Atorvastatin ameliorates viral burden and neural stem/progenitor cell (NSPC) death in an experimental model of Japanese encephalitis

Abstract

Japanese encephalitis virus, a neurotropic flavivirus, causes sporadic encephalitis with nearly 25% fatal case reports. JEV infects neural stem/progenitor cells (NSPCs) and decreases their proliferation. Statin, a commonly used class of cholesterol lowering drug, has been shown to possess potent anti-inflammatory and neuroprotective effects in acute brain injury and chronic neurodegenerative conditions. Here, we aimed to check the efficacy of atorvastatin in alleviating the symptoms of Japanese encephalitis (JE). Using BALB/c mouse model of JEV infection, we observed that atorvastatin effectively reduces viral load in the subventricular zone (SVZ) of infected pups and decreases the resultant cell death. Furthermore, atorvastatin abrogates microglial activation and production of proinflammatory cyto/chemokine production post JEV infection in vivo. It also reduced interferon-β response in the neurogenic environs. The neuroprotective role of atorvastatin is again evident from the rescued neurosphere size and decreased cell death in vitro. It has also been observed that upon atorvastatin administration, cell cycle regulatory proteins and cell survival proteins are also restored to their respective expression level as observed in uninfected animals. Thus the antiviral, immunomodulatory and neuroprotective roles of atorvastatin reflect in our experimental observations. Therefore, this drug broadens a path for future therapeutic measures against JEV infection.