Curcumin relieves oxaliplatin-induced neuropathic pain via reducing inflammation and activating antioxidant response.

Oxaliplatin (OXA) has shown high effectiveness in the treatment of cancers, but its anticancer clinical effects often induce neurotoxicity leading to neuropathic pain. Oxidative damage and NLRP3 inflammasome play important roles in neuropathic pain development. Here, neuropathic pain mouse model was constructed by continuous intraperitoneal injection of OXA. OXA administration induced mechanical pain, spontaneous pain, thermal hyperalgesia and motor disability in mice. The spinal cord tissues of OXA mice exhibited the suppressed antioxidative response, the activated NLRP3 inflammasome mediated inflammatory responses, and the increased GSK-3ß activity. Next, we injected curcumin (CUR) intraperitoneally in OXA mice for seven consecutive days. CUR-treated mice showed increased mechanical pain thresholds, reduced number of spontaneous flinches, increased paw withdrawal latency, and restored latency to fall. While in the spinal cord, CUR treatment inhibited the NLRP3 inflammasome mediated inflammatory response, increased Nrf2/GPX4-mediated antioxidant responses, and decreased mitochondrial oxidative generation. Additionally, CUR combined with GSK-3ß through four covalent bonds and reduced GSK-3ß activity. In conclusion, our findings suggest that CUR treatment inhibits GSK-3ß activation, increases Nrf2 mediated antioxidant responses, inhibits oxidative damage and inflammatory reaction, and alleviates OXA-induced neuropathic pain.

Alleviating effect of lycorine on CFA­induced arthritic pain via inhibition of spinal inflammation and oxidative stress.

Chronic pain is the primary symptom of osteoarthritis affecting a patient's quality of life. Neuroinflammation and oxidative stress in the spinal cord contribute to arthritic pain and represent ideal targets for pain management. In the present study, a model of arthritis was established by intra-articular injection of complete Freund's adjuvant (CFA) into the left knee joint in mice. After CFA inducement, knee width and pain hypersensitivity in the mice were increased, motor disability was impaired, spinal inflammatory reaction was induced, spinal astrocytes were activated, antioxidant responses were decreased, and glycogen synthase kinase 3ß (GSK-3ß) activity was inhibited. To explore the potential therapeutic options for arthritic pain, lycorine was intraperitoneally injected for 3 days in the CFA mice. Lycorine treatment significantly reduced mechanical pain sensitivity, suppressed spontaneous pain, and recovered motor coordination in the CFA-induced mice. Additionally, in the spinal cord, lycorine treatment decreased the inflammatory score, reduced NOD-like receptor protein 3 inflammasome (NLRP3) activity and IL-1ß expression, suppressed astrocytic activation, downregulated NF-κB levels, increased nuclear factor erythroid 2-related factor 2 expression and superoxide dismutase activity. Furthermore, lycorine was shown to bind to GSK-3ß through three electrovalent bonds, to inhibit GSK-3ß activity. In summary, lycorine treatment inhibited GSK-3ß activity, suppressed NLRP3 inflammasome activation, increased the antioxidant response, reduced spinal inflammation, and relieved arthritic pain.

LY294002 alleviates bone cancer pain by reducing mitochondrial dysfunction and the inflammatory response.

Bone cancer pain (BCP) is mainly caused by bone metastasis and markedly impairs the functional capacity and daily functions of patients. Neuroinflammation plays a pivotal role in the pathogenesis and maintenance of chronic pain. Oxidative stress in the mitochondria is a key contributor to neuroinflammation and neuropathic pain. Herein, a rat model of BCP was established which was characterized by bone destruction, pain hypersensitivity and motor disability. In the spinal cord, phosphatidylinositol 3­kinase (PI3K)/protein kinase B (Akt) signaling was activated, and the inflammatory response and mitochondrial dysfunction were also observed. The intrathecal injection of LY294002, a selective inhibitor of PI3K/Akt signaling, decreased mechanical pain sensitivity, suppressed spontaneous pain and recovered the motor coordination of rats with BCP. Second, LY294002 treatment blocked spinal inflammation by reducing astrocytic activation and downregulating the expression levels of inflammatory factors, such as NF­κB, IL­1ß and TNF­α. Moreover, LY294002 treatment recovered mitochondrial function by activating the manganese superoxide dismutase enzyme, increasing NADH:ubiquinone oxidoreductase subunit B11 expression, and decreasing BAX and dihydroorotate dehydrogenase expression. LY294002 treatment also increased the mitochondrial membrane potential and decreased the mitochondrial reactive oxygen species levels in C6 cells. On the whole, the results of the present study suggest that the inhibition of PI3K/Akt signaling by LY294002 restores mitochondrial function, suppresses spinal inflammation and alleviates BCP.

AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation.

Bone metastasis of cancer cells leads to severe pain by disrupting bone structure and inducing central sensitization. Neuroinflammation in the spinal cord plays a decisive role in the maintenance and development of pain. In the current study, male Sprague-Dawley (SD) rats are used to establish a cancer-induced bone pain (CIBP) model by intratibial injection of MRMT-1 rat breast carcinoma cells. Morphological and behavioral analyses verify the establishment of the CIBP model, which represents bone destruction, spontaneous pain and mechanical hyperalgesia in CIBP rats. Activation of astrocytes marked by upregulated glial fibrillary acidic protein (GFAP) and enhanced production of the proinflammatory cytokine interleukin-1ß (IL-1ß) are accompanied by increased inflammatory infiltration in the spinal cord of CIBP rats. Furthermore, activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is consistent with increased neuroinflammation. Adenosine monophosphate-activated protein kinase (AMPK) activation is involved in attenuating inflammatory pain and neuropathic pain. Intrathecal injection of the AMPK activator AICAR in the lumbar spinal cord reduces dynamin-related protein 1 (Drp1) GTPase activity and suppresses NLRP3 inflammasome activation. This effect consequently alleviates pain behaviors in CIBP rats. Cell research on C6 rat glioma cells indicates that AICAR treatment restores IL-1ß-induced impairment of mitochondrial membrane potential and elevation of mitochondrial reactive oxygen species (ROS). In summary, our findings indicate that AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation in the spinal cord.

Emodin suppresses oxaliplatin-induced neuropathic pain by inhibiting COX2/NF-κB mediated spinal inflammation.

Oxaliplatin (OXA) is a common chemotherapy drug for colorectal, gastric, and pancreatic cancers. The anticancer effect of OXA is often accompanied by neurotoxicity and acute and chronic neuropathy. The symptoms present as paresthesia and pain which adversely affect patients' quality of life. Herein, five consecutive intraperitoneal injections of OXA at a dose of 4 mg/kg were used to mimic chemotherapy. OXA administration induced mechanical allodynia, activated spinal astrocytes, and increased inflammatory response. To develop an effective therapeutic measure for OXA-induced neuropathic pain, emodin was intrathecally injected into OXA rats. Emodin developed an analgesic effect, as demonstrated by a significant increase in the paw withdrawal threshold of OXA rats. Moreover, emodin treatment reduced the pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) which upregulated in OXA rats. Furthermore, autodock data showed four hydrogen bonds were formed between emodin and cyclooxygenase-2 (COX2), and emodin treatment decreased COX2 expression in OXA rats. Cell research further proved that emodin suppressed nuclear factor κB (NF-κB)-mediated inflammatory signal and reactive oxygen species level. Taken together, emodin reduced spinal COX2/NF-κB mediated inflammatory signal and oxidative stress in the spinal cord of OXA rats which consequently relieved OXA-induced neuropathic pain.

Resveratrol ameliorates oxaliplatin-induced neuropathic pain via anti-inflammatory effects in rats.

Oxaliplatin (OXA) is a common chemotherapy drug and exhibits clinical activity in several cancer types. Its anticancer clinical effect is frequently accompanied by neurotoxicity. The symptoms include paresthesia and pain, which adversely affect the quality of life of patients. In the present study, five consecutive intraperitoneal injections of 4 mg/kg OXA were used to mimic chemotherapy in rats. OXA administration induced mechanical allodynia, activated spinal astrocytes and triggered the inflammatory response. To explore potential therapeutic options for OXA-induced neuropathic pain, resveratrol (Res) was intrathecally injected into the spinal cord of OXA-treated rats. Paw withdrawal threshold values of OXA-treated rats were increased, indicating an antinociception effect of Res on OXA-induced pain. Additionally, Res treatment reduced the levels of glial fibrillary acidic protein, TNF-α, IL-1ß and NF-κB, which were upregulated in OXA-treated rats (compared with control). Furthermore, Auto Dock data showed that Res binds to cyclooxygenase-2 (COX-2) through six hydrogen bonds. Western blot analysis and reactive oxygen species (ROS) assays indicated that Res treatment decreased COX-2 expression and suppressed ROS production. In summary, intrathecal injection of Res reduced the spinal COX-2-mediated ROS generation and inflammatory reaction, suppressed astrocytic activation, and alleviated OXA-induced neuropathic pain.

The role of LCN2 and LCN2-MMP9 in spondylitis radiographic development: gender and HLA-B27 status differences.

BACKGROUND: Male HLA-B27-positive radiographic-axial spondyloarthritis (r-axSpA) patients are prone to have severe spinal radiographic progression, but the underlying mechanisms are unclear. We recently showed that persistently elevated Lipocalin 2 (LCN2; L) reflects sacroiliac joint (SIJ) inflammation. LCN2 binds to MMP9. Concomitant elevation of L and LCN2-MMP9 (LM) was detected in many inflammatory diseases. We asked whether L and LM play similar roles in r-axSpA pathogenesis. METHODS: We analyzed 190 axSpA patients (123 radiographic and 67 non-radiographic axSpA) who had no detectable circulating Oncostatin M, to avoid complications due to cross-talk between pathways. L and LM levels from a single blood sample of each patient were measured and were correlated with MRI and modified stoke AS (mSASS) scoring. Association of elevated L (L+) or concurrent L+ and elevated LM (LM+) patterns with B27 status and gender were assessed. RESULTS: In L+LM+ axSpA patients, both L and LM levels correlated with MRI SPARCC SIJ scores, but only LM levels correlated with MRI Berlin Spine Scores, suggesting LM is a biomarker for both SIJ and spinal inflammation. Among patients with minimal spinal ankylosis (mSASSS < 10), 65% of male r-axSpA patients are L+LM+, while 30% and 64% of female patients are L+LM+ and L+, respectively, supporting the role of LM with disease progression. In B27+ L+LM+ male patients, both L and LM (but not CRP) levels correlate with mSASSS. B27 positivity and maleness have additive effects on spondylitis progression, suggesting concurrent high L and LM elevations are associated with B27+ male patients having more significant radiographic damage. L+ B27-negative male patients or L+ female patients are more likely to have milder disease. CONCLUSION: L and LM are informative biomarkers for SIJ and spinal inflammation, as well as for ankylosing development in r-axSpA patients. Distinctive L+LM+ or L+ patterns not only could distinguish clinically aggressive vs milder course of disease, respectively, but also provide an explanation for B27-positive male patients being the most susceptible to severe ankylosis.

Glycogen synthase kinase-3ß inhibition decreases inflammation and relieves cancer induced bone pain via reducing Drp1-mediated mitochondrial damage.

Bone is the preferential site of metastasis for breast cancer. Invasion of cancer cells induces the destruction of bone tissue and damnification of peripheral nerves and consequently induced central sensitization which contributes to severe pain. Herein, cancer induced bone pain (CIBP) rats exhibited destruction of tibia, mechanical allodynia and spinal inflammation. Inflammatory response mainly mediated by astrocyte and microglia in central nervous system. Our immunofluorescence analysis revealed activation of spinal astrocytes and microglia in CIBP rats. Transmission electron microscopy (TEM) observations of mitochondrial outer membrane disruption and cristae damage in spinal mitochondria of CIBP rats. Proteomics analysis identified abnormal expression of proteins related to mitochondrial organization and function. Intrathecally, injection of GSK-3ß activity inhibitor TDZD-8 significantly attenuated Drp1-mediated mitochondrial fission and recovered mitochondrial function. Inhibition of GSK-3ß activity also suppressed NLRP3 inflammasome cascade and consequently decreased mechanical pain sensitivity of CIBP rats. For cell research, TDZD-8 treatment significantly reversed TNF-α induced mitochondrial membrane potential (MMP) deficiency and high mitochondrial reactive oxygen species level. Taken together, GSK-3ß inhibition by TDZD-8 decreases spinal inflammation and relieves cancer induced bone pain via reducing Drp1-mediated mitochondrial damage.

Progressive Fatal Myelopathy Secondary to Isolated Spinal Cord Vasculitis.

A 56-year-old woman with various neurological signs which developed over a 1-year period was admitted for evaluation. MRI showed a markedly abnormal signal in the cervical spine. Despite treatment with IV steroids, she developed a progressive myelopathy, became quadriplegic, and required intubation. Immunomodulatory treatment was ineffective. The patient died 24 days after admission. Histopathological investigation revealed spinal cord necrosis with a lymphocyte predominant meningovascular inflammation involving arteries and veins along with evidence of prior occlusive disease of the anterior spinal artery. The changes were confined to the spinal cord. The present case represents an unusual cause of myelitis for which early and aggressive immunomodulatory treatment may have influenced outcomes.

Construct validity of clinical spinal mobility tests in ankylosing spondylitis: a systematic review and meta-analysis.

The study aimed to determine, using systematic review and meta-analysis, the level of evidence supporting the construct validity of spinal mobility tests for assessing patients with ankylosing spondylitis. Following the guidelines proposed in the Preferred Reporting Items for Systematic reviews and Meta-Analyses, three sets of keywords were used for data searching: (i) ankylosing spondylitis, spondyloarthritis, spondyloarthropathy, spondylarthritis; (ii) accuracy, association, construct, correlation, Outcome Measures in Rheumatoid Arthritis Clinical Trials, OMERACT, truth, validity; (iii) mobility, Bath Ankylosing Spondylitis Metrology Index-BASMI, radiography, spinal measures, cervical rotation, Schober (a further 19 keywords were used). Initially, 2558 records were identified, and from these, 21 studies were retained. Fourteen of these studies were considered high level of evidence. Compound indexes of spinal mobility showed mostly substantial to excellent levels of agreement with global structural damage. Individual mobility tests for the cervico-thoracic spine showed only moderate agreements with cervical structural damage, and considering structural damage at the lumbar spine, the original Schober was the only test that presented consistently substantial levels of agreement. Three studies assessed the construct validity of mobility measures for inflammation and low to fair levels of agreement were observed. Two meta-analyses were conducted, with assessment of agreement between BASMI and two radiological indexes of global structural damage. The spinal mobility indexes and the original Schober test show acceptable construct validity for inferring the extent of structural damage when assessing patients with ankylosing spondylitis. Spinal mobility measures do not reflect levels of inflammation at either the sacroiliac joints and/or the spine.