Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, and Academy of Sciences, Vienna, Austria.
Arthritis Rheumatol. 2020 Jan;72(1):57-66. doi: 10.1002/art.41060. Epub 2019 Nov 28.
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.
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.
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.
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.
评估蝶呤还原酶（SPR）抑制在炎性关节疾病小鼠模型中的抗炎和镇痛作用，并确定尿液蝶呤水平是否可作为 SPR 抑制/靶点结合的非侵入性转化生物标志物。
使用胶原抗体诱导的关节炎（CAIA）模型诱导小鼠关节炎症。在患有 CAIA 的小鼠中测试 SPR 药理学抑制对热、冷和机械诱发疼痛敏感性阈值以及炎症迹象的影响。此外，用 SPR 抑制剂治疗小鼠和健康人类志愿者，并通过高效液相色谱法分析尿液蝶呤水平的变化。
CAIA 诱导的小鼠表现为 2 个阶段：在急性炎症（早期）阶段，关节炎症和热、机械和冷诱发的疼痛过敏存在，而在炎症后（晚期）阶段，观察到没有关节炎症，但存在热和机械诱发的过敏，但不存在冷过敏。在患有 CAIA 的小鼠中抑制 SPR 显著减轻了两个阶段的热诱导性痛觉过敏，以及晚期的机械性痛觉过敏。炎症迹象不受 SPR 抑制的影响。尿液四氢生物蝶呤水平作为炎症性疼痛的标志物，在患有 CAIA 的小鼠的炎症期间增加（比对照组增加 2 倍；P <0.05），并被 SPR 抑制显著降低（与 vehicle 治疗的小鼠相比，P <0.05）。在存在 SPR 抑制的情况下，无论是在小鼠还是健康人类志愿者中，尿液蝶呤水平升高与 SPR 抑制/靶点结合的高灵敏度（70-85%）和高特异性（82-88%）相关。
SPR 抑制减轻与关节炎症相关的疼痛，因此显示其作为炎性关节疼痛的镇痛策略的潜力。此外，SPR 抑制增加了尿液蝶呤水平，表明该测量作为 SPR 抑制剂，如柳氮磺胺吡啶的靶点结合的非侵入性生物标志物的潜力，柳氮磺胺吡啶是一种目前用于类风湿关节炎的一线治疗的疾病修饰抗风湿药物。
