Inhibitory Effects of Dutasteride on TLR4: An In vitro Pain Study
-
Leila Taheran
,
Hakimeh Zali
,
Kazem Sharifi
,
Mohsen Yazdani
,
Mohammad Ajoudanian
,
Mir-Shahram Safari
,
Samira Rajaei
,
Ali Dabbagh
Abstract
Dutasteride was potentially proposed to control chronic pain by Toll-Like Receptor 4 (TLR4) inhibition through its effect on TLR4 expression, Myeloid differentiation primary response 88 (MyD88), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), secretory Interleukin-1β (IL-1β), and nitric oxide (NO) in the Lipopolysaccharides (LPS)-stimulated U-87 MG cell line.
Human astrocytoma U-87 MG cell line was cultured and incubated with 10 μg/mL of LPS for 24 hours to create a neuro-inflammation model, using two different treatment approaches. The first approach included LPS treatment for 24 hours, followed by dutasteride (20 μg/mL) incubation for the next 72 hours. In the second treatment approach, the cells were co-incubated with LPS and dutasteride for 72 hours. Expression of TLR4, MyD88, NF-κBp65, and secretory IL-1 was evaluated by Western blotting while expression of NO was assessed by NO assay.
TLR4, MyD88, NF-κBp65, and secretory IL-1β levels increased in LPS-treated cells after 24 hours. Dutasteride significantly decreased the secretion of NO and also, the levels of TLR4, MyD88, and NF-κBp65 in both treatment approaches. No difference in IL-1β level was seen with the second treatment approach.
Dutasteride has anti-inflammatory properties and probably analgesic effects, by mechanisms different from conventional analgesics.
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7. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461.
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13. Biancolella M, Valentini A, Minella D, Vecchione L, D'Amico F, Chillemi G, et al. Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines. Invest New Drugs. 2007;25(5):491-7.
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17. Su Q, Li L, Sun Y, Yang H, Ye Z, Zhao J. Effects of the TLR4/Myd88/NF-κB Signaling Pathway on NLRP3 Inflammasome in Coronary Microembolization-Induced Myocardial Injury. Cell Physiol Biochem. 2018;47(4):1497-508.
18. Lin X, Kong J, Wu Q, Yang Y, Ji P. Effect of TLR4/MyD88 signaling pathway on expression of IL-1β and TNF-α in synovial fibroblasts from temporomandibular joint exposed to lipopolysaccharide. Med Inflamm. 2015;2015:329405.
19. Talebi Z, Dabbagh A. Perioperative Pain: Molecular Mechanisms and Future Perspectives. J Cell Mol Anesth. 2017;2(3):134-41.
20. Sommer C, Leinders M, Üçeyler N. Inflammation in the pathophysiology of neuropathic pain. Pain. 2018;159(3):595-602.
21. Papa A, Salzano AM, Di Dato MT, Lo Bianco G, Tedesco M, Salzano A, et al. COVID-19 Related Acro-Ischemic Neuropathic-like Painful Lesions in Pediatric Patients: A Case Series. Anesth Pain Med. 2021;11(2):e113760.
22. Chapman CR, Vierck CJ. The Transition of Acute Postoperative Pain to Chronic Pain: An Integrative Overview of Research on Mechanisms. J Pain. 2017;18(4):359.e1-.e38.
23. Nobuhara R, Ito A, Nakagawa M, Ikemoto T, Narita K, Nishihara M, et al. A Pusher and a Clip Applied to Hind Paws Under Isoflurane Sedation to Evaluate Neuropathic Pain in a CCI Model. Anesth Pain Med. 2021;11(6):e118299.
24. Arai YC, Nobuhara R, Aono S, Owari K, Saisu H, Ito A, et al. Clipping Hind Paws Under Isoflurane Sedation as a Useful Tool for Evaluation of Chronic Pain in CCI Animals. Anesth Pain Med. 2020;10(2):e97758.
25. Guan Z, Hellman J, Schumacher M. Contemporary views on inflammatory pain mechanisms: TRPing over innate and microglial pathways. F1000Res. 2016;5.
26. Lurie DI. An Integrative Approach to Neuroinflammation in Psychiatric disorders and Neuropathic Pain. Journal of experimental neuroscience. 2018;12:1179069518793639.
27. Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71(1):67-80.
28. Amini H, Ahmadiani A. In vivo evidence for an increase in 5alpha-reductase activity in the rat central nervous system following morphine exposure. Int J Dev Neurosci. 2005;23(7):621-6.
29. Verdi J, Ahmadiani A. Finasteride, a 5alpha-reductase inhibitor, potentiates antinociceptive effects of morphine, prevents the development of morphine tolerance and attenuates abstinence behavior in the rat. Horm Behav. 2007;51(5):605-10.
30. Watkins LR, Hutchinson MR, Rice KC, Maier SF. The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends in pharmacological sciences. 2009;30(11):581-91.
