ArticleArthritis & rheumatology (Hoboken, N.J.)2020
Sepiapterin Reductase Inhibition Leading to Selective Reduction of Inflammatory Joint Pain in Mice and Increased Urinary Sepiapterin Levels in Humans and Mice.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- BH4 Oxidation-Derived HJournal of neurochemistry · 2025Article
- Resolution of Lipopolysaccharide-Induced Inflammation Followed by DNA Hypomethylation and Increased Tetrahydrobiopterin Biosynthesis in Mouse Hippocampus.Brain sciences · 2025Article
- Pain Hypersensitivity and Increased Urinary Tetrahydrobiopterin Levels in Mice Submitted to High-Fat Diet.Brain sciences · 2025Article
- From a clinically relevant pain target to a possible analgesic treatment strategy.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Implementation of a Drug Screening Platform to TargetBio-protocol · 2023Article
- Tetrahydrobiopterin: Beyond Its Traditional Role as a Cofactor.Antioxidants (Basel, Switzerland) · 2023Review
- Mast cell-derived BH4 is a critical mediator of postoperative pain.bioRxiv : the preprint server for biology · 2023Article
- Peripheralized sepiapterin reductase inhibition as a safe analgesic therapy.Frontiers in pharmacology · 2023Review
- Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer.Science translational medicine · 2022Article
- Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Impaired dopamine metabolism is linked to fatigability in mice and fatigue in Parkinson's disease patients.Brain communications · 2021Article
- Exercise-induced immune system response: Anti-inflammatory status on peripheral and central organs.Biochimica et biophysica acta. Molecular basis of disease · 2020Review
- Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain.Frontiers in neuroscience · 2020Article
- Kynurenine and Tetrahydrobiopterin Pathways Crosstalk in Pain Hypersensitivity.Frontiers in neuroscience · 2020Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
objectiveTo 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.
methodsThe 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.
resultsCAIA 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.
conclusionSPR 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.
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