Kappa opioid receptor agonists improve postoperative cognitive dysfunction in rats via the JAK2/STAT3 signaling pathway

Li, Xi; Sun, Yingjie; Jin, Qiang; Song, Dandan; Diao, Yugang

doi:10.3892/ijmm.2019.4339

Cited by 16 publications

(18 citation statements)

References 34 publications

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“…There is increasing evidence showing that the JAK2/STAT3 signaling pathway is activated in AD, and the inhibition of this (n = 6 in each group). **P < 0.01 vs. control group; # P < 0.05 and ## P < 0.01 vs. model group signaling pathway can alleviate neuroinflammation in AD [25,60]. In this study, we observed that in comparison with the control group, the expressions of hippocampal p-JAK2-Tyr1007 and p-Tyr705-STAT3 were augmented extensively in APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 53%

“…Phosphorylated JAK2 promotes the activation of STAT3 at the Tyr705 site, which finally leads to neuroinflammation and apoptosis [ 57 – 59 ]. There is increasing evidence showing that the JAK2/STAT3 signaling pathway is activated in AD, and the inhibition of this signaling pathway can alleviate neuroinflammation in AD [ 25 , 60 ]. In this study, we observed that in comparison with the control group, the expressions of hippocampal p-JAK2-Tyr1007 and p-Tyr705-STAT3 were augmented extensively in APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 99%

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Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

Long

et al. 2021

Chin Med

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Background Suan-Zao-Ren Decoction (SZRD) has been widely used to treat neurological illnesses, including dementia, insomnia and depression. However, the mechanisms underlying SZRD’s improvement in cognitive function remain unclear. In this study, we examined SZRD’s effect on APP/PS1 transgenic mice and mechanisms associated with SZRD’s action in alleviating neuroinflammation and improving synaptic plasticity. Methods The APP/PS1 mice were treated with different dosages of SZRD (12.96 and 25.92 g/kg/day, in L-SZRD and H-SZRD groups, respectively) for 4 weeks. Morris water maze was conducted to determine changes in behaviors of the mice after the treatment. Meanwhile, in the samples of the hippocampus, Nissl staining and Golgi-Cox staining were used to detect synaptic plasticity. ELISA was applied to assess the expression levels of Aβ1−40 and Aβ1−42 in the hippocampus of mice. Western blot (WB) was employed to test the protein expression level of Aβ1−42, APP, ADAM10, BACE1, PS1, IDE, IBA1, GFAP, PSD95 and SYN, as well as the expressions of JAK2, STAT3 and their phosphorylation patterns to detect the involvement of JAK2/STAT3 pathway. Besides, we examined the serum and hippocampal contents of IL-1β, IL-6 and TNF-α through ELISA. Results Compared to the APP/PS1 mice without any treatment, SZRD, especially the L-SZRD, significantly ameliorated cognitive impairment of the APP/PS1 mice with decreases in the loss of neurons and Aβ plaque deposition as well as improvement of synaptic plasticity in the hippocampus (P < 0.05 or 0.01). Also, SZRD, in particular, the L-SZRD markedly inhibited the serum and hippocampal concentrations of IL-6, IL-1β and TNF-α, while reducing the expression of p-JAK2-Tyr1007 and p-STAT3-Tyr705 in the hippocampus of the APP/PS1 mice (P < 0.05 or 0.01). Conclusions The SZRD, especially the L-SZRD, may improve the cognitive impairment and ameliorate the neural degeneration in APP/PS1 transgenic mice through inhibiting Aβ accumulation and neuroinflammation via the JAK2/STAT3 pathway.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

Long

et al. 2021

Chin Med

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“…Following the activation of KOR receptors in stroke rats, injury inhibits glutamic acid release and NO production at the presynaptic membrane ( 43 ). Activation of KOR receptors also reduces neurotoxicity, improves the survival rate of damaged neurons, reduces neuronal apoptosis and the incidence of cerebral infarction and can reverse the memory impairment caused by CPB ( 44 ). Using the CPB rat model, the present study confirmed that oxidative stress served an important role in brain injury following CPB.…”

Section: Discussionmentioning

confidence: 99%

κ‑opioid receptor agonist U50488H attenuates postoperative cognitive dysfunction of cardiopulmonary bypass rats through the PI3K/AKT/Nrf2/HO‑1 pathway

