Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors

Ádám Horváth; Valéria Tékus; Noémi Bencze; Nikolett Szentes; Bálint Scheich; Kata Bölcskei; Éva Szőke; Attila Mócsai; Éva Tóth-Sarudy; Péter Mátyus; Erika Pintér; Zsuzsanna Helyes

doi:10.1016/j.phrs.2018.02.006

Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors

Pharmacol Res. 2018 May:131:231-243. doi: 10.1016/j.phrs.2018.02.006. Epub 2018 Feb 10.

Authors

Affiliations

¹ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary. Electronic address: adam.horvath@aok.pte.hu.
² Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary. Electronic address: valeria.tekus@aok.pte.hu.
³ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary; National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary. Electronic address: noemi.bencze@aok.pte.hu.
⁴ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary. Electronic address: nikolett.szentes@aok.pte.hu.
⁵ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary. Electronic address: scheich.balint@med.semmelweis-univ.hu.
⁶ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary. Electronic address: kata.bolcskei@aok.pte.hu.
⁷ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary; National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary. Electronic address: eva.szoke@aok.pte.hu.
⁸ Department of Physiology & MTA-SE "Lendület" Inflammation Phisiology Research Group of the Hungarian Academy of Sciences, Semmelweis University, Faculty of Medicine, Tűzoltó u. 37-47., H-1094, Budapest, Hungary. Electronic address: mocsai.attila@med.semmelweis-univ.hu.
⁹ Department of Organic Chemistry, Semmelweis University, Faculty of Pharmacy, Hőgyes E. u. 7., H-1092, Budapest, Hungary. Electronic address: tothsarudy.eva@pharma.semmelweis-univ.hu.
¹⁰ Department of Organic Chemistry, Semmelweis University, Faculty of Pharmacy, Hőgyes E. u. 7., H-1092, Budapest, Hungary. Electronic address: matyus.peter@pharma.semmelweis-univ.hu.
¹¹ Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary; PharmInVivo Ltd., Szondi Gy. u. 7., H-7629, Pécs, Hungary. Electronic address: erika.pinter@aok.pte.hu.
¹² Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; János Szentágothai Research Centre & Centre for Neuroscience, University of Pécs, Ifjúság útja 20., H-7624, Pécs, Hungary; National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs, Medical School, Szigeti út 12., H-7624, Pécs, Hungary; PharmInVivo Ltd., Szondi Gy. u. 7., H-7629, Pécs, Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.

PMID: 29438782
DOI: 10.1016/j.phrs.2018.02.006

Abstract

Semicarbazide-sensitive amine oxidase (SSAO) produces tissue irritants by deamination of primary amines, which activate transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly on nociceptors. Since there are no data about its functions in pain, we studied the effects and mechanisms of action of our novel SSAO inhibitor and dual TRPA1/TRPV1 antagonist multi-target drug SZV 1287 in different pain models. Acute chemonociception was induced by TRPV1 and TRPA1 activation (resiniferatoxin and formalin, respectively), chronic arthritis by K/BxN serum transfer, traumatic mononeuropathy by sciatic nerve ligation. SZV 1287 (20 mg/kg i.p.) was investigated in C57BL/6J wildtype (WT), TRPA1- (TRPA1^-/-) and TRPV1-deficient (TRPV1^-/-) mice. Paw mechanonociception was measured by aesthesiometry, thermonociception by hot plate, nocifensive behavior by licking duration, volume by plethysmometry, myeloperoxidase activity by luminescence and plasma extravasation by fluorescence imaging, glia activation in pain-related brain regions by immunohistochemistry. SZV 1287 significantly inhibited both TRPA1 and TRPV1 activation-induced acute chemonociception and hyperalgesia. In K/BxN arthritis, daily SZV 1287 injections significantly decreased hyperalgesia, L4-L6 spinal dorsal horn microgliosis, edema and myeloperoxidase activity. SZV 1287-evoked antihyperalgesic and anti-edema effects were absent in TRPV1^-/-, and remarkably reduced in TRPA1^-/- mice. In contrast, myeloperoxidase-inhibitory effect was absent in TRPA1^-/-, but not in TRPV1^-/- animals. Acute SZV 1287 administration resulted in approximately 50% significant reduction of neuropathic hyperalgesia 7 days after nerve ligation, which was not observed in either TRPA1^-/- or TRPV1^-/- mice. SZV 1287 inhibits chronic inflammatory and neuropathic pain via TRPV1 and TRPA1/TRPV1 activation, respectively, highlighting its drug developmental potential.

Keywords: Arthritis; Microglia; Neuropathy; SSAO; TRPA1; TRPV1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
Amine Oxidase (Copper-Containing) / metabolism
Analgesics / pharmacology
Analgesics / therapeutic use*
Animals
Chronic Pain / drug therapy*
Chronic Pain / genetics
Chronic Pain / metabolism
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use*
Gene Deletion
Male
Mice, Inbred C57BL
Neuralgia / drug therapy
Neuralgia / genetics
Neuralgia / metabolism
Oxazoles / pharmacology
Oxazoles / therapeutic use*
Oximes / pharmacology
Oximes / therapeutic use*
TRPA1 Cation Channel / genetics
TRPA1 Cation Channel / metabolism*
TRPV Cation Channels / genetics
TRPV Cation Channels / metabolism*

Substances

3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime
Analgesics
Enzyme Inhibitors
Oxazoles
Oximes
TRPA1 Cation Channel
TRPV Cation Channels
TRPV1 protein, mouse
Trpa1 protein, mouse
Amine Oxidase (Copper-Containing)

Grants and funding

087782/Wellcome Trust/United Kingdom