The Kynurenine Pathway (KP) of tryptophan degradation and glutamate toxicity is implicated in several neurological disorders, including depression. The therapeutic potential of mesenchymal stromal cells (MSC), owing to their well documented phagocytosis-driven mechanism of immunomodulation and neuroprotection, has been tested in many neurological disorders. However, their potential to influence KP and the glutamatergic system has not yet been investigated. Hence, this study sought to investigate the effect of HUCPVC, a rich and potent source of MSC, on Lipopolysaccharide (LPS)-activated KP metabolites, KP enzymes, and key components of glutamate neurotransmission. The immunomodulatory effect of peripherally administered HUCPVC on the expression profile of kynurenine pathway metabolites and enzymes was assessed in the plasma and brain of mice treated with LPS using LCMS and QPCR. An assessment of the glutamatergic system, including selected receptors, transporters and related proteins was also conducted by QPCR, immunohistochemistry and Western blot. HUCPVC were found to modulate LPS-induced activation of KP enzymes and metabolites in the brain associated with neurotoxicity. Moreover, the reduced expression of the glutamatergic components due to LPS was also found to be significantly improved by HUCPVC. The immunomodulatory properties of HUCPVC appear to confer neuroprotection, at least in part, through their ability to modulate the KP in the brain. This KP modulation enhances neuroprotective regulators and downregulates neurotoxic consequences, including glutamate neurotoxicity, which is associated with neuroinflammation and depressive behavior.

中文翻译：

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孕早期人脐带血管周围细胞 (HUCPVC) 在 LPS 诱导的神经炎症小鼠模型中调节犬尿氨酸通路和谷氨酸神经传递

色氨酸降解和谷氨酸毒性的犬尿氨酸通路 (KP) 与多种神经系统疾病有关，包括抑郁症。间充质基质细胞 (MSC) 的治疗潜力，由于其有据可查的吞噬作用驱动的免疫调节和神经保护机制，已在许多神经系统疾病中进行了测试。然而，它们影响 KP 和谷氨酸能系统的潜力尚未得到研究。因此，本研究旨在研究 HUCPVC（一种丰富而有效的 MSC 来源）对脂多糖 (LPS) 激活的 KP 代谢物、KP 酶和谷氨酸神经传递的关键成分的影响。使用 LCMS 和 QPCR 在用 LPS 处理的小鼠的血浆和大脑中评估了外周给药的 HUCPVC 对犬尿氨酸途径代谢物和酶的表达谱的免疫调节作用。还通过 QPCR、免疫组织化学和蛋白质印迹对谷氨酸能系统进行了评估，包括选定的受体、转运蛋白和相关蛋白质。发现 HUCPVC 可调节 LPS 诱导的大脑中与神经毒性相关的 KP 酶和代谢物的激活。此外，还发现 HUCPVC 显着改善了 LPS 导致的谷氨酸能成分表达减少。HUCPVC 的免疫调节特性似乎至少部分地通过它们调节大脑中 KP 的能力来赋予神经保护作用。