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

Abstract

Summary 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.

Indoleamine-2,3-Dioxygenase 1 (IDO1) Deficiency Attenuates Spontaneous Recurrent Seizures (SRS) after Status Epilepticus(SE) in the Lithium-Pilocarpine Model of Epilepsy

“…We found that IDO1 de ciency attenuated the severity of SRS. A previous study showed that IDO1 deletion promotes Theiler's virus-induced seizures [9]. Conversely, our study revealed that IDO1 de ciency attenuated SRS after status epilepticus in the lithium-pilocarpine model of epilepsy.…”

“…IDO1 antagonist 1-methyltryptophan attenuates depressive-like behaviour but not spontaneous seizures [8]. However, a recent research indicates that IDO1 deletion increases the incidence of seizures during acute TMEV encephalitis [9]. Here, we observed that IDO level and KYN/TRP ratio were raised in the serum and CSF of patients with epilepsy.…”

“…IDO antagonist 1methyltryptophan eases depressive-like behaviour but fails to relieve spontaneous seizures [8]. However, a recent study suggested that IDO1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis [9]. In this study, we found that serum KYN/TRP ration was increased both in the patients with primary epilepsy and patients with seizure secondary to autoimmune encephalitis.…”

Indoleamine-2,3-Dioxygenase 1 Deficiency Suppresses Seizures in Epilepsy

“…1-Methyltryptophan attenuates depressive-like behavior but not spontaneous seizures (Xie et al, 2014). However, recent research indicates that IDO1 deletion increases the incidence of seizures in acute TMEV-induced encephalitis (Juda et al, 2019). Here, we observed that IDO levels and the KYN/TRP ratio were increased in the sera and CSF of patients with epilepsy.…”

“…Further studies involving IDO1 gene-deficient mice are needed. A recent study suggested that IDO1 deletion promotes seizures and neuropathogenesis in acute Theiler's murine encephalitis virus (TMEV)-induced encephalitis (Juda et al, 2019). IDO1 is upregulated by inflammatory mediators, such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and interferonγ (Jiang et al, 2018).…”