Abstract
Neurologic complications associated with viral encephalitis, including seizures and cognitive impairment, are a global health issue, especially in children. We previously showed that hippocampal injury during acute picornavirus infection in mice is associated with calpain activation and is the result of neuronal death triggered by brain-infiltrating inflammatory monocytes. We therefore hypothesized that treatment with a calpain inhibitor would protect neurons from immune-mediated bystander injury. C57BL/6J mice infected with the Daniel’s strain of Theiler’s murine encephalomyelitis virus were treated with the FDA-approved drug ritonavir using a dosing regimen that resulted in plasma concentrations within the therapeutic range for calpain inhibition. Ritonavir treatment significantly reduced calpain activity in the hippocampus, protected hippocampal neurons from death, preserved cognitive performance, and suppressed seizure escalation, even when therapy was initiated 36 hours after disease onset. Calpain inhibition by ritonavir may be a powerful tool for preserving neurons and cognitive function and preventing neural circuit dysregulation in humans with neuroinflammatory disorders.
Highlights
Neurologic complications associated with viral encephalitis, including seizures and cognitive impairment, are a global health issue, especially in children
We previously showed that acute brain injury associated with infection by the Daniel’s (DA) strain of Theiler’s murine encephalomyelitis virus (TMEV) in C57BL/6J mice is the result of infiltrating inflammatory monocytes[6,7]
While very little calpain activity was observed in the CA1 region in uninfected mice (Fig. 1c), a clear pattern of activity within CA1 pyramidal neurons was observed by 3 dpi (Fig. 1d)
Summary
Neurologic complications associated with viral encephalitis, including seizures and cognitive impairment, are a global health issue, especially in children. We previously showed that hippocampal injury during acute picornavirus infection in mice is associated with calpain activation and is the result of neuronal death triggered by brain-infiltrating inflammatory monocytes. Analysis of Mayo Clinic’s Olmsted County cohort over a 46 year period revealed a 16-fold increase in unprovoked seizures following viral encephalitis[5] These findings are consistent with encephalitis-induced neuronal injury and neural circuit dysregulation. While some neuronal loss during viral encephalitis may occur due to direct virus-mediated injury, much of the damage is associated with bystander pathology – the loss of cells that are not directly compromised by the pathogen but which are in proximity to an inflammatory focus. We previously showed that acute brain injury associated with infection by the Daniel’s (DA) strain of Theiler’s murine encephalomyelitis virus (TMEV) in C57BL/6J mice is the result of infiltrating inflammatory monocytes[6,7].
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