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

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

doi:10.1016/j.neuron.2015.05.033

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

Neuron. 2015 Jun 17;86(6):1393-406. doi: 10.1016/j.neuron.2015.05.033.

Authors

Alban Latremoliere¹, Alexandra Latini², Nick Andrews¹, Shane J Cronin³, Masahide Fujita¹, Katarzyna Gorska⁴, Ruud Hovius⁴, Carla Romero¹, Surawee Chuaiphichai⁵, Michio Painter¹, Giulia Miracca¹, Olusegun Babaniyi¹, Aline Pertile Remor², Kelly Duong¹, Priscilla Riva⁶, Lee B Barrett¹, Nerea Ferreirós⁷, Alasdair Naylor⁸, Josef M Penninger⁹, Irmgard Tegeder⁷, Jian Zhong¹⁰, Julian Blagg¹¹, Keith M Channon⁵, Kai Johnsson⁴, Michael Costigan¹², Clifford J Woolf¹³

Affiliations

¹ Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
² Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; LABOX, Universidade Federal de Santa Catarina, 88040-900 Florianópolis, Brazil.
³ Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
⁴ Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
⁵ Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
⁶ Department of Anesthesia, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
⁷ Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
⁸ The Canterbury Consulting Group, Unit 43 Canterbury Innovation Centre, University Road, Canterbury, Kent CT2 7FG, UK.
⁹ Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
¹⁰ Burke Medical Research Institute and Brain and Mind Research Institute, Weill Medical College of Cornell University, White Plains, NY 10605, USA.
¹¹ The Institute of Cancer Research, London SW7 3RP, UK.
¹² Department of Anesthesia, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
¹³ Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Alcohol Oxidoreductases / metabolism
Animals
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
Biopterins / analogs & derivatives*
Biopterins / 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
Gene Expression Regulation / physiology*
Inflammation / chemically induced
Inflammation / drug therapy
Inflammation / metabolism*
Macrophages / drug effects
Macrophages / metabolism
Mice
Mice, Transgenic
Neuralgia / chemically induced
Neuralgia / drug therapy
Neuralgia / metabolism*
Pain Measurement
Pain Threshold / drug effects
Pain Threshold / physiology
Reaction Time / drug effects
Reaction Time / genetics
Sciatic Nerve / metabolism
Sensory Receptor Cells / drug effects
Sensory Receptor Cells / metabolism
Sulfasalazine / therapeutic use
Time Factors

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding