κ‑opioid receptor agonist, U50488H, inhibits pyroptosis through NLRP3 via the Ca<sup>2+</sup>/CaMKII/CREB signaling pathway and improves synaptic plasticity in APP/PS1 mice

Song, Xiaofu; Cui, Zhiqiang; He, Jianyong; Yang, Tuo; Sun, Xiaohong

doi:10.3892/mmr.2021.12168

Cited by 20 publications

(15 citation statements)

References 37 publications

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“…Pyroptosis-related proteins are highly expressed in the brains of APP/PS1 transgenic mice [ 37 ]. A β triggers neuroinflammation by activating the pyroptosis pathway, causing neuronal damage, which may be an important mechanism of AD pathogenesis.…”

Section: Resultsmentioning

confidence: 99%

Jiedu-Yizhi Formula Improves Cognitive Impairment in an Aβ25–35-Induced Rat Model of Alzheimer’s Disease by Inhibiting Pyroptosis

Wang

Zhu

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Jiedu-Yizhi formula (JDYZF) is prescribed for the treatment of Alzheimer’s disease (AD) and was created by Jixue Ren, a master of traditional Chinese medicine, based on the “marrow deficiency and toxin damage” theory. In our clinic, this formula has been used for the treatment of AD for many years and has achieved good results. However, the mechanism by which JDYZF improves cognitive impairment has not been determined. In this study, we confirmed that orally administered JDYZF reversed the cognitive deficits in an Aβ25–35-induced rat model, increased the number of neurons in the hippocampal CA1 area, improved their structure, decreased the deposition of β-amyloid (Aβ), reduced the expression of proteins related to the NLRP3/Caspase-1/GSDMD and LPS/Caspase-11/GSDMD pyroptosis pathways, and reduced the levels of interleukin 1β (IL-1β) and IL-18, thereby inhibiting the inflammatory response. In addition, JDYZF exerted no hepatotoxicity in rats. In short, these results provide scientific support for the clinical use of JDYZF to improve the cognitive function of patients with AD.

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Section: Resultsmentioning

confidence: 99%

Jiedu-Yizhi Formula Improves Cognitive Impairment in an Aβ25–35-Induced Rat Model of Alzheimer’s Disease by Inhibiting Pyroptosis

Wang

Zhu

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Also, elevated dynorphin levels were reported in postmortem samples of AD patients ( Ménard et al, 2014 ). A recent study by Song et al (2021) reported that U50,488, when administered in a mouse model of AD, promoted enhanced learning and memory in the Morris water maze test. In this study, (APP)/presenilin-1 (PS1) mice treated with U50,488 (1.25 mg/kg) showed a significant improvement in their cognitive abilities.…”

Section: Diseases For Which the Kappa-opioid Receptors Has Therapeuti...mentioning

confidence: 99%

“…In U50,488 treated APP/PS1 mice, amyloid-beta (Aβ) plaque deposition was decreased in the prefrontal cortex and hippocampus. Within this AD model there was reduced damage to hippocampal neurons, reduced microglia-induced pyroptosis, and improved synaptic plasticity which was partially mediated by inhibition of the Ca2+/CaMKII/CREB signalling pathway ( Song et al, 2021 ).…”

Section: Diseases For Which the Kappa-opioid Receptors Has Therapeuti...mentioning

confidence: 99%

“…In this review, we highlight research into the therapeutic potential of KOR agonists within key diseases including nociception ( Paton et al, 2017 ), pruritis ( Wang et al, 2021 ), multiple sclerosis (MS) ( Denny et al, 2021 ), Alzheimer’s disease (AD) ( Song et al, 2021 ), immune mediated diseases such as osteoarthritis ( Wilson et al, 1996 ), atopic dermatitis ( Nakasone et al, 2015 ), food allergy ( Duncker et al, 2012 ), gastrointestinal diseases ( Mangel et al, 2008 ), cancer ( Yamamizu et al, 2013 ), and hypoxia and ischemia ( Wu et al, 2021 ). We also review the pharmacological strategies being used to develop safer, more effective KOR agonists with limited associated side effects.…”

Section: Introductionmentioning

confidence: 99%

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The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

et al. 2022

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Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimer’s disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein–biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.

