PGC-1α activation ameliorates cancer-induced bone pain via inhibiting apoptosis of GABAergic interneurons.

Cancer-induced bone pain (CIBP) stands out as one of the most challenging issues in clinical practice due to its intricate and not fully elucidated pathophysiological mechanisms. Existing evidence has pointed toward the significance of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) down-regulation in contributing to pain behaviors in various rodent models of neuropathic pain. In our current study, we aimed to investigate the role of PGC-1α in CIBP. Our results unveiled a reduction in PGC-1α expression within the spinal cord of CIBP rats, particularly in GABAergic interneurons. Notably, intrathecal administration of the PGC-1α activator ZLN005 suppressed the loss of spinal GABAergic interneurons. This suppression was achieved by inhibiting caspase-3-mediated apoptosis, ultimately leading to the alleviation of mechanical allodynia in CIBP rats. Further exploration into the mechanism revealed that PGC-1α activation played a pivotal role in mitigating ATP depletion and reactive oxygen species accumulation linked to mitochondrial dysfunction. This was achieved through the restoration of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. Impressively, the observed effects were prominently reversed upon the application of SR18292, a specific PGC-1α inhibitor. In conclusion, our findings strongly suggest that PGC-1α activation acts as a potent inhibitor of apoptosis in spinal GABAergic interneurons. This inhibition is mediated by the improvement of mitochondrial function, facilitated in part through the enhancement of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. The results of our study shed light on potential therapeutic avenues for addressing CIBP.

Targeting α7 nicotinic acetylcholine receptors for chronic pain.

Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

Dysfunction of the Brain-derived Neurotrophic Factor-Tyrosine Kinase B Signaling Pathway Contributes to Learning and Memory Impairments Induced by Neuroinflammation in Mice.

Accumulating evidence suggests that neuroinflammation is the main mechanism in cognitive dysfunction and that brain-derived neurotrophic factor (BDNF) is involved in learning and memory by binding to tyrosine kinase B (TrkB) receptors. Herein, we tested the roles of the BDNF-TrkB signaling pathway and its downstream cascade in lipopolysaccharide (LPS) induced cognitive dysfunction in mice. Mice were treated with LPS (0.25 mg/kg) for 7 days, and learning and memory function was evaluated by the novel object recognition test (NORT). Western blotting was performed to elucidate roles of the BDNF-TrkB signaling pathway and its downstream cascades in LPS mice. The NORT showed that LPS induced learning and memory deficits in mice. The levels of IL-1ß, IL-6, and TNF-α in the serum and central nervous system decreased in LPS mice. In addition, LPS reduced the protein levels of BDNF, p-TrkB, Bcl-2, p-ERK1/2, p-CaMK2, p-CREB and p-GluR1 and increased the expression of Bax in the hippocampus and medial prefrontal cortex regions. In the entorhinal cortex, the protein levels of BDNF, p-TrkB, Bcl-2, p-CaMK2 and p-CREB were decreased, and the protein level of Bax was increased in LPS mice. Interestingly, 7,8-DHF alleviated these disorders in LPS mice and improved learning and memory function; however, the TrkB antagonist ANA12 effectively reversed effects of 7,8-DHF. Therefore, we conclude that the BDNF-TrkB signaling pathway and its downstream cascades disorders in different regions are main mechanisms of cognitive dysfunction, and 7,8-DHF maybe useful as a new treatment for preventing or treating cognitive dysfunction induced by neuroinflammation in neurodegenerative diseases.

The Emerging Role of Quercetin in the Treatment of Chronic Pain.

Despite much research efforts being devoted to designing alternative pharmacological interventions, chronic pain remains to be an unresolved clinical problem. Quercetin, a compound that belongs to the flavonoids family, is abundantly found in fruits and vegetables. Emerging evidence indicates that quercetin possesses anti-nociceptive effects in different rodent models of chronic pain, including inflammatory pain, neuropathic pain and cancer pain. In this review, we summarize the mechanisms underlying the analgesic effect of quercetin in preclinical studies. These studies showed that quercetin exerts potent analgesic effects against chronic pain via suppressing neuroinflammation and oxidative stress as well as modulation of synaptic plasticity, GABAergic system, and opioidergic system. Considering that the safety of quercetin is well established, it has great potential for clinical use in pain treatment.

Naringenin promoted spinal microglia M2 polarization in rat model of cancer-induced bone pain via regulating AMPK/PGC-1α signaling axis.

Cancer-induced bone pain (CIBP) treatment remains a clinical challenge because the pathophysiological mechanisms are not fully understood. Recently, it was verified that shifting microglial polarization toward the M2 phenotype reveals a potential strategy for CIBP treatment. Naringenin, a natural flavone flavonoid, has been reported to have antioxidant, anti-inflammatory and neuroprotective properties. However, the role of naringenin on regulating microglial polarization in CIBP rats and the molecular mechanisms participating in this process have not been fully clarified. Herein, we investigated the potential effect of naringenin on M1/M2 microglial polarization and further explored the potential mechanisms of this action. Our study demonstrated that intraperitoneal administration of naringenin could upregulate the antioxidative molecule glutathione peroxidase 4 (GPx4) level in the spinal cord, as well as bone cancer-induced mechanical allodynia in rats. Moreover, naringenin treatment also suppressed microglia-mediated neuroinflammation by downregulating the phosphorylation of nuclear factor κB (NF-κB) p65 expression and promoting microglial polarization toward the M2 phenotype in CIBP rats. The promoting effects mediated by naringenin on M1/M2 microglial polarization are dependent on the serine/threonine protein kinase adenosine monophosphate-activated protein kinase (AMPK)/proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling pathway. Inhibition of AMPK activation with the classical AMPK inhibitor Compound C attenuated this effect of naringenin. These results improved the understanding of the anti-inflammatory property of naringenin on microglial polarization, which might provide new alternative avenues for CIBP treatment.

Galectin-3 in Microglia-Mediated Neuroinflammation: Implications for Central Nervous System Diseases.

Microglial activation is one of the common hallmarks shared by various central nervous system (CNS) diseases. Based on surrounding circumstances, activated microglia play either detrimental or neuroprotective effects. Galectin-3 (Gal-3), a group of ß-galactoside-binding proteins, has been cumulatively revealed to be a crucial biomarker for microglial activation after injuries or diseases. In consideration of the important role of Gal-3 in the regulation of microglial activation, it might be a potential target for the treatment of CNS diseases. Recently, Gal-3 expression has been extensively investigated in numerous pathological processes as a mediator of neuroinflammation, as well as in cell proliferation. However, the underlying mechanisms of Gal-3 involved in microgliamediated neuroinflammation in various CNS diseases remain to be further investigated. Moreover, several clinical studies support that the levels of Gal-3 are increased in the serum or cerebrospinal fluid of patients with CNS diseases. Thus, we summarized the roles and underlying mechanisms of Gal-3 in activated microglia, thus providing a better insight into its complexity expression pattern, and contrasting functions in CNS diseases.

Wnt signaling: A prospective therapeutic target for chronic pain.

Despite the rapid advance over the past decades to design effective therapeutic pharmacological interventions, chronic pain remains to be an unresolved healthcare concern. Long term use of opioids, the first line analgesics, often causes detrimental side effects. Therefore, a profound understanding of the mechanisms underlying the development and maintenance of chronic pain states is urgently needed for the management of chronic pain. Substantial evidence indicates aberrant activation of Wnt signaling pathways in sciatic nerve, dorsal root ganglia and spinal cord dorsal horn in rodent models of chronic pain. Moreover, growing evidence shows that pharmacological blockage of aberrant activation of Wnt signaling pathways attenuates pain behaviors in animal models of chronic pain. Importantly, both intrathecal injection of Wnt agonists and Wnt ligands to naïve rats lead to the development of mechanical allodynia, which was inhibited by Wnt inhibitors. In this review, we summarized and discussed the therapeutic potential of pharmacological inhibitors of Wnt signaling in chronic pain in preclinical studies. These evidence showed that aberrant activation of Wnt signaling pathways contributed to chronic pain via enhancing neuroinflammation, regulating synaptic plasticity and reducing intraepidermal nerve fiber density. However, these findings raise further questions. Overall, despite the future challenges, these pioneering studies suggest that Wnt signaling is a promising therapeutic target for chronic pain.

