Ferulik Asitin Periferik Analjezik Etkisi ve Olası Mekanizmaları

Abstract

Ferulik asit, Ferula assa-foetida L.. gibi geleneksel tıpta kullanılan bitkilerin içerisinde yoğun olarak yer alan biyoaktif bir fenolik bileşiktir. Çeşitli tıbbi bitkilerin analjezik etkileri içerdiği ferulik asit ile ilişkilendirilmektedir. Fakat, analjezik etkinin mekanizmasına ilişkin çalışmalar sınırlı sayıdadır. Bu çalışmada farelerde % 0.6 asetik asit, i.p., injeksiyonu ile indüklenen kıvranma testinde ferulik asitin periferal analjezik etkisine NO/sGMP/PKG/K_ATP yolağının katılımının araştırılması amaçlandı. Bu amaçla ferulik asitin 20, 40, 80 ve 160 mg/kg (p.o.) dozlarda oluşturduğu analjezik etkinin belirlenmesini takiben, etki mekanizmasının aydınlatılması için etkili bulunan dozda uygulanan ferulik asit öncesi ayrı ayrı, NO prekürsörü 100 mg/kg L-arjinin (i.p.), nitrik oksit sentaz inhibitörü 30 mg/kg L-NAME (i.p.), guanilat siklaz inhibitörü 20 mg/kg metilen mavisi (i.p.) ve K_ATP kanal blokörü 10 mg/kg glibenklamid (i.p.) kullanıldı. Kıvranma sayısındaki azalma analjezik aktivite olarak değerlendirildi. 40, 80 ve 160 mg/kg dozlarda ferulik asitin kıvranma sayılarını anlamlı olarak azalttığı gözlendi. 80 mg/kg ferulik asit ve 100 mg/kg asetil salisilik asitin birbirine yakın seviyelerde etkinlik gösterdiği belirlendi. 80 mg/kg ferulik asitin neden olduğu kıvranma sayısındaki azalmayı; L-arjinin ve metilen mavisinin göreceli olarak geri çevirdiği, L-NAME’nin ise geri çeviremediği gözlendi. Glibenklamid ön-uygulaması ise ferulik asit ile indüklenen bu azalmayı anlamlı bir şekilde önledi. Çalışma bulguları ferulik asitin periferal analjezik etkinliğe sahip olduğunu ve bu etkinliğe sGMP’nin kısmen fakat K_ATP kanalları aktivasyonunun daha baskın olarak katılımının olduğunu göstermektedir. Sonuç olarak, bu çalışma ferulik asitin ağrının K_ATP kanalları hedefli tedavisinde avantaj sağlayabileceğini ortaya koymaktadır.   

Keywords

• Ferulik asit,Nitrik oksit,Guanilat siklaz,KATP kanalları,Ağrı

Peripheral Analgesic Effect and Possible Mechanisms of Ferulic Acid

Abstract

Ferulic acid is a bioactive phenolic compound that is found intensely in plants used in traditional medicine such as Ferula assa-foetida L.. The analgesic effect of various medicinal plants has been associated with its constituent, ferulic acid. However, there are limited number of studies about mechanism of its analgesic action. The aim of this study was to evaluate the contribution of NO/cGMP/PKG/K_ATP pathway in peripheral analgesic effect of ferulic acid by acetic acid-induced (0.6 % acetic acid, i.p.) writhing test in mice. For this purpose, following the determination of the analgesic effect of ferulic acid at the doses of 20, 40, 80 and 160 mg/kg (p.o.), NO precursor 100 mg/kg L-arginine (i.p.), nitric oxide synthase inhibitor 30 mg/kg L-NAME (i.p.), guanylate cyclase inhibitor 20 mg/kg methylene blue (i.p.) and K_ATP channel blocker 10 mg/kg glibenclamide (i.p.) were administered separately prior to ferulic acid treatment at the dose effective for clarifying the mechanism of action. Reduction in the number of writhes was evaluated as peripheral analgesic activity. Ferulic acid significantly decreased the number of writhes at the doses of 40, 80 and 160 mg/kg. 80 mg/kg ferulic acid and 100 mg/kg acetyl salicylic acid demonstrated similar efficacy. L-arginine and methylene blue relatively reversed the reduction in the number of writhes caused by ferulic acid at 80 mg/kg, whereas L-NAME did not. Glibenclamide pre-treatment significantly inhibited analgesic effect induced by ferulic acid. The results of the study indicate that ferulic acid has peripheral analgesic activity and it is mediated predominantly by activation of K_ATP channels and partially by cGMP. In conclusion, findings of this study demonstrate that ferulic acid may provide an advantage in K_ATP channel-targeted management of pain.

