Sepiapterin reductase inhibition selectively reduces inflammatory joint pain and increases urinary sepiapterin.

Abstract

OBJECTIVE\nTo evaluate the anti-inflammatory and analgesic effect of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease and to evaluate sepiapterin as a non-invasive, translational biomarker of SPR inhibition/target engagement in mice and healthy human volunteers.\n\n\nMETHODS\nThe collagen antibody-induced arthritis (CAIA) mouse model was used to induce joint inflammation. The effect of pharmacological inhibition of SPR on heat, cold and mechanical threshold sensitivity and signs of inflammation was tested in mice. Urine from mice and healthy volunteers treated with SPR inhibitors were analyzed by HPLC for changes in sepiapterin levels.\n\n\nRESULTS\nCAIA presented joint inflammation with heat, mechanical and cold pain hypersensitivity (inflammatory acute phase), and heat, mechanical but not cold hypersensitivity without joint inflammation (post- inflammation; late phase). SPR inhibition significantly attenuated CAIA-induced heat hyperalgesia in both phases, and mechanical allodynia in the late phase. Signs of inflammation were unaffected by SPR inhibition. Urinary BH4 levels were increased (100%; p<0.05) during inflammation and reduced (p<0.05) by SPR inhibition. Increased urinary sepiapterin levels in the presence of SPR inhibition were associated with high sensitivity (70-85%) and specificity (82-88%) in both mice and healthy volunteers.\n\n\nCONCLUSION\nSPR inhibition reduces pain associated with joint inflammation, showing potential utility as an analgesic strategy for inflammatory joint pain. SPR inhibition also increases urinary sepiapterin, indicating the potential of this measurement as a non-invasive biomarker of target engagement of SPR inhibitors, such as sulfasalazine (SSZ), a disease-modifying anti-rheumatic drug used as a first line treatment for rheumatoid arthritis (RA). This article is protected by copyright. All rights reserved.