Morroniside, a secoiridoid glycoside from <scp><i>Cornus officinalis</i></scp><i>,</i> attenuates neuropathic pain by activation of spinal glucagon‐like peptide‐1 receptors

Xu, Meng; Wu, Haiyun; Líu, Hao; Gong, Nian; Wang, Yi-Rui; Wang, Yongxiang

doi:10.1111/bph.13720

Cited by 37 publications

(37 citation statements)

References 40 publications

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“…IL-10 has been considered the most important anti-inflammatory cytokine so far studied, and acts by binding to the IL-10 receptor-␣ followed by activation of IL-10 receptor-␤ localized on the cell membrane (Sabat et al, 2010;Glocker et al, 2011). Exogenous application of IL-10 exhibited antinociceptive activities in sciatic nerve chronic constriction injury-and paclitaxel-induced neuropathic pain, formalin-and CFA-induced inflammatory pain, bone cancer pain, and diabetic neuropathic pain (Milligan et al, 2005;Ledeboer et al, 2007;Zhou et al, 2008;Kim et al, 2011;Thakur et al, 2016). In the current study, multiple daily intrathecal injections of siRNA/IL-10 receptor-␣ progressively induced mechanical allodynia in the contralateral hindpaws, although it did not further attenuate the reduced withdrawal thresholds in the ipsilateral paws, which may be due to the ceiling effect.…”

Section: Discussionmentioning

confidence: 99%

“…Exenatide also showed neuroprotection in a mouse model of multiple sclerosis (Aharoni et al, 2011;Hölscher, 2012Hölscher, , 2014. In addition, we recently reported that activation of spinal GLP-1 receptors produced marked antinociception in a variety of rodent models of chronic pain, including neuropathic, inflammatory, bone cancer, and diabetic neuropathic pain (Gong et al, 2014a;Gong et al, 2014b;Zhu et al, 2014;Fan et al, 2015;Xu et al, 2017). Interestingly, GLP-1 receptor agonists have been in clinical trials to assess their neuroprotective effects on patients with Parkinson's disease (www.clinicaltrials.…”

Section: Introductionmentioning

confidence: 99%

“…IL-4 and particularly IL-10, two secretory cytokines, exhibited wide-ranging anti-inflammatory functions by inhibition of immune mediator release, antigen presentation, and phagocytosis (Sabat et al, 2010;Ul-Haq et al, 2016). They also exhibited marked neuroprotective and antinociceptive properties (Licinio and Wong, 1999;Vale et al, 2003). GLP-1 receptor agonists were also able to induce expression of these anti-inflammatory cytokines (IL-10 and IL-4) in peripheral macrophages (Shiraishi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…They also exhibited marked neuroprotective and antinociceptive properties (Licinio and Wong, 1999;Vale et al, 2003). GLP-1 receptor agonists were also able to induce expression of these anti-inflammatory cytokines (IL-10 and IL-4) in peripheral macrophages (Shiraishi et al, 2012). The herbal iridoid GLP-1 receptor agonist shanzhiside methylester (Zhu et al, 2014; upregulated the spinal IL-10 expression in neuropathic rats (Zheng et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial β-Endorphin Expression

Tang

Mao

et al. 2017

J. Neurosci.

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The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide stimulates microglial β-endorphin expression and subsequently produces neuroprotection and antinociception. This study illustrated an unrecognized autocrine role of IL-10 in mediation of exenatide-induced β-endorphin expression. Treatment with exenatide in cultured primary spinal microglia concentration dependently stimulated the expression of the M2 microglial markers IL-10, IL-4, Arg 1, and CD206, but not the M1 microglial markers TNF-α, IL-1β, IL-6, or CD68. Intrathecal exenatide injection also significantly upregulated spinal microglial expression of IL-10, IL-4, Arg 1, and CD206, but not TNF-α, IL-1β, IL-6, or CD68. Intrathecal injection of exenatide stimulated spinal microglial expression of IL-10 and β-endorphin in neuropathic rats. Furthermore, treatment with IL-10 (but not IL-4) stimulated β-endorphin expression in cultured primary microglia, whereas treatment with β-endorphin failed to increase IL-10 expression. The IL-10-neutralizing antibody entirely blocked exenatide-induced spinal microglial expression of β-endorphin and and fully blocked exenatide mechanical antiallodynia in neuropathic rats. Moreover, specific cAMP/PKA/p38 signal inhibitors and siRNA/p38β, but not siRNA/p38α, completely blocked exenatide-induced IL-10 expression in cultured primary microglia. Knock-down of IL-10 receptor-α mRNA using siRNA fully inhibited exenatide-induced spinal microglial β-endorphin expression and mechanical antiallodynia in neuropathy. Exenatide also markedly stimulated phosphorylation of the transcription factor STAT3 in cultured primary microglia and β-endorphin stimulation was completely inhibited by the specific STAT3 activation inhibitor. These results revealed that IL-10 in microglia mediated β-endorphin expression after GLP-1 receptor activation through the autocrine cAMP/PKA/p38β/CREB and subsequent IL-10 receptor/STAT3 signal pathways. Activation of GLP-1 receptors specifically and simultaneously stimulates the expression of anti-inflammatory cytokines IL-10 and IL-4, as well as the neuroprotective factor β-endorphin from microglia. GLP-1 receptor agonism induces β-endorphin expression and antinociception through autocrine release of IL-10. Activation of GLP-1 receptors stimulates IL-10 and β-endorphin expression subsequently through the Gs-cAMP/PKA/p38β/CREB and IL-10/IL-10 receptor-α/STAT3 signal transduction pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial β-Endorphin Expression

