Quercetin attenuates diabetic neuropathic pain by inhibiting mTOR/p70S6K pathway-mediated changes of synaptic morphology and synaptic protein levels in spinal dorsal horn of db/db mice

Wang, Ruiyao; Qiu, Zhuang; Wang, Guizhi; Hu, Qian; Shi, Naihao; Zhang, Zongqin; Wu, Yuqing; Zhou, Chenghua

doi:10.1016/j.ejphar.2020.173266

Cited by 30 publications

(18 citation statements)

References 58 publications

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“…Quercetin reduces pain arising from inflammation, cancer, chronic prostatitis/chronic pelvic pain syndrome, arthritis, and muscle injury by inhibiting the induction of oxidative stress and activating inflammatory and adrenergic pathways, neurotransmitters, and cytokines [327][328][329][330][331][332][333][334]. In addition, quercetin further modulates the activity of a variety of pathways, including Toll-like receptor, mTOR, protein kinase Cε (PKCε)-TRPV1, p70 ribosomal S6 kinase (p70S6K), and P2X 4 receptor signalings, as well as oxidative stress-and inflammation-associated mediators to exert its analgesic effects against diverse types of neuropathic pain [214,[335][336][337][338][339][340][341][342][343][344][345][346][347]. β-Sitosterol shows analgesic, antinociceptive, and anti-inflammatory activities [348][349][350][351][352][353].…”

Section: Discussionmentioning

confidence: 99%

An Investigation of the Molecular Mechanisms Underlying the Analgesic Effect of Jakyak‐Gamcho Decoction: A Network Pharmacology Study

Lee¹,

Kang

Park³

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Herbal drugs have drawn substantial interest as effective analgesic agents; however, their therapeutic mechanisms remain to be fully understood. To address this question, we performed a network pharmacology study to explore the system-level mechanisms that underlie the analgesic activity of Jakyak-Gamcho decoction (JGd; Shaoyao-Gancao-Tang in Chinese and Shakuyaku-Kanzo-To in Japanese), an herbal prescription consisting of Paeonia lactiflora Pallas and Glycyrrhiza uralensis Fischer. Based on comprehensive information regarding the pharmacological and chemical properties of the herbal constituents of JGd, we identified 57 active chemical compounds and their 70 pain-associated targets. The JGd targets were determined to be involved in the regulation of diverse biological activities as follows: calcium- and cytokine-mediated signalings, calcium ion concentration and homeostasis, cellular behaviors of muscle and neuronal cells, inflammatory response, and response to chemical, cytokine, drug, and oxidative stress. The targets were further enriched in various pain-associated signalings, including the PI3K-Akt, estrogen, ErbB, neurotrophin, neuroactive ligand-receptor interaction, HIF-1, serotonergic synapse, JAK-STAT, and cAMP pathways. Thus, these data provide a systematic basis to understand the molecular mechanisms underlying the analgesic activity of herbal drugs.

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Section: Discussionmentioning

confidence: 99%

An Investigation of the Molecular Mechanisms Underlying the Analgesic Effect of Jakyak‐Gamcho Decoction: A Network Pharmacology Study

Lee¹,

Kang

Park³

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…Recent studies have shown that the mammalian target of rapamycin (mTOR) signaling pathway plays an important role in the development and progression of chronic pain (Cho, Michailidis, & Martin, 2018; Li, Lu, Zhang, Zhou, & Zhang, 2015). The phosphorylation of mTOR and p70S6K in the spinal dorsal horn is increased in neuropathic pain models and administration of the mTOR inhibitor rapamycin effectively mitigates hyperalgesia in these models, in that context, QUER could alleviate neuropathic pain by inhibiting mTOR/p70S6K pathway‐mediated changes in synaptic morphology and synaptic function, as demonstrated in an experimental model of diabetic neuropathy (Wang et al, 2020). Another mechanism by which QUER generates a decrease in sensitivity in this work could be explained by its effect on the regulation of the P2X4 receptor (Yang et al, 2019), since the P2X4 receptor contributes to inflammatory pain and neuropathic pain (Cho et al, 2018; He et al, 2019; Wang et al, 2020) and studies have shown that peripheral nerve injury can increase the expression and activation of P2X4 in the DRG as a key factor in the initiation and sustained development of neuropathic pain (Yang et al, 2019; Ying et al, 2017).…”

