Akt (also known as protein kinase B, PKB) has been seen to play a role in astrocyte activation of neuroprotection; however, the underlying mechanism on deregulation of Akt signaling in brain injuries is not fully understood. We investigated the role of carboxy-terminal modulator protein (CTMP), an endogenous Akt inhibitor, in brain injury following kainic acid (KA)-induced neurodegeneration of mouse hippocampus. In control mice, there was a weak signal for CTMP in the hippocampus, but CTMP was markedly increased in the astrocytes 3 days after KA treatment. To further investigate the effectiveness of Akt signaling, the phosphorylation of CTMP was examined. KA treatment induced an increased p-CTMP expression in the astrocytes of hippocampus at 1 day. LPS/IFN-γ-treatment on primary astrocytes promoted the p-CTMP was followed by phosphorylation of Akt and finally upregulation of CTMP and p-CREB. Time-dependent expression of p-CTMP, p-Akt, p-CREB, and CTMP indicate that LPS/IFN-γ-induced phosphorylation of CTMP can activate Akt/CREB signaling, whereas lately emerging enhancement of CTMP can inhibit it. These results suggest that elevation of CTMP in the astrocytes may suppress Akt activity and ultimately negatively affect the outcome of astrocyte activation (astroglisiois). Early time point enhancers of phosphorylation of CTMP and/or late time inhibitors specifically targeting CTMP may be beneficial in astrocyte activation for neuroprotection within treatment in neuroinflammatory conditions.
Animals ; Astrocytes ; Brain Injuries ; Hippocampus* ; Kainic Acid ; Mice* ; Neuroprotection ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; Up-Regulation

Growth differentiation factor 15 (GDF15) is, a member of the transforming growth factor beta (TGF-beta) superfamily of proteins. Although GDF15 is well established as a potent neurotrophic factor for neurons, little is known about its role in glial cells under neuropathological conditions. We monitored GDF15 expression in astrocyte activation after a kainic acid (KA)-induced neurodegeneration in the ICR mice hippocampus. In control, GDF15 immunoreactivity (IR) was evident in the neuronal layer of the hippocampus; however, GDF15 expression had increased in activated astrocytes throughout the hippocampal region at day 3 after the treatment with KA. LPS treatment in astrocytes dramatically increased GDF15 expression in primary astrocytes. In addition, LPS treatment resulted in the decrease of the IkappaB-alpha degradation and increase of the phosphorylation level of RelA/p65. These results indicate that GDF15 has a potential link to NF-kappaB activation, making GDF15 a valuable target for modulating inflammatory conditions.
Animals ; Astrocytes* ; Growth Differentiation Factor 15* ; Hippocampus* ; Kainic Acid ; Mice* ; Mice, Inbred ICR ; Neuroglia ; Neurons ; NF-kappa B ; Phosphorylation ; Transforming Growth Factor beta

BACKGROUND: Recent research has shown that reactive oxygen species (ROS) play a significant role in the development and persistence of neuropathic pain through central sensitization via N-methyl-D-aspartate (NMDA) receptor activation. In the present study, we examined whether the intraperitoneal administration of vitamins C and E alone or together could alleviate mechanical allodynia in a chronic post-ischemia pain (CPIP) rat model. METHODS: Vitamins C and E were administered intraperitoneally to 48 male Sprague Dawley rats once per day for 3 days before hindpaw ischemia-reperfusion (I/R) injury was induced. On the third day, the CPIP rat model was produced by inducing ischemia in the left hindpaw by applying an O-ring for 3 h, followed by reperfusion. Three days after reperfusion, hindpaw mechanical allodynia was assessed by measuring the withdrawal response to von Frey filament stimulation. The rats were sacrificed immediately after behavioral testing to determine the phosphorylated NMDA receptor subunit 1 (pNR1) and extracellular-signal-regulated kinases (pERK) levels in the spinal cord. RESULTS: When the antioxidant vitamins C and E were administered intraperitoneally to CPIP rats, I/R injury-induced mechanical allodynia was attenuated, and pNR1 and pERK levels were decreased in the rat spinal cord. Additionally, the co-administration of both vitamins had an increased antiallodynic effect. CONCLUSIONS: The reduced phosphorylated NR1 and ERK levels indicate that vitamins C and E inhibit the modulation of spinal cord neuropathic pain processing. Co-administration of vitamins C and E had a greater antiallodynic effect.
Animals ; Antioxidants ; Ascorbic Acid* ; Central Nervous System Sensitization ; Complex Regional Pain Syndromes ; Humans ; Hyperalgesia ; Inositol Phosphates ; Ischemia ; Male ; Mitogen-Activated Protein Kinases ; Models, Animal* ; N-Methylaspartate ; Neuralgia ; Phosphotransferases ; Prostaglandins E ; Rats* ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Receptors, N-Methyl-D-Aspartate ; Reperfusion ; Reperfusion Injury ; Spinal Cord ; Vitamin E* ; Vitamins*

