Hiroyuki Hirate

Interleukin‐1β induces the expression of aquaporin‐4 through a nuclear factor‐κB pathway in rat astrocytes

Interleukin (IL)‐1β is known to play a role in the formation of brain edema after various types of injury. Aquaporin (AQP)4 is also reported to be involved in the progression of brain edema. We tested the hypothesis that AQP4 is induced in response to IL‐1β. We found that expression of AQP4 mRNA and protein was significantly up‐regulated by IL‐1β in cultured rat astrocytes, and that intracerebroventricular administration of IL‐1β increased the expression of AQP4 protein in rat brain. The effects of IL‐1β on induction of AQP4 were concentration and time dependent. The effects of IL‐1β on AQP4 were mediated through IL‐1β receptors because they were abolished by co‐incubation with IL‐1 receptor antagonist. It appeared that IL‐1β increased the level of AQP4 mRNA without involvement of de novo protein synthesis because cycloheximide, a protein synthesis inhibitor, did not inhibit the effects of IL‐1β. Inhibition of the nuclear factor‐κB (NF‐κB) pathway blocked the induction of AQP4 by IL‐1β in a concentration‐dependent manner. These findings show that IL‐1β induces expression of AQP4 through a NF‐κB pathway without involvement of de novo protein synthesis in rat astrocytes.

Lactic acid increases aquaporin 4 expression on the cell membrane of cultured rat astrocytes

The water channel protein aquaporin (AQP) may play roles in the homeostasis of water content in the brain and brain edema. One possible mechanism of brain edema is glial swelling due to lactic acidosis associated with ischemia. Here, we investigated the effect of lactic acid on the expression and cellular distribution of AQP 4 in cultured rat astrocytes. After 24h of incubation, the AQP4 expression level increased maximally with 35mM lactic acid. The AQP4 expression levels also increased with hydrochloric acid or acetic acid. In contrast, with sodium lactate, the AQP4 levels did not increase. The increase in AQP4 expression level occurred without a significant increase in AQP4 mRNA expression level by lactic acid. Under the conditions of de novo protein synthesis inhibition with cycloheximide, lactic acid increased the AQP4 expression level. Furthermore, lactic acid increased the AQP4 expression level on the cell surface of the astrocytes, as determined by a cell surface biotinylation assay and immunocytochemical examination. The increase in AQP4 expression level on the cell membrane of astrocytes induced by lactic acid may be a new regulation mechanism of AQP4 in the brain.

Ketamine reduces amyloid β-protein degradation by suppressing neprilysin expression in primary cultured astrocytes

Pathological accumulation of cortical amyloid β-protein (Aβ) is an early and consistent feature of Alzheimers disease (AD). Aβ levels in the brain are determined by production and catabolism. Previous studies have suggested that deficits in the brain expression of neprilysin (NEP) and the insulin-degrading enzyme (IDE), which are both proteases involved in amyloid degradation, may promote Aβ deposition in patients with sporadic late-onset AD. Because the incidence of AD increases after surgical intervention, we examined whether ketamine, which is a general anaesthetic with neuroprotective properties for excitotoxic ischaemic damage, is associated with Aβ degradation by inducing NEP and IDE expression. The non-competitive N-methyl-d-aspartate receptor antagonist ketamine and MK801 significantly decreased the expression of NEP, but not IDE, in a concentration- and time-dependent manner through the dephosphorylation of p38 mitogen-activated protein kinase (MAPK) in cultured rat astrocytes. Furthermore, NEP-reduced reagents significantly suppressed the degradation of exogenous Aβ in cultured astrocytes. These results suggested that ketamine suppresses the Aβ degradation of NEP by reducing p38 MAPK-mediated pathway activity.

