title: Neuroprotection mediated by inhibition of calpain during acute viral encephalitis.
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.
authors.affiliation: Departments of Neurology, Mayo Clinic, Rochester, Minnesota, 55905 USA.|Departments of Neuroscience, Mayo Clinic, Rochester, Minnesota, 55905 USA.|Departments of Immunology, Mayo Clinic, Rochester, Minnesota, 55905 USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Howe
authors.affiliation: Departments of Neurology, Mayo Clinic, Rochester, Minnesota, 55905 USA.
authors.forename: Reghann G
authors.initials: RG
authors.lastname: LaFrance-Corey
authors.affiliation: Departments of Neurology, Mayo Clinic, Rochester, Minnesota, 55905 USA.
authors.forename: Kanish
authors.initials: K
authors.lastname: Mirchia
authors.affiliation: Neurobiology of Disease PhD program, Mayo Graduate School, Mayo Clinic, Rochester, Minnesota, 55905 USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Sauer
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota, 55905 USA.
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota, 55905 USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.affiliation: Departments of Neurology, Mayo Clinic, Rochester, Minnesota, 55905 USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Buenz
mesh_terms: D000208:Acute Disease; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018188:Cardiovirus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D017945:Theilovirus / Q000378:metabolism*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D018696:Neuroprotective Agents; D002154:Calpain; D019438:Ritonavir