Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal proinflammatory cytokines

Hu, Song; Mao-Ying, Qi-Liang; Wang, Jun; Wang, Zhifu; Mi, Wen-Li; Wang, Xiaowei; Jiang, Jinju; Huang, Ya-Lin; Wu, Gen-Cheng; Wang, Yanqing

doi:10.1186/1742-2094-9-278

Cited by 56 publications

(53 citation statements)

References 43 publications

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“…MAPK pathways mediate chemokine-cytokine networks in the spinal cord of bone cancer pain rats Proinflammatory cytokines, such as TNF-a, IL-1b, and 6, are mainly produced by spinal glia, and lead to pain-related neuroinflammation (Hu et al 2012;Hui et al 2013). It has been validated that MAPKs are involvement in regulating the activity of proinflammatory cytokines in spinal glia, and act as essential downstream of CXCL12/CXCR4 signaling, as described above.…”

Section: R E T R a C T E Dmentioning

confidence: 95%

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Liu

Zhang

et al. 2015

Journal of Neurochemistry

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The activation of MAPK pathways in spinal cord and subsequent production of proinflammatory cytokines in glial cells contribute to the development of spinal central sensitization, the basic mechanism underlying bone cancer pain (BCP). Our previous study showed that spinal CXCL12 from astrocytes mediates BCP generation by binding to CXCR4 in both astrocyters and microglia. Here, we verified that CXCL12/CXCR4 signaling contributed to BCP through a MAPK-mediated mechanism. In na€ ıve rats, a single intrathecal administration of CXCL12 considerably induced pain hyperalgesia and phosphorylation expression of spinal MAPK members (including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase), which could be partially prevented by pre-treatment with CXCR4 inhibitor AMD3100. This CXCL12-induced hyperalgesia was also reduced by MAPK inhibitors. In bone cancer rats, tumor cell inoculation into the tibial cavity caused prominent and persistent pain hyperalgesia, and associated with up-regulation of CXCL12 and CXCR4, activation of glial cells, phosphorylation of MAPKs, and production of proinflammatory cytokines in the spinal cord. These tumor cell inoculation-induced behavioral and neurochemical alterations were all suppressed by blocking CXCL12/CXCR4 signaling or MAPK pathways. Taken together, these results demonstrate that spinal MAPK pathways mediated CXCL12/CXCR4-induced pain hypersensitivity in bone cancer rats, which could be druggable targets for alleviating BCP and glia-derived neuroinflammation. Keywords: astrocytes, bone cancer pain, chemokine, mitogenactivated protein kinase, microglia, neuroinflammation. Bone cancer pain (BCP) caused by primary tumors or bone metastases is the most common source of moderate and severe cancer pain, which not only makes patients less confident to receive therapeutic plan but also discourages tumor-burdened people from desiring to live (Knopp et al. 2011). With effective treatment strategies depending on a better understanding of BCP, intensive studies of underlying pathogenic mechanisms of BCP and development of novel analgesic targets are highly anticipated in the basic and clinical research communities.Following local inoculation of primary or metastatic bone tumor in the bone microenvironment, cellular and neurochemical alterations take place abundantly in the spinal cord, triggering hyperalgesic behaviors (Medhurst et al. 2002). In this complex pathophysiologic process, glial cells (especially astrocytes and microglia) react and release various proinflammatory cytokines, including tumor necrosis factor a (TNF-a), interleukin 1b (IL-1b) and IL-6, which enhance central sensitization and thus evoking pain hypersensitivity (Falk and Dickenson 2014). Indeed, inhibiting functional activation of astrocytes and microglia at the spinal level is sufficient to suppress BCP and these glia-derived mediators Moreover, numerous studies have shown that all three MAPK members are prone to be phosphorylated following the activation of certain GPCRs, especially che...

