). JEV infection targets the CNS leading to high mortality. The morbidity is high due to lingering neurological and/or psychiatric deficits in a large proportion of patients [5]. Japanese encephalitis (JE), the most common form of viral encephalitis occurs periodically in endemic areas leading to high mortality and neurological deficits in survivors. It is caused by a flavivirus, Japanese encephalitis virus (JEV), which is transmitted to humans through mosquitoes. No effective cure exists for reducing mortality and morbidity caused by JEV infection, which is primarily due to excessive inflammatory response. Fenofibrate up-regulates a class of proteins, cytochrome P4504Fs (Cyp4fs), which are involved in detoxification of the potent pro-inflammatory eicosanoid, leukotriene B4 (LTB4) to 20-hydroxy LTB4

Methods

Results

Conclusion