OBJECTIVE To evaluate the antiinflammatory and analgesic effects of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease, and to determine whether urinary sepiapterin levels, as measured in mice and healthy human volunteers, could be useful as a noninvasive, translational biomarker of SPR inhibition/target engagement. METHODS The collagen antibody-induced arthritis (CAIA) model was used to induce joint inflammation in mice. The effects of pharmacologic inhibition of SPR on thresholds of heat-, cold-, and mechanical-evoked pain sensitivity and on signs of inflammation were tested in mice with CAIA. In addition, mice and healthy human volunteers were treated with SPR inhibitors, and changes in urinary sepiapterin levels were analyzed by high-performance liquid chromatography. RESULTS CAIA in mice was characterized by 2 phases: in the acute inflammation (early) phase, joint inflammation and heat-, mechanical-, and cold-induced pain hypersensitivity were present, while in the postinflammation (late) phase, no joint inflammation was observed but heat- and mechanical-induced hypersensitivity, but not cold hypersensitivity, were present. Inhibition of SPR in mice with CAIA significantly attenuated the heat-induced hyperalgesia in both phases, and the mechanical allodynia in the late phase. Signs of inflammation were unaffected by SPR inhibition. Urinary tetrahydrobiopterin levels, as a marker of inflammatory pain, were increased during inflammation in mice with CAIA (2-fold increase over controls; P < 0.05) and significantly reduced by SPR inhibition (P < 0.05 versus vehicle-treated mice). Increased urinary sepiapterin levels in the presence of SPR inhibition in both mice and healthy human volunteers were associated with high sensitivity (70-85%) and high specificity (82-88%) for the prediction of SPR inhibition/target engagement. CONCLUSION SPR inhibition reduces the pain associated with joint inflammation, thus showing its potential utility as an analgesic strategy for inflammatory joint pain. In addition, SPR inhibition increases urinary sepiapterin levels, indicating the potential of this measurement as a noninvasive biomarker of target engagement of SPR inhibitors, such as sulfasalazine, a disease-modifying antirheumatic drug that is currently used as a first-line treatment for rheumatoid arthritis.

中文翻译：

---

墨蝶呤还原酶抑制导致小鼠炎症性关节疼痛的选择性减轻以及人类和小鼠尿液墨蝶呤水平的增加。


目的 在炎症性关节疾病小鼠模型中评估墨蝶呤还原酶 (SPR) 抑制的抗炎和镇痛作用，并确定在小鼠和健康人类志愿者中测量的尿墨蝶呤水平是否可用作非侵入性转化生物标志物SPR 抑制/目标参与。方法采用胶原抗体诱导关节炎（CAIA）模型诱导小鼠关节炎症。在患有 CAIA 的小鼠中测试了 SPR 的药理学抑制对热、冷和机械引起的疼痛敏感性阈值以及炎症迹象的影响。此外，小鼠和健康人类志愿者接受了SPR抑制剂治疗，并通过高效液相色谱分析了尿液中的七蝶呤水平的变化。结果 小鼠 CAIA 分为 2 个阶段：在急性炎症（早期）阶段，存在关节炎症以及热、机械和冷引起的疼痛超敏反应，而在炎症后（晚期）阶段，则不存在关节炎症。观察到，但存在热和机械引起的超敏反应，但不存在冷超敏反应。抑制 CAIA 小鼠的 SPR 可以显着减弱两个阶段的热诱导的痛觉过敏以及后期的机械异常性疼痛。炎症迹象不受 SPR 抑制的影响。作为炎性疼痛标志物的尿四氢生物蝶呤水平在患有 CAIA 的小鼠炎症期间增加（比对照组增加 2 倍；P < 0.05），并且通过 SPR 抑制显着降低（与媒介物处理的小鼠相比，P < 0.05）。 在存在 SPR 抑制的情况下，小鼠和健康人类志愿者的尿七蝶呤水平升高与预测 SPR 抑制/靶点参与的高灵敏度 (70-85%) 和高特异性 (82-88%) 相关。结论 SPR 抑制可减轻与关节炎症相关的疼痛，从而显示出其作为炎症性关节疼痛镇痛策略的潜在用途。此外，SPR 抑制会增加尿液中的七蝶呤水平，表明该测量有可能作为 SPR 抑制剂靶标参与的无创生物标志物，例如柳氮磺吡啶，一种缓解疾病的抗风湿药物，目前用作类风湿性关节炎的一线治疗。