BACKGROUND: Implantation of xenogenic chromaffin cells into the spinal subarachnoid space can produce analgesia in neuropathic pain models. However, transplantation of xenogeneic chromaffin cell has a potential risk of viral or bacterial infections from animals to humans including encephalopathy due to prion transmission. The aim of this study was to investigate the possibility of developing a homogeneic source of therapeutic chromaffin cells. METHODS: Anti-allodynic effects of human chromaffin cells (HCCs) were evaluated in a neuropathic pain model in rats induced by chronic constriction injury of the sciatic nerve. HCCs encapsulated with alginate-poly-L-lysine-alginate were intrathecally implanted into rats (n = 10), while empty capsules were intrathecally implanted as a control (n = 8). Levels of norepinephrine from encapsulated HCCs before and after nicotinic stimulation were measured. We then perfomed a behavior test (cold allodynia) with acetone. In addition, to assess the potential contribution to pain reduction of opioid peptides released from the HCCs, all animals were injected with naloxone. RESULTS: The concentration of norepinephrine after nicotine stimulation was significantly increased compared to basal levels. Intrathecal implantation of encapsulated HCCs, significantly reduced cold allodynia as compared to rats receiving empty capsules (P < 0.05). Fifteen minutes after the injection of naloxone, cold allodynia significantly decreased in rats with HCCs (P < 0.05), while the degree of cold allodynia in control animals was unaltered. CONCLUSIONS: From these results, it appears that HCCs have a possibility as an analgesic source for transplants delivering pain-reducing neuroactive substances.
Acetone ; Analgesia ; Analgesics ; Animals ; Bacterial Infections ; Capsules ; Chromaffin Cells ; Cold Temperature ; Constriction ; Humans ; Hyperalgesia ; Naloxone ; Neuralgia ; Nicotine ; Norepinephrine ; Opioid Peptides ; Rats ; Sciatic Nerve ; Subarachnoid Space ; Transplants

BACKGROUND: Withdrawal movement during rocuronium injection is a common, unresolved adverse effect. We aimed to investigate the effect of IV acetaminophen pretreatment on withdrawal movement during rocuronium injection. METHODS: This study enrolled 120 American Society of Anesthesiologists (ASA) I-II patients undergoing general anesthesia. They were randomly assigned to three treatment groups. After occluding venous drainage using a tourniquet on the upper arm, the saline group received 5 ml of 0.9% sodium chloride solution, the lidocaine group received 40 mg of lidocaine, and the acetaminophen group received 50 mg of acetaminophen. During injection of pretreatment drug, pain was assessed on a four-point scale. The tourniquet was released after 120 seconds and anesthesia was performed using thiopental sodium 5 mg/kg followed by rocuronium 0.6 mg/kg. The withdrawal movement was graded on a four-point scale in a double-blind manner. RESULTS: The incidence of pain on pretreatment injection in saline, lidocaine, and acetaminophen groups was 7.7%, 5.1%, and 2.5%, respectively. The incidence of withdrawal movements was 77.5% in saline group, 32.5% in lidocaine group, and 37.5% in acetaminophen group (P < 0.05). CONCLUSIONS: Acetaminophen and lidocaine reduced the incidence of withdrawal movement after rocuronium injection compared with saline.
Acetaminophen ; Androstanols ; Anesthesia ; Anesthesia, General ; Arm ; Drainage ; Humans ; Incidence ; Lidocaine ; Prospective Studies ; Sodium Chloride ; Thiopental ; Tourniquets