Tang

Mao

et al. 2017

J. Neurosci.

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“…Activation of GLP-1Rs in the central nervous system also mediates neuroprotection in preclinical animal models of neurodegenerative disorders, including Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, peripheral neuropathy, and ischemia and stroke (Kim et al, 2009;Harkavyi and Whitton, 2010;Hölscher, 2012;Hansen et al, 2015;Jia et al, 2015). Our laboratory also recently revealed that agonism of spinal GLP-1Rs by peptidic, nonpeptidic, and herbal iridoid agonists produced antinociception in a variety of rodent pain models of neuropathy, inflammation, bone cancers, and diabetes (Gong et al, 2014b;Zhu et al, 2014;Fan et al, 2015;Xu et al, 2017). The GLP-1R in pancreatic islet b cells evokes insulin synthesis during episodes of hyperglycemia (Baggio and Drucker, 2007;Lee and Jun, 2014).…”

Section: Introductionmentioning

confidence: 93%

p38βMitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglialβ-Endorphin Expression

Mao

Fan

et al. 2017

Mol Pharmacol

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Recent discoveries established that activation of glucagon-like peptide-1 receptors (GLP-1Rs) mediates neuroprotection and antinociception through microglial -endorphin expression. This study aimed to explore the underlying signaling mechanisms of microglial-endorphin. GLP-1Rs and -endorphin were coexpressed in primary cultures of microglia. Treatment with the GLP-1R agonist exenatide concentration-dependently stimulated microglial expression of the-endorphin precursor gene proopiomelanocortin (POMC) and peptides, with EC values of 4.1 and 7.5 nM, respectively. Exenatide also significantly increased intracellular cAMP levels and expression of -protein kinase A (PKA),-p38, and -cAMP response element binding protein (CREB) in cultured primary microglia. Furthermore, exenatide-induced microglial expression of POMC was completely blocked by reagents that specifically inhibit adenylyl cyclase and activation of PKA, p38, and CREB. In addition, knockdown of p38 (but not p38) using short interfering RNA (siRNA) eliminated exenatide-induced microglial p38 phosphorylation and POMC expression. In contrast, lipopolysaccharide increased microglial activation of p38, and knockdown of p38 (but not p38) partially suppressed expression of proinflammatory factors (including tumor necrosis factor-, interleukin-1, and interleukin-6). Exenatide-induced phosphorylation of p38 and CREB was also totally blocked by the PKA inhibitor and siRNA/p38, but not by siRNA/p38 Seven-day intrathecal injections of siRNA/p38 (but not siRNA/p38) completely blocked exenatide-induced spinal p38 activation, -endorphin expression, and mechanical antiallodynia in rats with established neuropathy, although siRNA/p38 and siRNA/p38 were not antiallodynic. To our knowledge, our results are the first to show a causal relationship between the PKA-dependent p38 mitogen-activated protein kinase/CREB signal cascade and GLP-1R agonism-mediated microglial -endorphin expression. The differential role of p38 and p38 activation in inflammation and nociception was also highlighted.

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Oral gavage delivery of Cornus officinalis extract delays type 1 diabetes onset and hyperglycemia in non‐obese diabetic (NOD) mice

Fletcher,

Olsson,

Zhang

et al. 2024

FEBS Open Bio

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Type 1 Diabetes (T1D) is an autoimmune disease initiated by genetic predisposition and environmental influences, which result in the specific destruction of insulin‐producing pancreatic β‐cells. Currently, there are over 1.6 million cases of T1D in the United States with a worldwide incidence rate that has been increasing since 1990. Here, we examined the effect of Cornus officinalis (CO), a well‐known ethnopharmacological agent, on a T1D model of the non‐obese diabetic (NOD) mouse. A measured dose of CO extract was delivered into 10 wk. old NOD mice by oral gavage for 15 weeks. T1D incidence and hyperglycemia were significantly lower in the CO‐treated group as compared to the water gavage (WT) and a no handling or treatment control group (NHT) following treatment. T1D onset per group was 30%, 60% and 86% for the CO, WT and NHT groups, respectively. Circulating C‐peptide was higher, and pancreatic insulitis was decreased in non‐T1D CO treated mice. Our findings suggest that CO may have therapeutic potential as both a safe and effective interventional agent to slow early stage T1D progression.

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Morroniside, a secoiridoid glycoside from Cornus officinalis, attenuates neuropathic pain by activation of spinal glucagon‐like peptide‐1 receptors

Abstract: Our data demonstrated that morroniside was an orthosteric agonist of GLP-1 receptors and produced antihypersensitivity in a neuropathic pain model by activation of spinal GLP-1 receptors.

Cited by 37 publications

References 40 publications

Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial β-Endorphin Expression

Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial β-Endorphin Expression

p38βMitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglialβ-Endorphin Expression

Oral gavage delivery of Cornus officinalis extract delays type 1 diabetes onset and hyperglycemia in non‐obese diabetic (NOD) mice

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