ß2-adrenoreceptor agonist ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain via induction of mitochondrial biogenesis.

Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment and so far no effective drug is available for treatment of the serious side effect. Previous studies have demonstrated ß2-adrenoreceptor (ADRB2) agonists can attenuate neuropathic pain. However, the role of ADRB2 in paclitaxel -induced neuropathic pain (PINP) remains unclear. In this study, we investigated the effect of formoterol, a long-acting ADRB2 agonist, and related mechanisms in PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to evaluate mechanical allodynia. Western blot was used to examine the expression of ADRB2, peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), nuclear respiratory factors 1 (NRF1) and mitochondrial transcription factor A (TFAM) and the immunofluorescence was to detect the cellular localization of ADRB2 and PGC-1α in the spinal cord. Moreover, we measured mitochondrial DNA (mtDNA) copy number by qPCR. In our study, formoterol attenuated established PINP and delayed the onset of PINP. Formoterol restored ADRB2 expression as well as mtDNA copy number and PGC-1α, NRF1, and TFAM protein expression, which are major genes involved in mitochondrial biogenesis, in the spinal cord of PINP rats. Moreover, we found the analgesic effect of formoterol against PINP was partially abolished by PGC-1α inhibitor SR-18292. Collectively, these results demonstrated the activation of ADRB2 with formoterol ameliorates PINP at least partially through induction of mitochondrial biogenesis.

The Role of the GABAergic System in Diseases of the Central Nervous System.

It is well known that the central nervous system (CNS) is a complex neuronal network and its function depends on the balance between excitatory and inhibitory neurons. Disruption of the excitatory/inhibitory (E/I) balance is the main cause for the majority of the CNS diseases. In this review, we will discuss roles of the inhibitory system in the CNS diseases. The GABAergic system as the main inhibitory system, is essential for the appropriate functioning of the CNS, especially as it is engaged in the formation of learning and memory. Many researchers have reported that the GABAergic system is involved in regulating synaptic plasticity, cognition and long-term potentiation. Some clinical manifestations (such as cognitive dysfunctions, attention deficits, etc.) have also been shown to emerge after abnormalities in the GABAergic system accompanied with concomitant diseases, that include Alzheimer's disease (AD), Parkinson's disease (PD), Autism spectrum disorder (ASD), Schizophrenia, etc. The GABAergic system consists of GABA, GABA transporters, GABAergic receptors and GABAergic neurons. Changes in any of these components may contribute to the dysfunctions of the CNS. In this review, we will synthesize studies which demonstrate how the GABAergic system participates in the pathogenesis of the CNS disorders, which may provide a new idea that might be used to treat the CNS diseases.

Nox2 contributes to reactive oxygen species-induced redox imbalance in cancer-induced bone pain.

We have recently demonstrated that reactive oxygen species (ROS) scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain (CIBP). In the present study, we investigated anti-nociceptive effect of Nox inhibitor apocynin in CIBP in rats. Mechanical allodynia was assessed by Von Frey tests in sham and CIBP group of rats. Western blotting and immunofluorescence technique were conducted to assess the expression levels and cellular localization of Nox2. Results illustrated that after intra-tibial implantation with tumor cells, Nox2 and ROS were both up-regulated in the spinal cord of rats. Injection of apocynin could dose-dependently decrease the abundance of Nox2 and inhibit the development of CIBP. Furthermore, pretreatment with the apocynin could delay the development of CIBP. This study for the first time proved that Nox2 inhibitors could downregulate the production of ROS in CIBP rats, which highlights the fact that Nox inhibitor is an important therapeutic option for CIBP and that, precise targeting inhibitor of different subtypes of Nox enzymes is needed to developed in future.

The therapeutic potential of Nrf2 inducers in chronic pain: Evidence from preclinical studies.

Chronic pain remains an enormous health problem affecting approximatively 30% of the world's population. Opioids as the first line analgesics often leads to undesirable side effects when used long term. Therefore, novel therapeutic targets are urgently needed to the development of more efficacious analgesics. Substantial evidence indicates that excessive reactive oxygen species (ROS) are extremely important to the development of chronic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor regulating endogenous antioxidant defense. Emerging evidence suggests that Nrf2 and its downstream effectors are implicated in chronic inflammatory and neuropathic pain. Notably, controversial results have been reported regarding the expression of Nrf2 and its downstream targets in peripheral and central regions involved in pain transmission. However, our recent studies and results from other laboratories demonstrate that Nrf2 inducers exert potent analgesic effects in various murine models of chronic pain. In this review, we summarized and discussed the preclinical evidence demonstrating the therapeutic potential of Nrf2 inducers in chronic pain. These evidence indicates that Nrf2 activation are beneficial in chronic pain mostly by alleviating ROS-associated pathological processes. Overall, Nrf2-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

Development and Validation of a Nomogram for Assessing Survival in Patients With COVID-19 Pneumonia.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has spread worldwide and continues to threaten peoples' health as well as put pressure on the accessibility of medical systems. Early prediction of survival of hospitalized patients will help in the clinical management of COVID-19, but a prediction model that is reliable and valid is still lacking. METHODS: We retrospectively enrolled 628 confirmed cases of COVID-19 using positive RT-PCR tests for SARS-CoV-2 in Tongji Hospital, Wuhan, China. These patients were randomly grouped into a training (60%) and a validation (40%) cohort. In the training cohort, LASSO regression analysis and multivariate Cox regression analysis were utilized to identify prognostic factors for in-hospital survival of patients with COVID-19. A nomogram based on the 3 variables was built for clinical use. AUCs, concordance indexes (C-index), and calibration curves were used to evaluate the efficiency of the nomogram in both training and validation cohorts. RESULTS: Hypertension, higher neutrophil-to-lymphocyte ratio, and increased NT-proBNP values were found to be significantly associated with poorer prognosis in hospitalized patients with COVID-19. The 3 predictors were further used to build a prediction nomogram. The C-indexes of the nomogram in the training and validation cohorts were 0.901 and 0.892, respectively. The AUC in the training cohort was 0.922 for 14-day and 0.919 for 21-day probability of in-hospital survival, while in the validation cohort this was 0.922 and 0.881, respectively. Moreover, the calibration curve for 14- and 21-day survival also showed high coherence between the predicted and actual probability of survival. CONCLUSIONS: We built a predictive model and constructed a nomogram for predicting in-hospital survival of patients with COVID-19. This model has good performance and might be utilized clinically in management of COVID-19.

Disruption of the GABAergic system contributes to the development of perioperative neurocognitive disorders after anesthesia and surgery in aged mice.

AIMS: Perioperative neurocognitive disorders (PND) are associated with cognitive impairment in the preoperative or postoperative period, and neuroinflammation is thought to be the most important mechanisms especially during the postoperative period. The GABAergic system is easily disrupted by neuroinflammation. This study investigated the impact of the GABAergic system on PND after anesthesia and surgery. METHODS: An animal model of laparotomy with inhalation anesthesia in 16-month-old mice was addressed. Effects of the GABAergic system were assessed using biochemical analysis. Pharmacological blocking of α5GABAA Rs or P38 mitogen-activated protein kinase (MAPK) were applied to investigate the effects of the GABAergic system. RESULTS: After laparotomy, the hippocampus-dependent memory and long-term potentiation were impaired, the levels of IL-6, IL-1ß and TNF-α up-regulated in the hippocampus, the concentration of GABA decreased, and the protein levels of the surface α5GABAA Rs up-regulated. Pharmacological blocking of α5GABAA Rs with L655,708 alleviated laparotomy induced cognitive deficits. Further studies found that the P38 MAPK signaling pathway was involved and pharmacological blocking with SB203,580 alleviated memory dysfunctions. CONCLUSIONS: Anesthesia and surgery caused neuroinflammation in the hippocampus, which consequently disrupted the GABAergic system, increased the expressions of surface α5GABAA Rs especially through the P38 MAPK signaling pathway, and eventually led to hippocampus-dependent memory dysfunctions.

