Peripheral Analgesic Effect and Possible Mechanisms of Ferulic Acid

Yıl 2019, Cilt: 9 Sayı: 3, 385 - 392, 25.09.2019

Merve Kaşık Hazal Eken Rana Arslan , Nurcan Bektas

https://doi.org/10.31020/mutftd.587236

Cited By: 1

Öz

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.

Anahtar Kelimeler

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

Destekleyen Kurum

Anadolu University

Proje Numarası

1802S034

Teşekkür

This article is based on the M.Sc. degree thesis of Merve KASIK and supported financially by Anadolu University Research Foundation (Eskisehir, Turkey), Project no: 1802S034. The authors declare no conflict of interest, financial or otherwise.

Ferulik Asitin Periferik Analjezik Etkisi ve Olası Mekanizmaları

Öz

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.   

Anahtar Kelimeler

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

Proje Numarası

1802S034

Kaynakça

• [1] Aydın ON. Ağrı ve ağrı mekanizmalarına güncel bakış. ADÜ Tip Fak Derg 2002;3(2):37- 48.
• [2] Cazacu I, Mogosan C, Loghin F. Safety issues of current analgesics: an update. Clujul Med 2015;88:128-36.
• [3] Zareba G. Phytotherapy for pain relief. Drugs Today 2009;45(6):445-467.
• [4] Kamboj VP. Herbal medicine. Curr Sci 2000;78(1):35-39.
• [5] Harput Ş. Yeni ilaç geliştirme çalışmalarında tıbbi bitkiler. Bitkilerle Tedavi Sempozyumu; 2010;Jun 5-6; Zeytinburnu, İstanbul, 45-46.
• [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] Bektaş N, Arslan, R. The centrally-mediated mechanisms of action of ferulic acid–induced antinociception. Marmara Pharm J 2016;20:303-310.
• [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.
• [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.
• [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.
• [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.
• [16] Gawade S. Acetic acid induced painful endogenous infliction in writhing test on mice. J Pharmacol Pharmacother 2012;3(4):348.
• [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.
• [18] Calabrese EJ, Baldwin LA. Hormesis: U-shaped dose responses and their centrality in toxicology. Trends Pharmacol Sci 2001;22(6):285-291.
• [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.
• [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.
• [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.
• [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.
• [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).
• [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.
• [25] Schmidt HHHW. NO∙, CO and ∙OH endogenous soluble guanylyl cyclaseactivating factors. FEBS Lett 1992;307(1):102-107.
• [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.
• [27] Liu L, et al. Voltage-gated ion channels in nociceptors: modulation by Cgmp. J Neurophysiol 2004;92:2323–2332.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [35] Ocana M, et al. Potassium channels and pain: present realities and future opportunities. Eur J Pharmacol 2004;500(1-3):203-219.