TY - JOUR
T1 - Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway
AU - Latremoliere, Alban
AU - Latini, Alexandra
AU - Andrews, Nick
AU - Cronin, Shane J.
AU - Fujita, Masahide
AU - Gorska, Katarzyna
AU - Hovius, Ruud
AU - Romero, Carla
AU - Chuaiphichai, Surawee
AU - Painter, Michio
AU - Miracca, Giulia
AU - Babaniyi, Olusegun
AU - Remor, Aline Pertile
AU - Duong, Kelly
AU - Riva, Priscilla
AU - Barrett, Lee B.
AU - Ferreirós, Nerea
AU - Naylor, Alasdair
AU - Penninger, Josef M.
AU - Tegeder, Irmgard
AU - Zhong, Jian
AU - Blagg, Julian
AU - Channon, Keith M.
AU - Johnsson, Kai
AU - Costigan, Michael
AU - Woolf, Clifford J.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/6/17
Y1 - 2015/6/17
N2 - 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. Video Abstract: Latremoliere et al. genetically manipulated the tetrahydrobiopterin synthesis pathway to formally validate its role in neuropathic and inflammatory pain hypersensitivity, and show that systemic inhibition of this pathway by targeting sepiapterin reductase reduces chronic pain with no adverse effects.
AB - 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. Video Abstract: Latremoliere et al. genetically manipulated the tetrahydrobiopterin synthesis pathway to formally validate its role in neuropathic and inflammatory pain hypersensitivity, and show that systemic inhibition of this pathway by targeting sepiapterin reductase reduces chronic pain with no adverse effects.
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U2 - 10.1016/j.neuron.2015.05.033
DO - 10.1016/j.neuron.2015.05.033
M3 - Article
C2 - 26087165
AN - SCOPUS:84931036239
SN - 0896-6273
VL - 86
SP - 1393
EP - 1406
JO - Neuron
JF - Neuron
IS - 6
ER -