PPARγ activation mitigates mechanical allodynia in paclitaxel-induced neuropathic pain via induction of Nrf2/HO-1 signaling pathway.

Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect and is refractory to widely used analgesic drugs. Previous studies have demonstrated a protective role of peroxisome proliferator-activated receptor gama (PPARγ) in neuropathic pain. However, whether PPARγ activation could alleviate PINP remains to be elucidated. Our previous study has validated the analgesic effect of oltipraz, an nuclear factor erythroid-2 related factor 2 (Nrf2) activator, in a rat model of PINP. In this study, we tested the hypothesis that rosiglitazone, a selective agonist of PPARγ, could attenuate PINP through induction of Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Paclitaxel was injected intraperitoneally on four alternate days to induce neuropathic pain. Paw withdrawal threshold was used to evaluate mechanical allodynia. Western blot and immunofluorescence were used to examine the expression and distribution of PPARγ, Nrf2 and HO-1 in the spinal cord. Our results showed that rosiglitazone attenuated established PINP and delayed the onset of PINP via activation of PPARγ, which were reversed by PPARγ antagonist GW9662. Moreover, rosiglitazone inhibited downregulation of PPARγ in the spinal cord of PINP rats. Furthermore, the analgesic effect of rosiglitazone against PINP was abolished by trigonelline, an Nrf2 inhibitor. Finally, rosiglitazone significantly increased expression of Nrf2 and HO-1 in the spinal cord of PINP rats. Collectively, these results indicated that PPARγ activation might mitigate PINP through activating spinal Nrf2/HO-1 signaling pathway. Our results may provide an alternative option for PINP patients.

Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain.

Paclitaxel-induced neuropathic pain (PINP) is refractory to currently used analgesics. Previous studies show a pivotal role of oxidative stress in PINP. Because the nuclear factor erythroid-2-related factor 2 (Nrf2) has been considered as the critical regulator of endogenous antioxidant defense, we here explored whether activation of Nrf2 could attenuate PINP. A rat model of PINP was established by intraperitoneal injection of paclitaxel (2 mg/kg) every other day with a final cumulative dose of 8 mg/kg. Hind paw withdrawal thresholds (PWTs) in response to von Frey filament stimuli were used to assess mechanical allodynia. We showed that a single dose of Nrf2 activator, oltipraz (10, 50, and 100 mg/kg), dose-dependently attenuated established mechanical allodynia, whereas repeated injection of oltipraz (100 mg· kg-1· d-1, i.p. from d 14 to d 18) almost abolished the mechanical allodynia in PINP rats. The antinociceptive effect of oltipraz was blocked by pre-injection of Nrf2 inhibitor trigonelline (20 mg/kg, i.p.). Early treatment with oltipraz (100 mg· kg-1· d-1, i.p. from d 0 to d 6) failed to prevent the development of the PINP, but delayed its onset. Western blot and immunofluorescence analysis revealed that the expression levels of Nrf2 and HO-1 were significantly upregulated in the spinal cord of PINP rats. Repeated injection of oltipraz caused further elevation of the expression levels of Nrf2 and HO-1 in the spinal cord of PINP rats, which was reversed by pre-injection of trigonelline. These results demonstrate that oltipraz ameliorates PINP via activating Nrf2/HO-1-signaling pathway in the spinal cord.

Src-family protein tyrosine kinases: A promising target for treating chronic pain.

