Zerumbone Alleviates Neuropathic Pain through the Involvement of l-Arginine-Nitric Oxide-cGMP-K+ ATP Channel Pathways in Chronic Constriction Injury in Mice Model

Zulazmi, Nurul Atiqah; Gopalsamy, Banulata; Chia, Jasmine Siew Min; Farouk, Ahmad Akira Omar; Sulaiman, Mohd Roslan; Bharatham, B. Hemabarathy; Perimal, Enoch Kumar

doi:10.3390/molecules22040555

Cited by 25 publications

(28 citation statements)

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“…Zerumbone has been shown to possess anti-inflammatory (Chien et al, 2008;Sulaiman et al, 2010a), antinociceptive (Sulaiman et al, 2010b), chemopreventive (Murakami et al, 1999), antimicrobial, and anti-oxidative properties (Habsah et al, 2000). Most importantly, we have reported the anti-allodynic and antihyperalgesic properties of zerumbone in a neuropathic pain mouse model (Zulazmi et al, 2015;Chia et al, 2016;Zulazmi et al, 2017).…”

Section: Introductionmentioning

confidence: 79%

“…We have previously demonstrated the antinociceptive properties of zerumbone in the chronic constriction injury neuropathic pain mice model and its mechanisms through serotoninergic (Chia et al, 2016) and the L-arginine-nitric oxide (Zulazmi et al, 2017) pathways. With this study, we now show that the noradrenergic system and excitatory receptors are crucial to zerumbone's anti-allodynic and antihyperalgesic properties.…”

Section: Resultsmentioning

confidence: 99%

“…The final concentration of DMSO did not exceed 5% of the total volume and caused no detectable effect on its own. Zerumbone was administered at 10 mg/kg through the intraperitoneal route based on our previous studies (Zulazmi et al, 2015;Chia et al, 2016;Zulazmi et al, 2017). The dosage of zerumbone (10 mg/kg) was chosen based on previous studies published by our colleagues Zulazmi et al (2015), where they found zerumbone at 10 mg/kg was sufficient to provide anti-allodynic and antihyperalgesic properties in the CCI-induced neuropathic pain mice model.…”

Section: Zerumbonementioning

confidence: 99%

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Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

et al. 2020

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the anti-allodynic and anti-hyperalgesic effects of zerumbone. b 1 -adrenoceptor antagonist only reversed the anti-allodynic effect of zerumbone. The anti-allodynic and anti-hyperalgesic effects of zerumbone were both absent when TRPV1 and NMDA receptors were antagonized in both nociceptive assays. Zerumbone treatment markedly decreased the expression of a 2Aadrenoceptor, while an up-regulation was observed of NMDA NR2B receptors. Expression of TRPV1 receptors however did not significantly change. The in vitro study, representing a peripheral model, demonstrated the reduction of both NMDA NR2B and TRPV1 receptors while significantly increasing a 2A -adrenoceptor expression in contrast to the brain samples. Our current findings suggest that the a 1 -, a 2 -, b 1 -and b 2 -adrenoceptors, TRPV1 and NMDA NR2B are essential for the anti-allodynic and antihyperalgesic effects of zerumbone. Alternatively, we demonstrated the plasticity of these receptors through their response to zerumbone's administration. Keywords: zerumbone, neuropathic pain, a 2A -adrenoceptor, TRPV1, NMDA NR2B, allodynia and hyperalgesia Chia et al. Zerumbone; a 2A -adrenergic, TRPV1 and NMDA NR2B Frontiers in Pharmacology | www.frontiersin.org March 2020 | Volume 11 | Article 92 Chia et al. Zerumbone; a 2A -adrenergic, TRPV1 and NMDA NR2B Frontiers in Pharmacology | www.frontiersin.org March 2020 | Volume 11 | Article 92 3

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Section: Introductionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Zerumbonementioning

confidence: 99%

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Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

et al. 2020

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“…It was stated that L-arginine administration causes nociceptive or inflammatory responses stimulated by hyperalgesia and bradykinin, substance P and dextran. 34 However, NO produced by L-arginine has the feature of inducing or reducing pain depending on the level of nociceptive system (peripheral, central), targeted tissue, animal pain model and concentration. 35 L-NAME, on the other hand, is a non-selective inhibitor of NOS isoforms and its administration reduces the production of NO.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Analgesic Effect and Possible Mechanisms of Ferulic Acid

Kaşik

Eken

Arslan

et al. 2019

Mersin Üniversitesi Tıp Fakültesi Lokman Hekim Tıp Tarihi Ve Folklorik Tıp Dergisi

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Ferulic acid is a bioactive phenolic compound that is found intensely in plants used in traditional medicine such as Ferula assafoetida 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/KATP 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 KATP 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 KATP channels and partially by cGMP.In conclusion, findings of this study demonstrate that ferulic acid may provide an advantage in KATP channel-targeted management of pain.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/KATP 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 KATP 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 belirle...

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“…51 Inwardly rectifying, ATP sensitive potassium (K-ATP) channels are widely expressed in numerous cell types including neurons and are linked to anti-allodynic and anti-hyperalgesic activity. ATP sensitive potassium channel agonist mediated antinociceptive effects are reversed with pre-treatment with ATP-sensitive K+ channel blockers 52,53 …”

Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic

Yekkirala

Yaksh

2017

Anesthesia &Amp; Analgesia

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Opioids Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management, has limitations and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of re-enforcing activity in the absence of a pain state. The present work provides a non-exclusive overview of current drug targets and potential future directions of research and development. We discuss channels activators and blockers, including: sodium channel blockers, potassium channel activators and calcium channel blockers; glutamate receptor targeted agents, including: NMDA, AMPA and metabotropic receptors). Further, we discuss therapeutics targeted at GABA, alpha2 adrenergic and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors, and agonists/antagonists of adenosine, purine receptors. And cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of drugable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising pre-clinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans’ targets, which should assist in developing non-addictive analgesics.

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Zerumbone Alleviates Neuropathic Pain through the Involvement of l-Arginine-Nitric Oxide-cGMP-K+ ATP Channel Pathways in Chronic Constriction Injury in Mice Model

Cited by 25 publications

References 72 publications

Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

Peripheral Analgesic Effect and Possible Mechanisms of Ferulic Acid

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

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