Toshitaka Nabeshima

ObjectivesReports have shown that the kynurenine pathway, one of the pathways by which tryptophan is metabolized, is activated in patients with diffuse large B-cell lymphoma (DLBCL). Activation of the kynurenine pathway triggers the production of various metabolites, such as kynurenine (Kyn), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), kynurenic acid (KA), and anthranilic acid (AA), which contribute to immune tolerance. The current study aimed to investigate the changes in metabolites of kynurenine pathway in DLBCL patients and evaluate their performance predicting DLBCL.MethodsChanges in metabolites of kynurenine pathway were examined using high-performance liquid chromatography in 35 DLBCL patients (age 61.2 ± 13.5 years) and 44 healthy controls (age 58.5 ± 12.5 years).ResultsDLBCL patients had significantly higher levels of 3-HK, AA, and 3-HAA but lower levels of tryptophan (Trp) and KA compared to healthy controls. Given that the ratio of each metabolite represents the change in the Kyn pathway, the 3-HK/KA ratio was examined. Notably, DLBCL patients had a significantly higher 3-HK/KA ratio compared to healthy controls. In DLBCL, the area under the receiver operative characteristic (ROC) curve for 3-HK/KA (0.999) was higher than that for lactate dehydrogenase (0.885) and comparable to that for soluble interleukin-2 receptor (sIL-2R) (0.997). Based on ROC curve analysis, the 3-HK/KA ratio was found to be useful biomarker for the diagnosis of DLBCL.ConclusionOur results suggest that the 3-HK/KA ratio is a clinically useful biomarker of DLBCL. Moreover, its combination with existing markers, such as sIL-2R, can improve its effectiveness of diagnosing DLBCL.

Abstract Background Rho-kinase is a serine/threonine kinase and regulates actin dynamics. There are two subtypes: Rho-kinase 1 and Rho-kinase 2. Recently, we found that a Rho-kinase1/2 inhibitor, fasudil, ameliorated schizophrenia-like behaviors in MK-801-treated mice (Takase et al., 2022). However, fasudil has been shown side effects, such as hypotension, which may hinder its clinical application for schizophrenia. Since Rho-kinase 2 is predominantly expressed in brain, we hypothesized that selective inhibition of Rho-kinase 2 might exhibit antipsychotic-like effects with fewer cardiovascular side effects. Aims & Objectives To investigate the potential of a Rho-kinase 2 inhibitor as a therapeutic agent for schizophrenia, we evaluated the effect of a selective Rho-kinase 2 inhibitor, belumosudil (KD025), on MK-801-indued schizophrenia-like behaviors and blood pressure in mice. Method Effects of KD025 on schizophrenia-like behaviors in MK-801-treated mice were evaluated by locomotor activity test, novel object recognition test (NORT), and visual discrimination test (VD). KD025 (100-200 mg/kg) was orally administered 120 min before the behavioral tests. The blood pressure was also measured after KD025 treatment by tail-cuff method. Furthermore, we evaluated the depolarization-evoked extracellular dopamine and serotonin levels in the nucleus accumbens (NAc) using an in vivo microdialysis method. Results KD025 (100 or 200 mg/kg) restored MK-801-induced hyperlocomotion and the cognitive impairments in the NORT and VD, while KD025 showed little effect on systolic blood pressure, not like fasudil. In addition, local perfusion of KD025 (10-20 μ M) in the NAc suppressed the depolarization- evoked serotonin-, but not dopamine-release in the NAc. Discussion & Conclusion Our findings indicate that Rho-kinase 2 has potential as a therapeutic target for schizophrenia and KD025 may be a candidate as an antipsychotic for schizophrenia. References TAKASE, S., LIAO, J., LIU, Y., TANAKA, R., MIYAGAWA, Y., SAWAHATA, M., SOBUE, A., MIZOGUCHI, H., NAGAI, T., KAIBUCHI, K., OZAKI, N. &YAMADA, K. 2022. Antipsychotic-like effects of fasudil, a Rho- kinase inhibitor, in a pharmacologic animal model of schizophrenia. Eur J Pharmacol, 931, 175207.

Background and Purpose Alterations in tryptophan‐kynurenine (TRP‐KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3‐monooxygenase (KMO) induces depression‐like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP‐KYN pathway in stress‐induced behavioural changes and the regulation of the HPA axis. Experimental Approach Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP‐KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS‐induced behavioural changes and an increase in serum corticosterone (CORT) concentration. Key Results CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo^+/− mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short‐term CUMS. Nicotine attenuated CUMS‐induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin‐releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine. Conclusions and Implications CUMS‐induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.