BACKGROUND: Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes including complex regional pain syndromes (CRPS). Underlying mechanisms for the development of such pain are still a matter of investigation. Several studies suggest that activation of the N-methyl-D-aspartate (NMDA) receptor is essential for central sensitization as a base for persistent pain. The aim is to assess whether alteration of NMDA receptor expression correlates with the contralateral allodynia in the chronic post-ischemia pain (CPIP) model rats representing CRPS-Type I. METHODS: Application of a tight-fitting tourniquet for a period of 3 hours before reperfusion produced CPIP in male Sprague-Dawley rats. The mechanical paw withdrawal thresholds to von Frey stimuli (using a dynamic plantar aesthesiometer) were measured as pain indicators in ipsilateral and contralateral hindpaws. Phosphorylation of the NMDA receptor 1 subunit (pNR1), assessed with Western blot, was measured in the contralateral L4-6 spinal cord. RESULTS: Ipsilateral and contralateral mechanical allodynia is present at 4 hours after reperfusion, peaked at 3 days, and continued for 7 days after reperfusion. The relative density of pNR1 of CPIP rats significantly decreased in the contralateral L4-6 spinal cord compared to baseline value (P < 0.05). There was significant correlation between paw withdrawal threshold and the relative density of pNR1 (ipsilateral; R2 = 0.75, P < 0.01, contralateral; R2 = 0.60, P < 0.01). CONCLUSIONS: These data suggest that pNR1 is correlated to the contralateral mechanical allodynia in CPIP rats.
Animals ; Blotting, Western ; Central Nervous System Sensitization ; Complex Regional Pain Syndromes ; Humans ; Hyperalgesia ; Inositol Phosphates ; Male ; N-Methylaspartate ; Phosphorylation ; Prostaglandins E ; Rats ; Rats, Sprague-Dawley ; Reperfusion ; Specific Gravity ; Spinal Cord ; Tourniquets

BACKGROUND: The aim of this study was to compare the clinical properties of sevoflurane-N2O-alfentanil with propofol- remifentanil anesthesia for patients undergoing laryngeal microscopic surgery. METHODS: Sixty patients scheduled for elective ambulatory surgery received either total intravenous anesthesia (TIVA group) with remifentanil and propofol or balanced anesthesia with sevoflurane-N2O-alfentanil (sevoflurane-N2O-alfentanil group). The TIVA group patients were induced with an effective-site concentration of 4microgram/ml propofol and a bolus dose of 0.5microgram/ml remifentanil. The anesthesia was maintained with a continuous infusions with an effective-site concentration of 2-5microgram/kg propofol and 0.05-0.5microgram/kg/min remifentanil, according to the hemodynamic response. The sevoflurane-N2O-alfentanil group patients were induced with 5 mg/kg thiopental and 20microgram/kg IV alfentanil. Maintenance was obtained with 1.5-3.0 vol% sevoflurane and a bolus dose of 10microgram/kg IV alfentanil if needed. The anesthetic depth was controlled under bispectral index (BIS) monitoring: propofol and sevoflurane concentrations were adjusted to achieve target BIS values, and were between levels of 40-60 during surgery. RESULTS: Both anesthetic methods provided acceptable hemodynamic responses during surgery. The late recovery times (postanesthetic discharge scoring system), patient satisfaction and postoperative side effects were similar between patients in the two groups. Early recovery times (eye opening and the aldrete score) were shorter in the TIVA group patients, but this difference was not associated with a shorter hospital length of stay. CONCLUSIONS: Total intravenous anesthesia with remifentanil-propofol and balanced anesthesia with sevoflurane-N2O-alfentanil both provided satisfactory anesthesia for laryngeal microscopic surgeryd
Alfentanil ; Ambulatory Surgical Procedures ; Anesthesia* ; Anesthesia, Intravenous* ; Balanced Anesthesia ; Hemodynamics ; Humans ; Length of Stay ; Patient Satisfaction ; Propofol ; Thiopental

BACKGROUND: The gut is an important area for inflammatory responses. Gut manipulation during open laparotomy compared with laparoscopic surgery, increases the inflammatory responses. Laparoscopic assisted colectomy (LC) with less bowel manipulation might minimize the inflammatory responses and oxidative stress, and offer a faster postanesthetic recovery than an open colectomy (OC). This study evaluated the effect of N-acetyl-cysteine (NAC), an antioxidant, on the recovery after colectomy. METHODS: 116 colorectal tumor patients were reviewed retrospectively. The patients were divided into 3 groups; LC by surgeon A (A - L), OC by surgeon A (A - O) and OC by surgeon B (B - O). The postanesthetic recovery scores (PARS) were compared. In the prospective randomized controlled trial, the colorectal tumor patients were assigned to one of four groups; laparoscopic assisted colectomy (L - N) with NAC infusion (L + N), open colectomy (O - N) with NAC infusion (O + N). In the NAC groups, NAC (5 mg/kg/h) was infused after intubation to extubation. The PARS were compared. RESULTS: In the retrospective study, the time to reach 10 points, which satisfies the discharge criteria in the PACU, was significantly lower in the A-L group than in the other groups. In the prospective study, the time to 10 points was shorter in the O + N group than in the O-N group. NAC offered no added benefits to the L + N and L-N groups. CONCLUSIONS: NAC offered faster recovery in the OC group but not in the LC group.
Colectomy ; Colorectal Neoplasms ; Colorectal Surgery* ; Humans ; Intubation ; Laparoscopy ; Laparotomy ; Oxidative Stress ; Prospective Studies ; Retrospective Studies

