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Background: It is known that some analgesics as well as pain can affect the immune system. The aim of this study was to investigate the analgesic effect and immunomodulation of pregabalin (PGB) in a mouse incisional pain model. Methods: A postoperative pain model was induced by hind paw plantar incision in male BALB/c mice. Mice were randomly divided into four groups (n = 8): a salinetreated incision (incision), PGB-treated incision (PGB-incision), sham controls without incision or drug treatment (control), and a PGB-treated control (PGB-control). In the PGB treated groups, PGB was administered intraperitoneally (IP) 30 minutes before and 1 hour after the plantar incision. Changes of the mechanical nociceptive thresholds following incision were investigated. Mice were euthanized for spleen harvesting 12 hours after the plantar incision, and natural killer (NK) cytotoxicity to YAC 1 cells and lymphocyte proliferation responses to phytohemagglutinin were compared among these four groups. Results: Mechanical nociceptive thresholds were decreased after plantar incision and IP PGB administration recovered these decreased mechanical nociceptive thresholds (P < 0.001). NK activity was increased by foot incision, but NK activity in the PGB-incision group was significantly lower than that in the Incision group (P < 0.001). Incisional pain increased splenic lymphocyte proliferation, but PGB did not alter this response. Conclusions: Incisional pain alters cell immunity of the spleen in BALB/c mice. PGB showed antinocieptive effect on mouse incisional pain and attenuates the activation of NK cells in this painful condition. These results suggest that PGB treatment prevents increases in pain induced NK cell activity.

Objective Autophagy is one of the key responses of cells to programmed cell death. Memantine, an approved anti-dementia drug, has an antiproliferative effect on cancer cells but the mechanism is poorly understood. The aim of the present study was to test the possibility of induction of autophagic cell death by memantine in glioma cell lines. Methods Glioma cell lines (T-98 G and U-251 MG) were used for this study. Results The antiproliferative effect of memantine was shown on T-98 G cells, which expressed N-methyl-D-aspartate 1 receptor (NMDAR1). Memantine increased the autophagic-related proteins as the conversion ratio of light chain protein 3-II (LC3-II)-/LC3-I and the expression of beclin-1. Memantine also increased formation of autophagic vacuoles observed under a transmission electron microscope. Transfection of small interfering RNA (siRNA) to knock down NMDAR1 in the glioma cells induced resistance to memantine and decreased the LC3-II/LC3-I ratio in T-98 G cells. Conclusion Our study demonstrates that in glioma cells, memantine inhibits proliferation and induces autophagy mediated by NMDAR1.

BACKGROUND: The outcome of hematopoietic stem cell transplantation (HSCT) is poor in patients with secondary iron overload (SIO). We evaluated the relationship between SIO and veno-occlusive disease (VOD) in an animal model with radiation for HSCT. METHODS: We used a 6-week-old female BDF1 (H-2(b/d)) and a male C57/BL6 (H-2(b)) as recipient and donor, respectively. Recipient mice were injected intraperitoneally with 10 mg of iron dextran (cumulative doses of 50 mg, 100 mg, and 200 mg). All mice received total body irradiation for HSCT. We obtained peripheral blood for alanine transaminase (ALT) and liver for pathologic findings, lipid hyperoxide (LH) as reactive oxygen species (ROS), and liver iron content (LIC) on post-HSCT day 1 and day 7. The VOD score was assessed by pathologic findings. RESULTS: ALT levels increased depending on cumulative iron dose, with significant differences between days 1 and 7 for mice loaded with 200 mg of iron (P

Matrix metalloproteinases (MMPs) are proteolytic enzymes that play important roles in cancer progression and metastasis. Although serum MMP expression is known to correlate with the primary lesion of breast cancer, there has yet to be a study regarding the correlation between serum MMP expression and metastatic lesions, particularly lymph nodes. The present study evaluated the correlation of serum and lymph node MMP expression with axillary node metastasis. The preoperative serum levels of MMP-2 and MMP-9 in 77 patients with breast cancer and in 10 patients with benign breast tumor were determined by ELISA and zymography. One hundred and twelve axillary lymph nodes were collected for zymography during breast cancer surgery. Significantly higher serum levels of MMP-2 and MMP-9 were found in breast cancer patients compared to patients with benign tumor. High serum levels of MMP-2 and MMP-9 were significantly associated with node metastasis. ELISA and zymography results for serum MMP-2 and MMP-9 correlated significantly, with a Pearson correlation coefficient (r) of 0.76 for MMP-2 (P=0.001) and 0.81 for MMP-9 (P=0.001). In terms of lymph node, total MMP-2, MMP-9 and MMP-9 activity were significantly higher in metastatic than in non-metastatic nodes. There was a correlation between serum and lymph node MMP-9 levels on zymographic measurements (r=0.34, P=0.011), but not in terms of MMP-2 levels. Serum MMP-9 levels may have a diagnostic value for predicting axillary node metastasis.