Keywords

• Ferulic acid,Nitric oxide,Guanylate cyclase,KATP channels,Pain

References

1. [1] Aydın ON. Ağrı ve ağrı mekanizmalarına güncel bakış. ADÜ Tip Fak Derg 2002;3(2):37- 48.
2. [2] Cazacu I, Mogosan C, Loghin F. Safety issues of current analgesics: an update. Clujul Med 2015;88:128-36.
3. [3] Zareba G. Phytotherapy for pain relief. Drugs Today 2009;45(6):445-467.
4. [4] Kamboj VP. Herbal medicine. Curr Sci 2000;78(1):35-39.
5. [5] Harput Ş. Yeni ilaç geliştirme çalışmalarında tıbbi bitkiler. Bitkilerle Tedavi Sempozyumu; 2010;Jun 5-6; Zeytinburnu, İstanbul, 45-46.
6. [6] Zhang A, et al. Effect of sodium ferulate on the hyperalgesia mediated by P2X3 receptor in the neuropathic pain rats. Brain Res 2010;1313:215-221.
7. [7] Bektaş N, Arslan, R. The centrally-mediated mechanisms of action of ferulic acid–induced antinociception. Marmara Pharm J 2016;20:303-310.
8. [8] Vashistha B, Sharma A, Jain V. Ameliorative potential of ferulic acid in vincristine-induced painful neuropathy in rats: An evidence of behavioral and biochemical examination. Nutr Neurosci 2017;20(1):60-70.[9] Vanegas H, Vazquez H, Tortorici V. NSAIDs, opioids, cannabinoids and the control of pain by the central nervous system. Pharmaceuticals 2010;3(5):1335–1347.[10] Sommer C. Serotonin in pain and pain control. In: Müller CP, Jacobs BL, editors. Handbook of Behavioral Neurobiology of Serotonin. USA:Elsevier; 2010. pp:457-471.[11] Staurengo-Ferrari L, et al. Nitroxyl inhibits overt pain-like behavior in mice: role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Pharmacol Rep 2014;66(4): 691–698.

