Intraplantar injection of tetrahydrobiopterin induces nociception in mice

Nasser, Arafat; Ali, Sawsan; Wilsbech, Signe; Bjerrum, Ole J.; Møller, Lisbeth Birk

doi:10.1016/j.neulet.2014.10.050

Cited by 12 publications

(10 citation statements)

References 30 publications

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“…One such factor is NO (Gorren and Mayer, 2002), and indeed we find that SPR inhibition in vitro blocked NO production in macrophages. We found evidence for a contribution of NO to the heat pain hypersensitivity resulting from high constitutive BH4 levels in sensory neurons, but BH4 can also produce a non-NO-mediated sensitization of nociceptors (Nasser et al, 2015), indicating that this cofactor may modify pain via diverse mechanisms in different pathological circumstances. For example, serotonin, whose synthesis is dependent on BH4 (Friedman et al, 1972), sensitizes nociceptors through the activation of 5-HT 2A (Okamoto et al, 2002) and 5-HT 3 receptors (Kayser et al, 2007).…”

Section: Discussionmentioning

confidence: 83%

Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway

Latrémolière

Latini

Andrews

et al. 2015

Neuron

108

164

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SUMMARY Human genetic studies have revealed an association between GTP cyclohydrolase 1 polymorphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients. We now show that excessive BH4 is produced in mice by both axotomized sensory neurons and macrophages infiltrating damaged nerves and inflamed tissue. Constitutive BH4 overproduction in sensory neurons increases pain sensitivity, whereas blocking BH4 production only in these cells reduces nerve injury-induced hypersensitivity without affecting nociceptive pain. To minimize risk of side effects, we targeted sepiapterin reductase (SPR), whose blockade allows minimal BH4 production through the BH4 salvage pathways. Using a structure-based design, we developed a potent SPR inhibitor and show that it reduces pain hypersensitivity effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neurons and macrophages, with no development of tolerance or adverse effects. Finally, we demonstrate that sepiapterin accumulation is a sensitive biomarker for SPR inhibition in vivo.

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Section: Discussionmentioning

confidence: 83%

Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway

Latrémolière

Latini

Andrews

et al. 2015

Neuron

108

164

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“…1B), in which all enzymes are BH 4 -independent. Inhibition of BH 4 biosynthesis by any of the metabolites in the kynurenine pathway has not been reported. The physiological role of xanthurenic acid in mammals remains elusive.…”

Section: Resultsmentioning

confidence: 99%

“…BH 4 levels are constitutively high in cells carrying out aromatic amino acid hydroxylation (for example, dopamine-and serotonin-producing cells in brain or intestine and phenylalanine-hydroxylating cells in liver), but also up-regulated in certain cell types by stimulation with pro-inflammatory cytokines (2). The latter observation suggests that BH 4 plays a role in inflammatory processes.…”

Section: Tetrahydrobiopterin (Bh 4 )mentioning

confidence: 99%

“…These BH 4 -dependent enzymes play essential roles in synthesis of signaling molecules such as dopamine, serotonin, and nitric oxide in animals.…”

Section: Tetrahydrobiopterin (Bh 4 )mentioning

confidence: 99%

“…The latter observation suggests that BH 4 plays a role in inflammatory processes. Furthermore, accumulating evidence shows that increased levels of BH 4 intensify pain sensitivity, whereas reduction of BH 4 biosynthesis is an efficient strategy to diminish neuropathic and inflammatory pain (3)(4)(5).…”

Section: Tetrahydrobiopterin (Bh 4 )mentioning

confidence: 99%

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Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid

Haruki

Hovius

Pedersen

et al. 2016

Journal of Biological Chemistry

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Tryptophan metabolites in the kynurenine pathway are upregulated by pro-inflammatory cytokines or glucocorticoids, and are linked to anti-inflammatory and immunosuppressive activities. In addition, they are up-regulated in pathologies such as cancer, autoimmune diseases, and psychiatric disorders. The molecular mechanisms of how kynurenine pathway metabolites cause these effects are incompletely understood. On the other hand, pro-inflammatory cytokines also up-regulate the amounts of tetrahydrobiopterin (BH 4 ), an enzyme cofactor essential for the synthesis of several neurotransmitter and nitric oxide species. Here we show that xanthurenic acid is a potent inhibitor of sepiapterin reductase (SPR), the final enzyme in de novo BH 4 synthesis. The crystal structure of xanthurenic acid bound to the active site of SPR reveals why among all kynurenine pathway metabolites xanthurenic acid is the most potent SPR inhibitor. Our findings suggest that increased xanthurenic acid levels resulting from up-regulation of the kynurenine pathway could attenuate BH 4 biosynthesis and BH 4 -dependent enzymatic reactions, linking two major metabolic pathways known to be highly up-regulated in inflammation.

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Combining Human and Rodent Genetics to Identify New Analgesics

Latrémolière

Costigan

2017

Neurosci. Bull.

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Most attempts at rational development of new analgesics have failed, in part because chronic pain involves multiple processes that remain poorly understood. To improve translational success, one strategy is to select novel targets for which there is proof of clinical relevance, either genetically through heritable traits, or pharmacologically. Such an approach by definition yields targets with high clinical validity. The biology of these targets can be elucidated in animal models before returning to the patients with a refined therapeutic. For optimal treatment, having biomarkers of drug action available is also a plus. Here we describe a case study in rational drug design: the use of controlled inhibition of peripheral tetrahydrobiopterin (BH4) synthesis to reduce abnormal chronic pain states without altering nociceptive-protective pain. Initially identified in a population of patients with low back pain, the association between BH4 production and chronic pain has been confirmed in more than 12 independent cohorts, through a common haplotype (present in 25% of Caucasians) of the rate-limiting enzyme for BH4 synthesis, GTP cyclohydrolase 1 (GCH1). Genetic tools in mice have demonstrated that both injured sensory neurons and activated macrophages engage increased BH4 synthesis to cause chronic pain. GCH1 is an obligate enzyme for de novo BH4 production. Therefore, inhibiting GCH1 activity eliminates all BH4 production, affecting the synthesis of multiple neurotransmitters and signaling molecules and interfering with physiological function. In contrast, targeting the last enzyme of the BH4 synthesis pathway, sepiapterin reductase (SPR), allows reduction of pathological BH4 production without completely blocking physiological BH4 synthesis. Systemic SPR inhibition in mice has not revealed any safety concerns to date, and available genetic and pharmacologic data suggest similar responses in humans. Finally, because it is present in vivo only when SPR is inhibited, sepiapterin serves as a reliable biomarker of target engagement, allowing potential quantification of drug efficacy. The emerging development of therapeutics that target BH4 synthesis to treat chronic pain illustrates the power of combining human and mouse genetics: human genetic studies for clinical selection of relevant targets, coupled with causality studies in mice, allowing the rational engineering of new analgesics.

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Intraplantar injection of tetrahydrobiopterin induces nociception in mice

Cited by 12 publications

References 30 publications

Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway

Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway

Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid

Combining Human and Rodent Genetics to Identify New Analgesics

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