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“…5◊10 6 Hep3B cells were injected into the right axilla of 20 mice. The mice were randomly divided into four groups: PBS (control), U50488h (1.25 mg/kg) ( 21 ), oxycodone (0.307mg/kg/d for first 15 days and then 0.715 mg/kg/d, equivalent to the analgesic potency of morphine), and morphine (0.714 mg/kg/d for first 15 days and then 1.43 mg/kg/d) ( 22 ). PBS and drug treatments were started on day 5 (the tumor grew to about 30-60mm 3 ), intraperitoneally injected every two days.…”

Section: Methodsmentioning

confidence: 99%

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

Tan¹,

Wang²,

Cheng³

et al. 2022

Front. Oncol.

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Cancer pain is an important factor affecting life quality of patients especially in the advanced stage and relieving pain is one of fundamental strategies for cancer treatment. Opioids such as morphine are the most widely used in clinics. However, they have been reported to be associated with the occurrence and development of several types of cancer. Thus, search for an opioid that has analgesic effect and can retard cancer progress simultaneously is critical for cancer management. In this study, we first examined the expression of μ and κ (MOR and KOR) in cell lines and tumor tissues of hepatocellular carcinoma (HCC), a malignant tumor with high mortality, and then compared the effects of opioid receptors-specific agonists on malignant phenotypes of HCC cells in vitro and tumor growth in an HCC xenograft mouse model. KOR and MOR were found to be highly expressed in HCC cell lines and HCC tissues. The KOR-specific agonist U50488h, oxycodone (agonist for both KOR and MOR) and the MOR-specific agonist morphine inhibited HCC cell proliferation, while only U50488h and oxycodone suppressed colony formation and migration of HCC cells. U50488h and oxycodone, but not morphine, induced HCC apoptosis. Further detection of PERK, GRP78 and CHOP revealed that PERK signaling was upregulated by treatment with U50488h, while treatment with the PERK inhibitor GSK2656157 partially reversed the promotion of apoptosis and inhibition of cell proliferation by U50488h, indicating that endoplasmic reticulum stress is associated with its suppressing effect on HCC malignant phenotypes. Similar to the in vitro results, HCC growth was significantly reduced by administration of U50488h and oxycodone, but not by morphine, in the HCC xenograft mouse model. PERK and caspase-3 in the HCC tissues were up-regulated by U50488h treatment as detected by immunohistochemistry and western blotting. Taken together, our results revealed that activation of KOR by U50488h inhibited malignant phenotypes of HCC both in vitro and in vivo, while activation of MOR by morphine did not have such effect. Because of their dual roles in the relief of pain and in the suppression of malignant phenotypes, opioids such as U50488h that act on KOR should be considered as the first choice for HCC management.

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κ‑opioid receptor agonist, U50488H, inhibits pyroptosis through NLRP3 via the Ca²⁺/CaMKII/CREB signaling pathway and improves synaptic plasticity in APP/PS1 mice

Cited by 20 publications

References 37 publications

Jiedu-Yizhi Formula Improves Cognitive Impairment in an Aβ25–35-Induced Rat Model of Alzheimer’s Disease by Inhibiting Pyroptosis

Jiedu-Yizhi Formula Improves Cognitive Impairment in an Aβ25–35-Induced Rat Model of Alzheimer’s Disease by Inhibiting Pyroptosis

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

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κ‑opioid receptor agonist, U50488H, inhibits pyroptosis through NLRP3 via the Ca2+/CaMKII/CREB signaling pathway and improves synaptic plasticity in APP/PS1 mice

Cited by 20 publications

References 37 publications

Jiedu-Yizhi Formula Improves Cognitive Impairment in an Aβ25–35-Induced Rat Model of Alzheimer’s Disease by Inhibiting Pyroptosis

Jiedu-Yizhi Formula Improves Cognitive Impairment in an Aβ25–35-Induced Rat Model of Alzheimer’s Disease by Inhibiting Pyroptosis

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

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Product

Resources

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κ‑opioid receptor agonist, U50488H, inhibits pyroptosis through NLRP3 via the Ca²⁺/CaMKII/CREB signaling pathway and improves synaptic plasticity in APP/PS1 mice