Fan

et al. 2021

Mol Med Rep

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Postoperative cognitive dysfunction (POCD) is a common complication following cardiopulmonary bypass (CPB). U50488H, a κ-opioid receptor (KOR) agonist, can specifically activate KORs on hippocampal nerve cells, resulting in neuroprotective effects. The present study established a CPB rat model, observed the protective effect of U50488H on CPB-induced POCD and brain damage and explored the regulatory mechanism of the PI3K/AKT/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway. Sprague-Dawley rats were divided into the following groups: Sham operation (Sham group), CPB (CPB group), KOR agonist (U50488H) + CPB (U50488H group), CPB + U50488H + HO-1 antagonist (ZnPP-IX; ZnPP group) and CPB + U50488H + PI3K antagonist (LY294002; LY294002 group), with 10 rats in each group. Neurological scores and the Morris water maze test were used to evaluate cognitive function; hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed to observe hippocampal neuron damage in rats. Immunofluorescence was used to detect reactive oxygen species, glial fibrillary acidic protein and Nrf2 expression in the hippocampus. Enzyme-linked immunosorbent assays were used to detect inflammatory and oxidative stress factors. Western blotting was used to examine the expression of PI3K/AKT/Nrf2/HO-1-related proteins. It was demonstrated that U50488H significantly reduced the neural function score of rats with POCD induced by CPB, relieved cognitive dysfunction, reduced hippocampal neuron damage, inhibited the rate of apoptosis, repaired oxidative stress injury and protected against brain damage caused by CPB. In addition, U50488H could promote Nrf2 entry into the nucleus and upregulate HO-1 and thioredoxin 1 (Trx1) expression. In CPB rats treated with PI3K inhibitors, less Nrf2 was detected in the nucleus and HO-1 and Trx-1 expression levels were reduced in the nucleus. Therefore, U50488H, a KOR agonist, can activate Nrf2/HO-1 via the PI3K/AKT pathway to improve cognitive function and reduce brain damage in CPB rats.

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“…STAT3 is a key player in regulating inflammatory gene expression and glial reactivity in CNS to various insults and stimulations ( 42 ). Specifically, JAK2/STAT3 signaling pathway was involved in POCD in rat model by increasing their phosphorylation, and inhibiting the levels of p-JAK2 and p-STAT3 could attenuate the symptoms of POCD in rats ( 43 ). A study has shown that VLX possesses anti-inflammation property ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Venlafaxine Attenuated the Cognitive and Memory Deficit in Mice Exposed to Isoflurane Alone

Chun-hai

2021

Front. Neurol.

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Post-operative cognitive dysfunction (POCD) is a common complication during the post-operative period. It affects the recovery time of the patient after surgery and the stay time in hospital, which causes a great deal of burden to patients and families emotionally and financially. However, there is no specific and effective treatment available for this disorder. Recent study indicated exposure to general anesthetics contributed to POCD by triggering gamma-amino butyric acid type A (GABAA) receptors hyperactivities that persisted even the anesthetic compounds have been eliminated. Here, we investigated the antidepressant, venlafaxine (VLX), in a mouse model of POCD and studied whether VLX attenuated the cognitive dysfunction of mice exposed to general anesthetic, isoflurane (ISO). We found that ISO significantly induced an increased surface expression of the GABAA receptor subunit, α5, in the hippocampus of the mice. However, VLX treatment reduced the increase in α5 subunit expression. Meanwhile, we found the expression levels of interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), and IL-6 in the brains of mice exposed to ISO were significantly increased. However, VLX could prevent the increase in these cytokines. We also investigated the memory deficit of these mice by using a Y maze behavioral test. Mice with ISO exposure showed decreased alternation performance that could be prevented by the VLX treatment. Collectively, our results here are in line with the previous findings that α5 subunit plays an important role of the formation of POCD, but VLX may be a promising candidate compound for the treatment of POCD.

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Kappa opioid receptor agonists improve postoperative cognitive dysfunction in rats via the JAK2/STAT3 signaling pathway

Cited by 16 publications

References 34 publications

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

Suan-Zao-Ren Decoction ameliorates synaptic plasticity through inhibition of the Aβ deposition and JAK2/STAT3 signaling pathway in AD model of APP/PS1 transgenic mice

κ‑opioid receptor agonist U50488H attenuates postoperative cognitive dysfunction of cardiopulmonary bypass rats through the PI3K/AKT/Nrf2/HO‑1 pathway

Venlafaxine Attenuated the Cognitive and Memory Deficit in Mice Exposed to Isoflurane Alone

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