ObjectiveAutophagy 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.MethodsGlioma cell lines (T-98 G and U-251 MG) were used for this study.ResultsThe 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.ConclusionOur study demonstrates that in glioma cells, memantine inhibits proliferation and induces autophagy mediated by NMDAR1.

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 <0.001). Formalin-induced pain led to higher activity of NK cells than in sham-treated mice (p <0.05), but NK activity was not increased significantly by ip dexmedetomidine treatment. Formalin-induced pain significantly increased splenic lymphocyte proliferation (p <0.05), but dexmedetomidine did not alter this response. There was a significant increase in plasma TNF-α (p = 0.048) and IL-6 (p = 0.014) levels after formalin-induced pain. However, the differences between the responses after ip dexmedetomidine did not change significantly.Conclusions: Dexmedetomidine showed antinociceptive effect on both of acute pain phase 1 and hyperalgesic phase 2 of formalin pain model. Formalin-induced pain alters cellular immunity of spleen in mice. Dexmedetomidine attenuates the activation of NK cells under pain condition, but neither the proliferative response of the splenic lymphocytes nor the cytokine production was affected by dexmedetomidine.

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 saline-treated 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.