Section: Discussionmentioning

confidence: 96%

“…Flavonoids are not only abundant in plants but are also important in the human diet. One of the best‐known flavonoids is quercetin (QUER), which has been shown to exert antinociceptive effects on experimental models of neuropathic pain (Ji et al, 2017; Wang et al, 2020; Yang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Sigma‐1 receptor antagonist (BD‐1063) potentiates the antinociceptive effect of quercetin in neuropathic pain induced by chronic constriction injury

Espinosa-Juárez

Jaramillo-Morales

Déciga-Campos

et al. 2020

Drug Development Research

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Neuropathic pain is characterized by the presence of hyperalgesia and allodynia. Pharmacological treatments include the use of antiepileptics such as pregabalin or gabapentin, as well as antidepressants; however, given the role of the sigma‐1 receptor in the generation and maintenance of pain, it has been suggested that sigma‐1 receptor antagonists may be effective. There are also other alternatives that have been explored, such as the use of flavonoids such as quercetin. Due to the relevance of drug combinations in therapeutics, the objective of this work was to evaluate the effect of the combination of BD‐1063 with quercetin in a chronic sciatic nerve constriction model using the “Surface of Synergistic Interaction” analysis method. The combination had preferable additive or synergistic effects, with BD‐1063 (17.8 mg/kg) + QUER (5.6 mg/kg) showing the best antinociceptive effects. The required doses were also lower than those used individually to obtain the same level of effect. Our results provide the first evidence that the combination of a sigma‐1 receptor antagonist and the flavonoid quercetin may be useful in the treatment of nociceptive behaviors associated with neuropathic pain, suggesting a new therapeutic alternative for this type of pain.

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“…In addition, quercetin alleviates diabetic neuropathic pain by inhibiting mTOR/p70S6K pathway-mediated changes of synaptic morphology and synaptic protein levels in spinal dorsal horn neurons. It also inhibits the peripheral and central sensitization of bone cancer pain by inhibiting the PAR2/TRPV1 signaling pathway [ 23 , 24 ]. Taxifolin inhibits the leukocyte infiltration and the expressions of COX-2 and iNOS in the brain with cerebral ischemic reperfusion injury, also prevents the expression of Mac-1 and ICAM-1, and inhibits the activity of NF- κ B [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Hong-Hui-Xiang Alleviates Pain Hypersensitivity in a Mouse Model of Monoarthritis

Gao

Wang

Yang

et al. 2020

Pain Research and Management

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Background. Hong-Hui-Xiang (HHX) is a sterilized aqueous solution extracted from Illicium lanceolatum A.C. Smith widely used for pain relief in China. Despite its history, it is not well understood. In the present study, we used a mouse model of arthritic knee pain to investigate the antinociceptive effects of HHX and its potential side effects on weight and respiratory function, as well as on the liver, kidney, and heart. Methods. Mice were randomly assigned to four groups: saline and HHX at three doses (1 μl, 10 μl, and 50 μl). Each group was randomly divided to two subgroups: saline and CFA. After the first injection of HHX or saline on day 7, mechanical hyperalgesia was tested via the hind paw. Only after the tests had established that the analgesic effect had subsided was the next injection administered. A total of five injections were administered. Blood, knee joints, and other organs were collected for histopathological observation and biochemical detection. Objectives. We found that mechanical threshold of hind paw increased 2 h after of the initial injection HHX (10 μl and 50 μl), which lasted for at least 3 h. The analgesic effect lasted for three days after the second injection on day 8 and was approximately maintained for five days each time after the third injection. We also found a reduction in the diameter of the knee joint and suppression of synovial inflammation in response to treatment of HHX (10 μl and 50 μl). Meanwhile, HHX had no toxic effects on the liver, kidneys, and heart via histological and biochemical assays in all groups. Conclusion. HHX exerts antinociceptive and anti-inflammatory effects in a mouse model of arthritic knee pain. There were no obvious side effects on the liver, kidneys, or heart.

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Quercetin attenuates diabetic neuropathic pain by inhibiting mTOR/p70S6K pathway-mediated changes of synaptic morphology and synaptic protein levels in spinal dorsal horn of db/db mice

Cited by 30 publications

References 58 publications

An Investigation of the Molecular Mechanisms Underlying the Analgesic Effect of Jakyak‐Gamcho Decoction: A Network Pharmacology Study

An Investigation of the Molecular Mechanisms Underlying the Analgesic Effect of Jakyak‐Gamcho Decoction: A Network Pharmacology Study

Sigma‐1 receptor antagonist (BD‐1063) potentiates the antinociceptive effect of quercetin in neuropathic pain induced by chronic constriction injury

Hong-Hui-Xiang Alleviates Pain Hypersensitivity in a Mouse Model of Monoarthritis

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