Neuroprotection mediated by inhibition of calpain during acute viral encephalitis

Charles L Howe, Reghann G. Lafrance-Corey, Kanish Mirchia, Brian M. Sauer, Renee M. McGovern, Joel M Reid, Eric J. Buenz

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Article number28699
JournalScientific Reports
Volume6
DOIs
StatePublished - Jun 27 2016

Fingerprint

Viral Encephalitis
Calpain
Ritonavir
Neurons
Picornaviridae Infections
Seizures
Theilovirus
Brain Death
Wounds and Injuries
Therapeutics
Inbred C57BL Mouse
Cognition
Nervous System
Monocytes
Hippocampus
Neuroprotection
Inhibition (Psychology)
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Howe, C. L., Lafrance-Corey, R. G., Mirchia, K., Sauer, B. M., McGovern, R. M., Reid, J. M., & Buenz, E. J. (2016). Neuroprotection mediated by inhibition of calpain during acute viral encephalitis. Scientific Reports, 6, [28699]. https://doi.org/10.1038/srep28699

Neuroprotection mediated by inhibition of calpain during acute viral encephalitis. / Howe, Charles L; Lafrance-Corey, Reghann G.; Mirchia, Kanish; Sauer, Brian M.; McGovern, Renee M.; Reid, Joel M; Buenz, Eric J.

In: Scientific Reports, Vol. 6, 28699, 27.06.2016.

Research output: Contribution to journalArticle

Howe, Charles L ; Lafrance-Corey, Reghann G. ; Mirchia, Kanish ; Sauer, Brian M. ; McGovern, Renee M. ; Reid, Joel M ; Buenz, Eric J. / Neuroprotection mediated by inhibition of calpain during acute viral encephalitis. In: Scientific Reports. 2016 ; Vol. 6.
@article{0c4094321d1b414da713beff20df681b,
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.",
author = "Howe, {Charles L} and Lafrance-Corey, {Reghann G.} and Kanish Mirchia and Sauer, {Brian M.} and McGovern, {Renee M.} and Reid, {Joel M} and Buenz, {Eric J.}",
year = "2016",
month = "6",
day = "27",
doi = "10.1038/srep28699",
language = "English (US)",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Neuroprotection mediated by inhibition of calpain during acute viral encephalitis

AU - Howe, Charles L

AU - Lafrance-Corey, Reghann G.

AU - Mirchia, Kanish

AU - Sauer, Brian M.

AU - McGovern, Renee M.

AU - Reid, Joel M

AU - Buenz, Eric J.

PY - 2016/6/27

Y1 - 2016/6/27

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84976546672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84976546672&partnerID=8YFLogxK

U2 - 10.1038/srep28699

DO - 10.1038/srep28699

M3 - Article

C2 - 27345730

AN - SCOPUS:84976546672

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 28699

ER -