9. [12] Vale ML, et al. Role of NO/cGMP/KATP pathway in antinociceptive effect of sildenafil in zymosan writhing response in mice. Inflamm res 2007;56:83–88.
10. [13] Florentino IF, et al. Involvement of the NO/cGMP/KATP pathway in the antinociceptive effect of the new pyrazole 5-(1- (3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021). Nitric Oxide 2015;47:17-24.
11. [14] Jaiswal SR, Sontakke SD. Experimental evaluation of analgesic and antiinflammatory activity of simvastatin and atorvastatin. Indian J Pharmacol 2012;44(4):475–479.[15] Ping CP, et al. Antinociceptive effects of cardamonin in mice: possible involvement of TRPV1, glutamate, and opioid receptors. Molecules 2018;23(9):2237.
12. [16] Gawade S. Acetic acid induced painful endogenous infliction in writhing test on mice. J Pharmacol Pharmacother 2012;3(4):348.
13. [17] Patel PK, Sahu J, Chandel SS.; A detailed review on nociceptive models for the screening of analgesic activity in experimental animals. J Neurol Phys Ther 2016;2(6):44-50.
14. [18] Calabrese EJ, Baldwin LA. Hormesis: U-shaped dose responses and their centrality in toxicology. Trends Pharmacol Sci 2001;22(6):285-291.
15. [19] Xu Y, et al. The antinociceptive effects of ferulic acid on neuropathic pain: involvement of descending monoaminergic system and opioid receptors. Oncotarget 2016;7(15):20455–20468.
16. [20] Xu Y, et al. Ferulic acid increases pain threshold and ameliorates depression-like behaviors in reserpine-treated mice: behavioral and neurobiological analyses. Metab Brain Dis 2013;28(4):571-83.
17. [21] Sachs D, Cunha FQ, Ferreira SH. Peripheral analgesic blockade of hypernociception: activation of arginine/NO/cGMP/protein kinase G/ATPsensitive K+ channel pathway. Proc Natl Acad Sci 2004;101(10):3680-5.
18. [22] Zulazmi NA, et al. Zerumbone alleviates neuropathic pain through the involvement of L-Arginine-Nitric Oxide-cGMP-K+ ATP channel pathways in chronic constriction injury in mice model. Molecules 2017;22(4):555.
19. [23] Parvardeh S, et al. Role of L-arginine/NO/cGMP/KATP channel signaling pathway in the central and peripheral antinociceptive effect of thymoquinone in rats. Iran J Basic Med Sci 2018;21:(6).
20. [24] Perimal EK, et al. Zerumbone-induced antinociception: involvement of the L-arginine-nitric oxide-cGMP-PKC-K+ATP channel pathways. Basic Clin Pharmacol Toxicol 2010;108(3):155–162.
21. [25] Schmidt HHHW. NO∙, CO and ∙OH endogenous soluble guanylyl cyclaseactivating factors. FEBS Lett 1992;307(1):102-107.
22. [26] Cury Y, et al. Pain and analgesia: The dual effect of nitric oxide in the nociceptive system. Nitric Oxide 2011;25(3):243-54.
23. [27] Liu L, et al. Voltage-gated ion channels in nociceptors: modulation by Cgmp. J Neurophysiol 2004;92:2323–2332.
24. [28] Jin Y, Kim J, Kwak J. Activation of the cGMP/Protein Kinase G pathway by nitric oxide can decrease TRPV1 activity in cultured rat dorsal root ganglion neurons. Korean J Physiol Pharmacol 2012;16(3):211-217.
25. [29] Gediz EI, et al. Antinociceptive effect of vardenafil on carrageenan-induced hyperalgesia in rat: involvement of nitric oxide/cyclic guanosine monophosphate/ calcium channels pathway. Iran J Pharm Res 2015;14(4):1137-1143.
26. [30] Mansouri MT, et al. central and peripheral antinociceptive effects of ellagic acid in different animal models of pain. Eur J Pharmacol 2013;707(1-3):46-53.
27. [31] Robles LI, et al. Effects of K+ channel blockers and openers on antinociception induced by agonists of 5-HT1A receptors. Eur J Pharmacol 1996;295:181-188.
28. [32] Asano T, Dohi S, Iida H. Antinociceptive action of epidural KATP + channel openers via interaction with morphine and an a2-adrenergic agonist in rats. Anesth Analg 2000;(90):1146-1151.
29. [33] Yamazumi I, Okuda T, Koga Y. Involvement of potassium channels in spinal antinociceptions induced by fentanyl, clonidine and bethanechol in rats. Jpn J Pharmacol 2001;87:268-276.
30. [34] Picolo G, Cassola AC, Cury Y. Activation of peripheral ATP-sensitive K+ channels mediates the antinociceptive effect of Crotalus durissus terrificus snake venom. Eur J Pharmacol 2003;469:57–64.
31. [35] Ocana M, et al. Potassium channels and pain: present realities and future opportunities. Eur J Pharmacol 2004;500(1-3):203-219.