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Section: R E T R a C T E Dmentioning

confidence: 95%

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Liu

Zhang

et al. 2015

Journal of Neurochemistry

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“…38 Ticagrelor increased myocardial levels of 15-epi-lipoxin A 4 , an eicosanoid mediator with potent anti-inflammation effects, 15 that has been shown to inhibit TNFα and IL1β secretion and to attenuate the effects of TNFα. [39][40][41] Future studies are needed to explore whether the effects of ticagrelor on the expression of the proinflammatory mediators are dependent on the upregulation of 15-epi-lipoxin A 4 levels. As the synthesis of 15-epilipoxin A 4 is dependent on COX2, these anti-inflammatory effects of ticagrelor might be COX2 dependent and could be potentially inhibited by high-dose aspirin.…”

Section: Discussionmentioning

confidence: 99%

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Ye¹,

Birnbaum

Perez‐Polo

et al. 2015

ATVB

107

111

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Objective-In addition to P2Y 12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function. Approach and Results-Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks.(1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%±1.8%; P<0.001) and 30 mg/ kg (21.4%±2.6%; P<0.001) versus control (45.3±1.7%), whereas clopidogrel had no effect (42.4%±2.6%). Ticagrelor, but not clopidogrel, increased myocardial adenosine levels, increased phosphorylation of Akt, endothelial NO synthase, and extracellular-signal-regulated kinase 1/2 4 hours after reperfusion and decreased apoptosis. (2) After 4 weeks, left ventricular ejection fraction was reduced in the vehicle-treated group (44.8%±3.5%) versus sham (77.6%±0.9%).All ticagrelor treatments improved left ventricular ejection fraction, acute (69.5%±1.6%), chronic (69.2%±1.0%), and acute+chronic (76.3%±1.2%), whereas clopidogrel had no effect (37.4%±3.7%). Ticagrelor, but not clopidogrel, attenuated fibrosis and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor, but not clopidogrel, attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1β, and interleukin-18, and increased anti-inflammatory 15-epi-lipoxin-A 4 levels. Conclusions-Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect. addition to platelet inhibition, ticagrelor, but not clopidogrel, has protective effects against ischemia-reperfusion that may help explain the differences in clinical benefit in the PLATO trial. 7,8 However, a recent multicenter, randomized, double-blind clinical trial did not show a clear clinical benefit in patients with STEMI receiving ticagrelor en route to the hospital versus in the catheterization laboratory. 16 As the study was not powered for benefit on cardiovascular events, it is inconclusive about the hypothesis that administration of ticagrelor after onset of ischemia (in contrast to pretreatment just before reperfusion) can ameliorate reperfusion injury. In addition, as the median time difference between the prehospital and the in-hospital ticagrelor administration groups was only 31 minutes, 16 it is plausible that ticagrelor absorption was insufficient an...

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“…Hence, neuroinflammation is an important pathogenic characteristic of this model (Hu S. et al, 2012; Song et al, 2015). …”

Section: Nature Of Pain Manifestationmentioning

confidence: 99%

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

et al. 2016

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The majority of patients with terminal breast cancer show signs of bone metastasis, the most common cause of pain in cancer. Clinically available drug treatment options for the relief of cancer-associated bone pain are limited due to either inadequate pain relief and/or dose-limiting side-effects. One of the major hurdles in understanding the mechanism by which breast cancer causes pain after metastasis to the bones is the lack of suitable preclinical models. Until the late twentieth century, all animal models of cancer induced bone pain involved systemic injection of cancer cells into animals, which caused severe deterioration of animal health due to widespread metastasis. In this mini-review we have discussed details of a recently developed and highly efficient preclinical model of breast cancer induced bone pain: Walker 256 cancer cell- induced bone pain in rats. The model involves direct localized injection of cancer cells into a single tibia in rats, which avoids widespread metastasis of cancer cells and hence animals maintain good health throughout the experimental period. This model closely mimics the human pathophysiology of breast cancer induced bone pain and has great potential to aid in the process of drug discovery for treating this intractable pain condition.

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Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal proinflammatory cytokines

Cited by 56 publications

References 43 publications

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Retracted: CXCL12/CXCR4 chemokine signaling in spinal glia induces pain hypersensitivity through MAPKs‐mediated neuroinflammation in bone cancer rats

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

The Walker 256 Breast Cancer Cell- Induced Bone Pain Model in Rats

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