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

Abstract

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.

• Authors: Alban Latremoliere, Alexandra Latini, Nick Andrews, Shane J Cronin, Masahide Fujita, Katarzyna Gorska, Ruud Hovius, Carla Romero, Surawee Chuaiphichai, Michio Painter, Giulia Miracca, Olusegun Babaniyi, Aline Pertile Remor, Kelly Duong, Priscilla Riva, Lee B Barrett, Nerea Ferreirós, Alasdair Naylor, Josef M Penninger, Irmgard Tegeder, Jian Zhong, Julian Blagg, Keith M Channon, Kai Johnsson, Michael Costigan, Clifford J Woolf
• Journal: Neuron (Neuron) Vol. 86 Issue 6 Pg. 1393-406 (Jun 17 2015) ISSN: 1097-4199 [Electronic] United States
• PMID: 26087165 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Video-Audio Media)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Enzyme Inhibitors
• Biopterins
• Sulfasalazine
• Alcohol Oxidoreductases
• sepiapterin reductase
• GTP Cyclohydrolase
• sapropterin
• Calcitonin Gene-Related Peptide

Topics

• Alcohol Oxidoreductases (metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Biopterins (analogs & derivatives, metabolism)
• Blood Pressure (drug effects)
• Calcitonin Gene-Related Peptide (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• GTP Cyclohydrolase (genetics)
• Gene Expression Regulation (drug effects, physiology)
• Inflammation (chemically induced, drug therapy, metabolism)
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Transgenic
• Neuralgia (chemically induced, drug therapy, metabolism)
• Pain Measurement
• Pain Threshold (drug effects, physiology)
• Reaction Time (drug effects, genetics)
• Sciatic Nerve (metabolism)
• Sensory Receptor Cells (drug effects, metabolism)
• Sulfasalazine (therapeutic use)
• Time Factors