Background: Pain plays roles in both the nervous system and immune system. Changes in the neuroendocrine pathway under pain conditions give rise to sympathetic outflow with increased plasma catecholamines and activate immune reactions. Dexmedetomidine exerts sedative, analgesic, and anesthetic-sparing effects and is known to diminish pro-inflammatory processes by central sympatholytic effects. To investigate the influence of the analgesic effect of dexmedetomidine on immunomodulation under pain conditions, splenic natural killer (NK) tumoricidal cytotoxic activity, proliferative ability of T lymphocytes, and cytokine changes were assessed. Methods: After evaluation of the analgesic efficacy of dexmedetomidine in C57BL mice that were subjected to formalin-induced pain, dexmedetomidine (30 µg/kg) or saline was injected intraperitoneally (ip) 30 min before formalin (20 µL of 2% formalin in 0.9% saline) injection. NK cell activity against NK-sensitive YAC-1 lymphoma cells was evaluated by the percentage of specific lactate dehydrogenase (LDH) release. Various numbers of effector cells (NK cells) were added to the wells of a microtiter plate containing 2 × 104 target YAC-1 cells in 100 μL, to achieve final effector-to-target cell ratios of 80:1, 40:1, and 20:1. The level of lymphocyte proliferation in response to phytohemagglutinin (PHA) was detected by bromodeoxyuridine (BrdU) incorporation assay. TNF-α, IL-1β, and IL-10 levels were determined in blood samples and supernatants of splenocyte preparations. Results: IP administration of dexmedetomidine significantly decreased the time of licking and biting during the first and second phases of the formalin test (p

BACKGROUND There is a strong relationship between pain and immune function. The development of neuropathic pain after peripheral nerve damage occurs with inflammation at the injury site. T lymphocyte function, a part of cell-mediated immunity, has been implicated in the pathogenesis and nociceptive processing of peripheral neuropathic pain. Pregabalin [(S)-3-(aminomethyl)-5-methylhexanoic acid], which was developed as an antiepileptic drug, has shown clinical and laboratory efficacy for neuropathic pain. To assess the possible influence of pregabalin therapy on immunomodulation, we assessed natural killer (NK) tumoricidal activity against YAC-1 murine lymphoma cells and phytohemagglutinin-stimulated T lymphocyte proliferation in a neuropathic mouse model. METHODS The neuropathic model was induced by chronic constriction injury (CCI) to the right sciatic nerve in male BALB/c mice. Mechanical hyperalgesia was measured with a dynamic plantar aesthesiometer. After confirming hyperalgesia, pregabalin or saline (for control mice) in a volume of 10 mL/kg was administered orally at a dosage of 30 mg/kg, twice daily from day 2 after surgery. On day 7 postsurgery, NK cell cytotoxic activity and splenocyte proliferation were measured. NK cell activity was assessed by lactate dehydrogenase assay. Various numbers of effector cells were added to the wells of a microtiter plate containing 1 × 10(4) target YAC-1 cells in 100 μL, to achieve final effector-to-target cell ratios of 80:1, 40:1, and 20:1. The proliferative response of splenocytes to phytohemagglutinin was measured by bromodeoxyuridine detection. Stimulation index was calculated to quantify cell proliferation based on the measurement of bromodeoxyuridine incorporation in cellular DNA. For in vitro study, NK cell activity and splenocyte proliferation from isolated spleen cells were determined at different concentrations of pregabalin (3, 10, and 30 μg/mL). RESULTS CCI caused marked mechanical allodynia on day 7 and orally administered pregabalin reversed mechanical hyperalgesia. NK cell activity and splenocyte proliferation were significantly increased in CCI mice compared with control mice. Pregabalin treatment in CCI mice significantly suppressed NK cell activity and proliferation of splenocytes. NK cell activity was 8.4% ± 4.7% in control and 29.2% ± 20.2% in CCI mice; pregabalin treatment reduced cytotoxicity to 6.8% ± 2.4% in CCI mice. Stimulation index was 169% ± 71% in CCI mice but pregabalin treatment reduced it to 67% ± 52% compared with control. In vitro, NK cell activity was suppressed at a pregabalin concentration of ≥10 μg/mL (P < 0.05). CONCLUSIONS Neuropathic pain increased immunological reactivity and pregabalin treatment modulated this reactivity. Increased NK cell activity and splenocyte proliferation were inhibited by pregabalin treatment.