Background: Indoleamine-2,3-dioxygenase 1 (IDO1) is the initial and rate-limiting enzyme in the metabolism of tryptophan (TRP) to kynurenine (KYN). IDO1-dependent neurotoxic KYN metabolism plays a crucial role in the pathogenesis of many neurodegenerative disorders. However, the function of IDO1 in epilepsy is still unclear.Objective: In this study, we investigated whether IDO1 deficiency could affect epilepsy in a lithium-pilocarpine-induced model.Methods: Patients with epilepsy and controls were enrolled. Male C57BL/6 mice and IDO1 knockout (KO, IDO1−/−) mice were subjected to intraperitoneal injection of lithium and pilocarpine to induce epilepsy. The levels of IDO1 and concentrations of TRP and KYN in patients with epilepsy and epileptic mice were evaluated by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (LC-MS), respectively. Then, behavioral phenotypes related to epileptic seizures and neuronal damage were compared between KO and wild-type (WT) mice with lithium-pilocarpine-induced epilepsy. To explore the underlying pathways involved in the effects of IDO1 deficiency, the concentrations of kynurenic acid (KYNA) and quinolinic acid (QUIN), glial cell activation, the levels of major pro-inflammatory cytokines, and antioxidant enzyme activity were measured by LC-MS, immunohistochemistry, and ELISA.Results: In this study, IDO1 levels and the KYN/TRP ratio in the sera and cerebrospinal fluid (CSF) were increased in patients with epilepsy. Also, IDO1 levels, the KYN/TRP ratio, and the levels of pro-inflammatory cytokines in the sera and hippocampi were increased in mice during the acute phase and chronic phase after status epilepticus (SE). Furthermore, IDO1 was localized in microglial cells in epileptic mice. IDO1 deficiency delayed SE onset and attenuated the frequency, duration, and severity of spontaneous recurrent seizures (SRSs). Moreover, IDO1 deficiency improved neuronal survival. Additionally, IDO1−/− epileptic mice showed progressive declines in QUIN production, glial cell activation and pro-inflammatory cytokines levels, and enhanced antioxidant enzyme activity.Conclusions: IDO1 deletion suppressed seizures and alleviated neuronal damage by reducing the IDO1-dependent production of neurotoxic metabolites, which finally inhibited glial cell activation and pro-inflammatory cytokine production and improved antioxidant enzyme activity. Our study demonstrates that IDO1 may be involved in the pathogenesis of epilepsy and has the potential to be a therapeutic target for epilepsy treatment.

ObjectivesWhile stimulation of the peripheral nerves increases the pain threshold, chronic pressure stimulation of the sciatic nerve is associated with sciatica. We recently found that acute pressure block of the sciatic nerve inhibits pain. Therefore, we propose that, the pain pathology-causing pressure is chronic, not acute. Here, we report a novel self-administered method: acute pressure block of the sciatic nerves is applied by the patients themselves for short-term relief of pain from dental diseases.DesignThis was a randomized, single-blind study.SettingHospital patients.PatientsPatients aged 16–60 years with acute pulpitis, acute apical periodontitis, or pericoronitis of the third molar of the mandible experiencing pain ≥3 on the 11-point numerical pain rating scale.InterventionsThree-minute pressure to sciatic nerves was applied by using the hands (hand pressure method) or by having the patients squat to force the thigh and shin as tightly as possible on the sandwiched sciatic nerve bundles (self-administered method).OutcomesThe primary efficacy variable was the mean difference in pain scores from the baseline.ResultsOne hundred seventy-two dental patients were randomized. The self-administered method produced significant relief from pain associated with dental diseases (P ≤ 0.001). The analgesic effect of the self-administered method was similar to that of the hand pressure method.ConclusionsThe self-administered method is easy to learn and can be applied at any time for pain relief. We believe that patients will benefit from this method.

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.