Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

Michal B. Juda, Alexandra K. Brooks, Albert E. Towers, Gregory G Freund, Robert H. McCusker, Andrew Jonathan Steelman

Research output: Contribution to journalArticle

Abstract

Objective: Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. Methods: C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. Results: Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice. Significance: Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.

Original languageEnglish (US)
Pages (from-to)626-635
Number of pages10
JournalEpilepsia
Volume60
Issue number4
DOIs
StatePublished - Apr 1 2019

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Inbred C57BL Mouse
Seizures
Kynurenine
Theilovirus
Viral Encephalitis
Cytokines
Quinolinic Acid
Viral RNA
Pathology
Kynurenic Acid
Encephalitis
Locomotion
Knockout Mice
Tryptophan
Real-Time Polymerase Chain Reaction
Epilepsy
Animal Models
Immunohistochemistry
Genotype

Keywords

  • 3-dioxygenase 1
  • Theiler's murine encephalomyelitis virus
  • acute seizures
  • epilepsy
  • indoleamine 2
  • infection-induced seizures
  • neuropathogenesis
  • viral encephalitis

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice. / Juda, Michal B.; Brooks, Alexandra K.; Towers, Albert E.; Freund, Gregory G; McCusker, Robert H.; Steelman, Andrew Jonathan.

In: Epilepsia, Vol. 60, No. 4, 01.04.2019, p. 626-635.

Research output: Contribution to journalArticle

Juda, Michal B. ; Brooks, Alexandra K. ; Towers, Albert E. ; Freund, Gregory G ; McCusker, Robert H. ; Steelman, Andrew Jonathan. / Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice. In: Epilepsia. 2019 ; Vol. 60, No. 4. pp. 626-635.
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abstract = "Objective: Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. Methods: C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. Results: Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice. Significance: Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.",
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T1 - Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

AU - Juda, Michal B.

AU - Brooks, Alexandra K.

AU - Towers, Albert E.

AU - Freund, Gregory G

AU - McCusker, Robert H.

AU - Steelman, Andrew Jonathan

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Objective: Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. Methods: C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. Results: Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice. Significance: Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.

AB - Objective: Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. Methods: C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. Results: Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice. Significance: Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.

KW - 3-dioxygenase 1

KW - Theiler's murine encephalomyelitis virus

KW - acute seizures

KW - epilepsy

KW - indoleamine 2

KW - infection-induced seizures

KW - neuropathogenesis

KW - viral encephalitis

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VL - 60

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JO - Epilepsia

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SN - 0013-9580

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