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Antinociceptive, antiedematous, and antiallodynic activity of 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione derivatives in experimental models of pain

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Abstract

The aim of the presented study was to examine the potential antinociceptive, antiedematous (anti-inflammatory), and antiallodynic activities of two 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione derivatives (DSZ 1 and DSZ 3) in various experimental models of pain. For this purpose, the hot plate test, the capsaicin test, the formalin test, the carrageenan model, and oxaliplatin-induced allodynia tests were performed. In the hot plate test, only DSZ 1 in the highest dose (20 mg/kg) was active but its effects appear to be due to sedatation rather than antinociceptiveness. In capsaicin-induced neurogenic pain model, both compounds displayed a significant antinociceptive activity. In the formalin test, DSZ 1 and DSZ 3 (5–20 mg/kg) revealed antinociceptive activity in both phases but it was more pronounced in the second phase of the test. In this test, pretreatment with caffeine, DPCPX reversed the antinociceptive effect of DSZ 3. On the other hand, pretreatment with L-NAME diminished the antinociceptive effect of DSZ 1. Pretreatment with naloxone did not affect antinociceptive activity of both compounds. Similar to ketoprofen, DSZ 1 and DSZ 3 showed antiedematous (antiinflammatory) and antihyperalgesic activity, and similar to lidocaine local anesthetic activity. Furthermore, both compounds (5 and 10 mg/kg) reduced tactile allodynia in acute and chronic phases of neuropathic pain. In the in vitro studies, DSZ 1 and DSZ 3 reduced the COX-2 level in LPS-activated RAW 264.7 cells, which suggests their anti-inflammatory activity. In conclusion, both DSZ 1 and DSZ 3 displayed broad spectrum of activity in several pain models, including neurogenic, tonic, inflammatory, and chemotherapy-induced peripheral neuropathic pain.

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Funding

The study was financially supported by Jagiellonian University Collegium Medicum statutory grant: K/ZDS/006237 and N42/DBS/000049.

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Authors and Affiliations

  1. Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland

    Anna Dziubina, Magdalena Kotańska & Barbara Filipek

  2. Department of Chemistry of Drugs, Faculty of Pharmacy with Division of Laboratory Diagnostics, Wroclaw Medical University, Borowska 211, 50-556, Wrocław, Poland

    Dominika Szkatuła

  3. Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland

    Joanna Gdula-Argasińska

Authors
  1. Anna Dziubina
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  2. Dominika Szkatuła
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  4. Magdalena Kotańska
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  5. Barbara Filipek
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Contributions

AD was responsible for the study concept, design, acquisition, and analysis of animal data, conducted the in vivo experiment, and drafted the manuscript.

DS was responsible for the generation, synthesis of the novel compounds, and critical revision for manuscript.

G-A J was responsible for in vitro experiment in cell line.

MK was responsible for determination of antioxidant activity.

BF provided critical revision for the manuscript.

All authors critically reviewed content and approved final version for publication.

Corresponding author

Correspondence to Anna Dziubina.

Ethics declarations

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All experimental procedures were conducted in accordance with the European Union Directive of 22 September 2010 (2010/63/EU) and Polish legislation concerning animal experimentation. The study was carried out under experimental protocols approved by the Local Ethical Committee in Kraków, Poland (Approval No. 4/2016, 180/2017, 181/2017, 151/2018, 218/2019).

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The authors declare that they have no conflicts of interests.

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Dziubina, A., Szkatuła, D., Gdula-Argasińska, J. et al. Antinociceptive, antiedematous, and antiallodynic activity of 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione derivatives in experimental models of pain. Naunyn-Schmiedeberg's Arch Pharmacol 393, 813–827 (2020). https://doi.org/10.1007/s00210-019-01783-3

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