Despite the growing knowledge of the mechanisms of chronic pain, the treatment of this disorder in the clinic remains a major challenge. Src-family protein tyrosine kinases (SFKs), a group of non-receptor protein tyrosine kinases, have been implicated in neuronal development and synaptic plasticity. SFKs are critical for the regulate of N-methyl-D-aspartic acid receptor (NMDAR) 2B subunit phosphorylation by various transmembrane receptors, e.g., G-protein coupled receptors (GPCRs), EphB receptors (EphBRs), increased intracellular calcium, epidermal growth factor (EGF) and other growth factors, and thus contribute to the development of chronic pain. SFKs have also been regarded as important points of convergence of intracellular signalling components for the regulation of microglial functions and the immune response. Additionally, the intrathecal administration of SFK inhibitors significantly alleviates mechanical allodynia in different chronic pain models. Here, we reviewed the current evidence for the role of SFKs in the development of chronic pain caused by complete Freund's adjuvant (CFA) injection, peripheral nerve injury (PNI), streptozotocin (STZ) injection and bone metastasis. Moreover, the role of SFKs in the development of morphine tolerance is also discussed. The regulation of SFKs therefore has emerged as a potential therapeutic target for the treatment of chronic pain in terms of safety and efficacy.

The endocannabinoid system: Novel targets for treating cancer induced bone pain.

Treating Cancer-induced bone pain (CIBP) continues to be a major clinical challenge and underlying mechanisms of CIBP remain unclear. Recently, emerging body of evidence suggested the endocannabinoid system (ECS) may play essential roles in CIBP. Here, we summarized the current understanding of the antinociceptive mechanisms of endocannabinoids in CIBP and discussed the beneficial effects of endocannabinoid for CIBP treatment. Targeting non-selective cannabinoid 1 receptors or selective cannabinoid 2 receptors, and modulation of peripheral AEA and 2-AG, as well as the inhibition the function of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have produced analgesic effects in animal models of CIBP. Management of ECS therefore appears to be a promising way for the treatment of CIBP in terms of efficacy and safety. Further clinical studies are encouraged to confirm the possible translation to humans of the very promising results already obtained in the preclinical studies.

Berberine protects against ischemia-reperfusion injury: A review of evidence from animal models and clinical studies.

Ischemia-reperfusion (I/R) injury is accompanied with high morbidity and mortality and has seriously negative social and economic influences. Unfortunately, few effective therapeutic strategies are available to improve its outcome. Berberine is a natural medicine possessing multiple beneficial biological activities. Emerging evidence indicates that berberine has potential protective effects against I/R injury in brain, heart, kidney, liver, intestine and testis. However, up-to-date review focusing on the beneficial role of berberine against I/R injury is not yet available. In this paper, results from animal models and clinical studies are concisely presented and its mechanisms are discussed. We found that berberine ameliorates I/R injury in animal models via its anti-oxidant, anti-apoptotic and anti-inflammatory effects. Moreover, berberine also attenuates I/R injury by suppressing endoplasmic reticulum stress and promoting autophagy. Additionally, regulation of periphery immune system may also contributes to the beneficial effect of berberine against I/R injury. Although clinical evidence is limited, the current studies indicate that berberine may attenuate I/R injury via inhibiting excessive inflammatory response in patients. Collectively, berberine might be used as an alternative therapeutic strategy for the management of I/R injury.

Pharmacological inhibition of the NLRP3 inflammasome as a potential target for cancer-induced bone pain.

Cancer-induced bone pain (CIBP) remains a major challenge in patients suffering from bone metastases because of the complex mechanisms and unsatisfactory treatments. Emerging evidence have shown that activation of inflammasomes contribute to the development of inflammatory and neuropathic pain. However, the role of spinal inflammasomes in CIBP remains unclear. In the present study, we explored the specific cellular mechanisms of NLRP3 inflammasome in the process of CIBP in rats. MCC950 is a small molecule inhibitor of the NLRP3 inflammasome that exhibits remarkable activity in inflammatory diseases. Our behavioral results confirmed that both single and persistent treatment with MCC950 markedly attenuated CIBP-related mechanical allodynia. The expression of NLRP3 inflammasome, including NLRP3, ASC, Caspase-1, were significantly increased in a time-dependent manner. Furthermore, spinal IL-1ß, cleaved by cysteine-aspartic acid protease, was upregulated in this study. Chronic administration with MCC950 restored the protein expression of NLRP3 inflammasome and significantly suppressed the upregulation of IL-1ß. Spinal NLRP3 inflammasome might be a novel therapeutic target for treatment of CIBP.