[6]-Shogaol Attenuates Oxaliplatin-Induced Allodynia through Serotonergic Receptors and GABA in the Spinal Cord in Mice

Kim, S.; Gang, Juan; Lee, Ji Hwan; Yang, Hyejin; Cheon, Chunhoo; Ko, Seong‐Gyu; Bae, Hyunsu; Kim, Woojin

doi:10.3390/ph15060726

Cited by 10 publications

(56 citation statements)

References 61 publications

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“…GABA is an inhibitory neurotransmitter in the central nervous system. Elevated concentrations of GABA inhibit pain, whereas reduced concentrations can induce neuropathic pain [ 113 ]. These studies have shown that 6-shogaol not only has good anti-cancer potential on its own but also has the advantage of being used in combination with chemotherapeutic agents to increase efficiency and reduce toxicity.…”

Section: Synergiesmentioning

confidence: 99%

Anticancer perspective of 6-shogaol: anticancer properties, mechanism of action, synergism and delivery system

Jia,

Li,

Meng

et al. 2023

Chin Med

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Cancer is a malignant disease that has plagued human beings all the time, but the treatment effect of commonly used anticancer drugs in clinical practice is not ideal by reason of their drug tolerance and Strong adverse reactions to patients. Therefore, it is imperative to find effective and low-toxic anticancer drugs. Many research works have shown that natural products in Chinese herbal medicine have great anticancer potential, such as 6-shogaol, a monomer composition obtained from Chinese herbal ginger, which has been confirmed by numerous in vitro or vivo studies to be an excellent anti-cancer active substance. In addition, most notably, 6-shogaol has different selectivity for normal and cancer cells during treatment, which makes it valuable for further research and clinical development. Therefore, this review focus on the anti-cancer attributes, the mechanism and the regulation of related signaling pathways of 6-shogaol. In addition, its synergy with commonly used anticancer drugs, potential drug delivery systems and prospects for future research are discussed. This is the first review to comprehensively summarize the anti-cancer mechanism of 6-shogaol, hoping to provide a theoretical basis and guiding significance for future anti-cancer research and clinical development of 6-shogaol. Graphical Abstract

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Section: Synergiesmentioning

confidence: 99%

Anticancer perspective of 6-shogaol: anticancer properties, mechanism of action, synergism and delivery system

Jia,

Li,

Meng

et al. 2023

Chin Med

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“…Previously, our laboratory focused on finding an optimal treatment to alleviate oxaliplatin-induced neuropathic pain [6][7][8][9]. As a potential candidate, Zingiber officinale Roscoe (Z. officinale) extract was suggested, as it could significantly alleviate cold and mechanical allodynia induced by oxaliplatin injection [7].…”

Section: Introductionmentioning

confidence: 99%

“…The major components of Z. officinale are known to be gingerol and shogaol. Thus, in our subsequent study, the effect of [6]-shogaol was assessed. We found that 10 mg/kg, but not 1 mg/kg, of [6]-shogaol could alleviate the cold and mechanical allodynia induced by oxaliplatin injections [6].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, in our subsequent study, the effect of [6]-shogaol was assessed. We found that 10 mg/kg, but not 1 mg/kg, of [6]-shogaol could alleviate the cold and mechanical allodynia induced by oxaliplatin injections [6]. In that study, the role of [6]-shogaol in modulating the spinal serotonergic system and gamma-aminobutyric acid (GABA) was demonstrated, but changes in serotonin levels and in the gene and protein expression of serotonergic receptors in the spinal cord were not investigated.…”

Section: Introductionmentioning

confidence: 99%

“…In that study, the role of [6]-shogaol in modulating the spinal serotonergic system and gamma-aminobutyric acid (GABA) was demonstrated, but changes in serotonin levels and in the gene and protein expression of serotonergic receptors in the spinal cord were not investigated. To date, only two studies have assessed the role of [6]-shogaol in pain [10,11]. In these studies, intraperitoneally administered [6]-shogaol decreased streptozotocin-induced heat and mechanical pain in mice.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of the Spinal Serotonergic System in the Analgesic Effect of [6]-Shogaol in Oxaliplatin-Induced Neuropathic Pain in Mice

