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

Overview

MeSH

  • Alcohol Oxidoreductases
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Blood Pressure
  • Calcitonin Gene-Related Peptide
  • Disease Models, Animal
  • Enzyme Inhibitors
  • GTP Cyclohydrolase
  • Macrophages
  • Mice
  • Mice, Transgenic
  • Pain Measurement
  • Pain Threshold
  • Reaction Time
  • Sciatic Nerve
  • Sensory Receptor Cells
  • Sulfasalazine
  • Time Factors

MeSH Major

  • Biopterin
  • Gene Expression Regulation
  • Inflammation
  • Neuralgia

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. Copyright © 2015 Elsevier Inc. All rights reserved.

publication date

  • June 17, 2015

has subject area

  • Alcohol Oxidoreductases
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal
  • Biopterin
  • Blood Pressure
  • Calcitonin Gene-Related Peptide
  • Disease Models, Animal
  • Enzyme Inhibitors
  • GTP Cyclohydrolase
  • Gene Expression Regulation
  • Inflammation
  • Macrophages
  • Mice
  • Mice, Transgenic
  • Neuralgia
  • Pain Measurement
  • Pain Threshold
  • Reaction Time
  • Sciatic Nerve
  • Sensory Receptor Cells
  • Sulfasalazine
  • Time Factors

Research

keywords

  • Journal Article
  • Video-Audio Media

Identity

Language

  • eng

PubMed Central ID

  • PMC4485422

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2015.05.033

PubMed ID

  • 26087165

Additional Document Info

start page

  • 1393

end page

  • 1406

volume

  • 86

number

  • 6