31. Moradi-Azani M, Ahmadiani A, Amini H. Increase in formalin-induced tonic pain by 5alpha-reductase and aromatase inhibition in female rats. Pharmacol Biochem Behav. 2011;98(1):62-6.
32. Savoca MP, Inferrera A, Verderio EAM, Caccamo D. Search for Novel Diagnostic Biomarkers of Prostate Inflammation-Related Disorders: Role of Transglutaminase Isoforms as Potential Candidates. Mediators Inflamm. 2019;2019:7894017.
33. Duborija-Kovacevic N, Jakovljevic V, Sabo A, Tomic Z. Anti-nociceptive and anti-inflammatory properties of 5alpha-reductase inhibitor finasteride in experimental animals. Eur J Drug Metab Pharmacokinet. 2008;33(3):181-6.
34. Kapoor S. Role of 5α-reductase inhibitors in modulation of the analgesic effects of morphine: an emerging concept in pain management. Neurol Sci. 2013;34(4):577.
35. Cury Y, Picolo G, Gutierrez VP, Ferreira SH. Pain and analgesia: The dual effect of nitric oxide in the nociceptive system. Nitric Oxide. 2011;25(3):243-54.
36. Soonthornsit N, Pitaksutheepong C, Hemstapat W, Utaisincharoen P, Pitaksuteepong T. In Vitro Anti-Inflammatory Activity of Morus alba L. Stem Extract in LPS-Stimulated RAW 264.7 Cells. Evid Based Complement Alternat Med. 2017;2017:3928956.
37. Di Penta A, Moreno B, Reix S, Fernandez-Diez B, Villanueva M, Errea O, et al. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PLoS One. 2013;8(2):e54722.
2. Nazemian V, Nasseri B, Manaheji H, Zaringhalam J. Effects of mesenchymal stem cells conditioned medium on behavioral aspects of inflammatory arthritic pain induced by CFA adjuvant. J Cell Mol Anesth. 2016;1(2):47-55.
3. Sezari P. The role of Toll-like receptors in pain control. J Cell Mol Anesth. 2017;2(1):24-9.
4. Baral P, Udit S, Chiu IM. Pain and immunity: implications for host defence. Nat Rev Immunol. 2019;19(7):433-47.
5. Lacagnina MJ, Watkins LR, Grace PM. Toll-like receptors and their role in persistent pain. Pharmacol Ther. 2018;184(15):145-58.
6. Zali H, Golchin A, Farahani M, Yazdani M, Ranjbar MM, Dabbagh A. FDA Approved Drugs Repurposing of Toll-Like Receptor4 (TLR4) Candidate for Neuropathy. Iran J Pharm Res. 2019;18(3):1639-47.
7. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461.
8. Li H, Li C, Shi H, Liu J. Continuous infusion of intraoperative dexmedetomidine improves chronic pain after thoracotomy via the Toll-like receptor 4/nuclear factor kappa B signaling pathway. Am J Transl Res. 2021;13(12):14133-40.
9. Gao W, Xiong Y, Li Q, Yang H. Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics. Front Physiol. 2017;8:508.
10. Mizoguchi S, Mori K, Shin T, Wang Z, DeFranco DB, Yoshimura N, et al. Effects of dutasteride in a rat model of chemically induced prostatic inflammation-Potential role of estrogen receptor β. Prostate. 2020;80(16):1413-20.
11. Mediesse FK, Boudjeko T, Hasitha A, Gangadhar M, Mbacham WF, Yogeeswari P. Inhibition of lipopolysaccharide (LPS)-induced neuroinflammatory response by polysaccharide fractions of Khaya grandifoliola (C.D.C.) stem bark, Cryptolepis sanguinolenta (Lindl.) Schltr and Cymbopogon citratus Stapf leaves in raw 264.7 macrophages and U87 glioblastoma cells. BMC Complement Altern Med. 2018;18(1):86.
12. Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep. 2019; 8;9(1):5790.
13. Biancolella M, Valentini A, Minella D, Vecchione L, D'Amico F, Chillemi G, et al. Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines. Invest New Drugs. 2007;25(5):491-7.
14. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75.
15. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3(1):17002.
16. Basheer AS, Abas F, Othman I, Naidu R. Role of Inflammatory Mediators, Macrophages, and Neutrophils in Glioma Maintenance and Progression: Mechanistic Understanding and Potential Therapeutic Applications. Cancers (Basel). 2021;13(16).
17. Su Q, Li L, Sun Y, Yang H, Ye Z, Zhao J. Effects of the TLR4/Myd88/NF-κB Signaling Pathway on NLRP3 Inflammasome in Coronary Microembolization-Induced Myocardial Injury. Cell Physiol Biochem. 2018;47(4):1497-508.
