Qiao Chen-Meng, Ma Xiao-Yu, Tan Lu-Lu, Xia Yi-Meng, Li Ting, Wu Jian, Cui Chun, Zhao Wei-Jiang, Shen Yan-Qin
Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
Laboratory of Neurodegenerative Diseases and Neuroinjury Diseases, Wuxi, School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.
Exp Neurol. 2025 Mar;385:115142. doi: 10.1016/j.expneurol.2025.115142. Epub 2025 Jan 8.
Abnormal tryptophan metabolism is closely linked with neurological disorders. Research has shown that indoleamine 2,3-dioxygenase 1 (IDO-1), the first rate-limiting enzyme in tryptophan degradation, is upregulated in Parkinson's disease (PD). However, the precise role of IDO-1 in PD pathogenesis remains elusive. In this study, we administered 1-methyl-tryptophan (1-MT), an IDO-1 inhibitor, intraperitoneally at 15 mg/kg daily for 21 days to PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 30 mg/kg daily for 5 days. Our results show that IDO-1 inhibition improves behavioral performance, reduces dopaminergic neuron loss, and decreases serum quinolinic acid (QA) content and the aryl hydrocarbon receptor (AHR) expression in the striatum and colon. It also alleviates glial-associated neuroinflammation and mitigates colonic inflammation (decreasing iNOS, COX2) by suppressing the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway. Furthermore, IDO-1 inhibition promotes hippocampal neurogenesis (increasing doublecortin positive (DCX) cells and SOX2 cells), which have recently been recognized as key pathological features and potential therapeutic targets in PD, likely through the activation of the BDNF/TrkB pathway. We further explored the gut-brain connection by depleting the gut microbiota in mice using antibiotics. Notably, the neuroprotective effects of IDO-1 inhibition were completely abolished in pseudo-germ-free mice (administrated an antibiotic mixture orally for 14 days prior to 1-MT treatment), highlighting the dependency of 1-MT's neuroprotective effects on the presence of gut microbiota. Finally, we found IDO-1 inhibition corrects the abnormal elevation of fecal short chain fatty acids (SCFAs). Collectively, these findings suggest that IDO-1 inhibition may represent a promising therapeutic approach for PD.
色氨酸代谢异常与神经紊乱密切相关。研究表明，色氨酸降解过程中的首个限速酶吲哚胺2,3-双加氧酶1（IDO-1）在帕金森病（PD）中表达上调。然而，IDO-1在PD发病机制中的具体作用仍不清楚。在本研究中，我们以每天15毫克/千克的剂量腹腔注射IDO-1抑制剂1-甲基色氨酸（1-MT），持续21天，对每天以30毫克/千克的剂量腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），持续5天诱导的PD小鼠进行实验。我们的结果显示，抑制IDO-1可改善行为表现，减少多巴胺能神经元损失，并降低纹状体和结肠中的血清喹啉酸（QA）含量以及芳烃受体（AHR）表达。它还通过抑制Toll样受体4/核因子-κB（TLR4/NF-κB）途径减轻胶质细胞相关的神经炎症并缓解结肠炎症（降低诱导型一氧化氮合酶、环氧化酶2）。此外，抑制IDO-1可促进海马神经发生（增加双皮质素阳性（DCX）细胞和SOX2细胞），最近这些已被认为是PD的关键病理特征和潜在治疗靶点，这可能是通过激活脑源性神经营养因子/酪氨酸激酶受体B（BDNF/TrkB）途径实现的。我们通过使用抗生素清除小鼠肠道微生物群进一步探索了肠-脑联系。值得注意的是，在无菌小鼠（在1-MT治疗前口服抗生素混合物14天）中，IDO-1抑制的神经保护作用完全消失，这突出了1-MT的神经保护作用对肠道微生物群存在的依赖性。最后，我们发现抑制IDO-1可纠正粪便短链脂肪酸（SCFA）的异常升高。总的来说，这些发现表明抑制IDO-1可能是一种有前景的PD治疗方法。