BACKGROUND: Adrenal medullary transplants into the subarachnoid space have been demonstrated to reduce pain sensitivity. This analgesia most likely results from the release of neuroactive substances, particularly catecholamines and opioid peptides from the transplanted cells into spinal cord. METHODS: Isolated bovine chromaffin cells were encapsulated with alginate and poly-L-lysine prior to implantation into rat's subarachnoid space to protect them from host immune system. And then catecholamines from encapsulated chromaffin cells were measured quantitatively in vitro by High Performance Liquid Chromatograph. The animals were randomized into 2 groups, one of which received microencapsulated chromaffin cells and the other empty capsules. The effects of such implants were evaluated on the pain behavior resulting from a chronic constriction injury of the rat sciatic nerve for 30 days. RESULTS: Catecholamine concentration in cerebrospinal fluid (CSF) was analyzed. Data (mean SD) are considered significant at P <0.05 (ANOVA for repeated measure and Dunnett's test). Continuous release of catecholamine and met-enkephalin with responsiveness to nicotine stimulation was measured from encapsulated cells in vitro. A significant reduction of allodynic response to acetone evaporation was observed in the animals implanted with cell loaded capsules compared to control animals with empty capsules. Catecholamine concentration in CSF was higher in the cell loaded capsule group. There were no complications related to implantation. CONCLUSION: We found that encapsulated chromaffin cells released continuously catehcolamines and opioids peptides in vitro and in the CSF. Those results may prove chromaffin cell's anagesic effect indirectly.
Acetone ; Analgesia ; Analgesics, Opioid ; Animals ; Capsules ; Catecholamines* ; Cerebrospinal Fluid ; Chromaffin Cells* ; Constriction ; Drug Compounding ; Enkephalin, Methionine ; Immune System ; Nicotine ; Opioid Peptides ; Peptides ; Rats ; Sciatic Nerve ; Spinal Cord ; Subarachnoid Space

BACKGROUND: Sevoflurane is the most recently available volatile agent which permits the rapid induction with its nonirritant nature. The goal of this study was to compare the hemodynamic responses of sevoflurane induction and maintenance period with those of fentanyl-midazolam/isoflurane anesthesia for CABG. METHODS: Twenty-eight patients who underwent CABG were given anesthesia, and were randomly assigned to receive sevoflurane (Sevo Group, n = 15) or fentanyl-midazolam/isoflurane (Iso-Fent Group, n = 13), as induction and maintenance agents. In the Sevo group, anesthesia was induced with two or three deep breaths of 7.5% sevoflurane, and maintained with 2% sevoflurane after intubation. The Iso-Fent Group received fentanyl 5microgram/kg and midazolam 0.2 mg/kg with oxygen for induction and maintained with 0.8% isoflurane and 5microgram/kg/hr of fentanyl by infusion. All were given vecuronium as a muscle relaxant. Cardiac and oxygen metabolic profiles were measured before and 10 minutes after tracheal intubation. RESULTS: Before induction, there was no difference between Sevo and Iso-Fent group in terms of cardiac and oxygen metabolic profiles. After intubation, mean arterial pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, heart rate and mixed venous oxygen saturation in the Sevo group were higher than in the Iso-Fent group (P < 0.05). The ST-segment changes in the EKG monitoring was unremarkable during anesthesia induction in either group. CONCLUSIONS: For the induction and early anesthesia maintenance in patients undergoing CABG surgery, sevoflurane may be a substitute for fentanyl-midazolam/isoflurane without any significant hemodynamic changes.
Anesthesia* ; Arterial Pressure ; Coronary Artery Bypass* ; Coronary Vessels* ; Electrocardiography ; Fentanyl ; Heart Rate ; Hemodynamics* ; Humans ; Intubation ; Isoflurane ; Metabolome ; Midazolam ; Oxygen ; Pulmonary Wedge Pressure ; Vecuronium Bromide