18. Lin X, Kong J, Wu Q, Yang Y, Ji P. Effect of TLR4/MyD88 signaling pathway on expression of IL-1β and TNF-α in synovial fibroblasts from temporomandibular joint exposed to lipopolysaccharide. Med Inflamm. 2015;2015:329405.
19. Talebi Z, Dabbagh A. Perioperative Pain: Molecular Mechanisms and Future Perspectives. J Cell Mol Anesth. 2017;2(3):134-41.
20. Sommer C, Leinders M, Üçeyler N. Inflammation in the pathophysiology of neuropathic pain. Pain. 2018;159(3):595-602.
21. Papa A, Salzano AM, Di Dato MT, Lo Bianco G, Tedesco M, Salzano A, et al. COVID-19 Related Acro-Ischemic Neuropathic-like Painful Lesions in Pediatric Patients: A Case Series. Anesth Pain Med. 2021;11(2):e113760.
22. Chapman CR, Vierck CJ. The Transition of Acute Postoperative Pain to Chronic Pain: An Integrative Overview of Research on Mechanisms. J Pain. 2017;18(4):359.e1-.e38.
23. Nobuhara R, Ito A, Nakagawa M, Ikemoto T, Narita K, Nishihara M, et al. A Pusher and a Clip Applied to Hind Paws Under Isoflurane Sedation to Evaluate Neuropathic Pain in a CCI Model. Anesth Pain Med. 2021;11(6):e118299.
24. Arai YC, Nobuhara R, Aono S, Owari K, Saisu H, Ito A, et al. Clipping Hind Paws Under Isoflurane Sedation as a Useful Tool for Evaluation of Chronic Pain in CCI Animals. Anesth Pain Med. 2020;10(2):e97758.
25. Guan Z, Hellman J, Schumacher M. Contemporary views on inflammatory pain mechanisms: TRPing over innate and microglial pathways. F1000Res. 2016;5.
26. Lurie DI. An Integrative Approach to Neuroinflammation in Psychiatric disorders and Neuropathic Pain. Journal of experimental neuroscience. 2018;12:1179069518793639.
27. Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71(1):67-80.
28. Amini H, Ahmadiani A. In vivo evidence for an increase in 5alpha-reductase activity in the rat central nervous system following morphine exposure. Int J Dev Neurosci. 2005;23(7):621-6.
29. Verdi J, Ahmadiani A. Finasteride, a 5alpha-reductase inhibitor, potentiates antinociceptive effects of morphine, prevents the development of morphine tolerance and attenuates abstinence behavior in the rat. Horm Behav. 2007;51(5):605-10.
30. Watkins LR, Hutchinson MR, Rice KC, Maier SF. The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends in pharmacological sciences. 2009;30(11):581-91.
31. Moradi-Azani M, Ahmadiani A, Amini H. Increase in formalin-induced tonic pain by 5alpha-reductase and aromatase inhibition in female rats. Pharmacol Biochem Behav. 2011;98(1):62-6.
32. Savoca MP, Inferrera A, Verderio EAM, Caccamo D. Search for Novel Diagnostic Biomarkers of Prostate Inflammation-Related Disorders: Role of Transglutaminase Isoforms as Potential Candidates. Mediators Inflamm. 2019;2019:7894017.
33. Duborija-Kovacevic N, Jakovljevic V, Sabo A, Tomic Z. Anti-nociceptive and anti-inflammatory properties of 5alpha-reductase inhibitor finasteride in experimental animals. Eur J Drug Metab Pharmacokinet. 2008;33(3):181-6.
34. Kapoor S. Role of 5α-reductase inhibitors in modulation of the analgesic effects of morphine: an emerging concept in pain management. Neurol Sci. 2013;34(4):577.
35. Cury Y, Picolo G, Gutierrez VP, Ferreira SH. Pain and analgesia: The dual effect of nitric oxide in the nociceptive system. Nitric Oxide. 2011;25(3):243-54.
36. Soonthornsit N, Pitaksutheepong C, Hemstapat W, Utaisincharoen P, Pitaksuteepong T. In Vitro Anti-Inflammatory Activity of Morus alba L. Stem Extract in LPS-Stimulated RAW 264.7 Cells. Evid Based Complement Alternat Med. 2017;2017:3928956.
37. Di Penta A, Moreno B, Reix S, Fernandez-Diez B, Villanueva M, Errea O, et al. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation. PLoS One. 2013;8(2):e54722.
| Files | ||
| Issue | Vol 21 No 5 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i5.11044 | |
| Keywords | ||
| Dutasteride Neuropathic pain Toll-like receptor 4 | ||
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How to Cite
1.
Taheran L, Zali H, Sharifi K, Yazdani M, Ajoudanian M, Safari M-S, Rajaei S, Dabbagh A. Inhibitory Effects of Dutasteride on TLR4: An In vitro Pain Study. Iran J Allergy Asthma Immunol. 2022;21(5):574-583.
