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

Abstract BackgroundIDO1 is the initial and rate-limiting enzyme that metabolizes tryptophan (TRP) to kynurenine (KYN). IDO1-dependent neurotoxic KYN metabolism plays a crucial role in pathogenesis of many neurodegenerative disorders. However, the function of IDO1 in epilepsy is still unclear. MethodsPatients with epilepsy and controls were enrolled. Male C57BL/6 mice and IDO1 knockout (KO) mice were subjected to intraperitoneal injection of lithium and pilocarpine to induce epilepsy. The level of IDO1 and concentrations of TRP and KYN in the patients with epilepsy and epileptic mice were evaluated by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (LC-MS) respectively. Then, SRS and neuronal damage was compared between KO and wild-type (WT) mice in lithium-pilocarpine-induced epilepsy. To explore underlying pathways involved in IDO1 deficiency, concentrations of kynurenic acid (KYNA) and quinolinic acid (QUIN), glial cells activation, major pro-inflammatory cytokines, and antioxidant enzymes activity were measured by LC-MS, immunohistochemistry and ELISA.ResultsIn this study, IDO1 level and KYN/TRP ratio were increased in the patients with epilepsy and epileptic mice. IDO1 deficiency attenuated the frequency, duration and severity of SRS and improved neuronal survival. Additionally, IDO1-/- epileptic mice showed a progressive decline in QUIN production, glial cells activation and pro-inflammatory cytokines and enhanced antioxidant enzymes activity.ConclusionsIDO1 deletion alleviated SRS and neuronal damage in the chronic period after SE through a reduction in IDO1-dependent neurotoxic metabolites, which finally inhibited pro-inflammatory cytokine production and glial cells activation and improved antioxidant enzymes activity. Our study demonstrates that IDO1 may be involved in the pathogenesis of epilepsy and has potential to be a therapeutic target for the treatment of epilepsy.