Gang,

Park,

Kim

et al. 2023

Pharmaceuticals

Self Cite

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Oxaliplatin is a chemotherapy drug that can induce severe acute neuropathy in patients within hours of treatment. In our previous study, 10 mg/kg [6]-shogaol (i.p.) significantly alleviated cold and mechanical allodynia induced by a 6 mg/kg oxaliplatin injection (i.p.); however, the precise serotonin-modulatory effect has not been investigated. In this study, we showed that intrathecal injections of NAN-190 (5-HT1A receptor antagonist, 1 µg) and MDL-72222 (5-HT3 receptor antagonist, 15 µg), but not ketanserin (5-HT2A receptor antagonist, 1 µg), significantly blocked the analgesic effect of [6]-shogaol (10 mg/kg, i.p.). Furthermore, the gene expression of the serotonin-synthesizing enzyme tryptophan hydroxylase 2 (TPH2) and serotonin levels in the spinal cord and serum were significantly downregulated (p < 0.0001 and p = 0.0002) and upregulated (p = 0.0298 and p = 0.0099) after oxaliplatin and [6]-shogaol administration, respectively. Moreover, both the gene and protein expression of the spinal serotonin receptors 5-HT1A and 5-HT3 significantly increased after [6]-shogaol injections (p < 0.0001). Finally, intrathecal injections of both receptor agonists (8-OH-DPAT; 5-HT1A receptor agonist, 10 µg and m-CPBG; 5-HT3 receptor agonist, 15 µg) mimicked the effects of [6]-shogaol in oxaliplatin-injected mice. Taken together, these results demonstrate that [6]-shogaol attenuates oxaliplatin-induced neuropathic pain by modulating the spinal serotoninergic system.

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Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies

Famurewa,

Akhigbe,

George

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient’s quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that ferroptosis, a non-apoptotic, iron-dependent cell death pathway, is also involved in the pathophysiology of CT organ toxicity. CT provokes organ ferroptosis via system Xc–/GPX-4/GSH/SLC7A11 axis depletion, ferritinophagy, iron overload, lipid peroxidation and upregulation of ferritin-related proteins. Cisplatin (CP) and doxorubicin (DOX) are common CT drugs indicated to induce ferroptosis in vitro and in vivo. Studies have explored natural preventive and therapeutic strategies using ginger rhizome and its major bioactive compounds, 6-gingerol (6G) and zingerone (ZG), to combat mechanisms of CT side effect toxicity. Ginger extract, 6G and ZG mitigate non-ferroptotic oxidative inflammation, apoptosis and mitochondrial dysfunction mechanisms of CT side effect toxicity, but their effects on CT-induced ferroptosis remain unclear. Systematic investigations are, therefore, needed to unfold the roles of ginger, 6G and ZG on ferroptosis involved in CT side effect toxicity, as they are potential natural agents for the prevention of CT toxicity. This review reveals the ferroptotic and non-ferroptotic toxicity mechanisms of CT and the protective mechanisms of ginger, 6G and ZG against CT-induced, ferroptotic and non-ferroptotic organ toxicities.

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[6]-Shogaol Attenuates Oxaliplatin-Induced Allodynia through Serotonergic Receptors and GABA in the Spinal Cord in Mice

Cited by 10 publications

References 61 publications

Anticancer perspective of 6-shogaol: anticancer properties, mechanism of action, synergism and delivery system

Anticancer perspective of 6-shogaol: anticancer properties, mechanism of action, synergism and delivery system

Involvement of the Spinal Serotonergic System in the Analgesic Effect of [6]-Shogaol in Oxaliplatin-Induced Neuropathic Pain in Mice

Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies

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