Propofol and Thiopental Suppress Amyloid Fibril Formation and GM1 Ganglioside Expression through the γ-Aminobutyric Acid A Receptor

Background:The incidence of Alzheimer disease may increase after surgical interventions. Amyloid &bgr;-protein (A&bgr;) fibrillogenesis, which is closely related to Alzheimer disease, is reportedly accelerated by exposure to anesthetics. However, the effects of GM1 ganglioside (GM1) on &Agr;&bgr; fibrillogenesis have not yet been reported. The current study was designed to examine whether the anesthetics propofol and thiopental are associated with &Agr;&bgr; assembly and GM1 expression on the neuronal cell surface. Methods:PC12N cells and cultured neuronal cells were treated with propofol or thiopental, and GM1 expression in treated and untreated cells was determined by the specific binding of horseradish peroxidase-conjugated cholera toxin subunit B (n = 5). The effects of an inhibitor of the &ggr;-aminobutyric acid A receptor was also examined (n= 5). In addition, the effects of the anesthetics on GM1 liposome-induced &Agr;&bgr; assembly were investigated (n = 5). Finally, the neurotoxicity of the assembled &Agr;&bgr; fibrils was studied by the lactate dehydrogenase release assay (n = 6). Results:Propofol (31.2±4.7%) and thiopental (34.6±10.5%) decreased GM1 expression on the cell surface through the &ggr;-aminobutyric acid A receptor. The anesthetics inhibited &Agr;&bgr; fibril formation from soluble &Agr;&bgr; in cultured neurons. Moreover, propofol and thiopental suppressed GM1-induced fibril formation in a cell-free system (propofol, 75.8±1.9%; thiopental, 83.6±1.9%) and reduced the neurotoxicity of a mixture containing A&bgr; and GM1 liposomes (propofol, 35.3±16.4%; thiopental, 21.3±11.6%). Conclusions:Propofol and thiopental have direct and indirect inhibitory effects on &Agr;&bgr; fibrillogenesis.

A New Enteral Diet, MHN-02, Which Contains Abundant Antioxidants and Whey Peptide, Protects Against Carbon Tetrachloride–Induced Hepatitis:

BACKGROUND Inflammatory or oxidative stress is related to various diseases, including not only inflammatory diseases, but also diabetes, cancer, and atherosclerosis. The aim of this study was to evaluate the anti-inflammatory effects of a new enteral diet, MHN-02, which contains abundant antioxidants and whey peptide. The study also investigated the ability of MHN-02 to attenuate lethality, liver injury, the production of inflammatory cytokines, and the production of oxidized products using a carbon tetrachloride-induced rat model of severe fulminant hepatitis. METHODS Male Sprague-Dawley rats were fed either a control diet or the MHN-02 diet for 14 days and injected with 2 mL/kg of carbon tetrachloride. Survival of rats was monitored from day 0 to day 3. To evaluate liver injury, inflammation, and oxidative stress, blood and liver samples were collected, and aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, interleukin 6, tumor necrosis factor-α, and superoxide dismutase activity as a free radical scavenger were measured. A portion of the liver was evaluated histologically. RESULTS The survival rates of rats receiving the MHN-02 diet and the control diet were 90% and 55%, respectively. In the MHN-02 diet group, levels of serum liver enzymes and serum cytokines were significantly lower than in the control group. Superoxide dismutase activity in the MHN-02 diet was significantly higher in the MHN-02 group. Pathological lesions were significantly larger in the control group. CONCLUSION Supplementation of enteral diets containing whey peptide and antioxidants may protect against severe hepatitis.

Skin-traction method prevents the collapse of the internal jugular vein caused by an ultrasound probe in real-time ultrasound-assisted guidance

PurposeReal-time ultrasound-assisted guidance for catheterization of the internal jugular vein (IJV) is known to be useful, especially for a small-sized vein, which is difficult to catheterize. However, one of the problems with real-time ultrasound-assisted guidance is that the ultrasound probe itself can collapse the vein. We have developed a novel “skintraction method (STM)”, in which the puncture point of the skin over the IJV is stretched upwards with several pieces of surgical tape in the cephalad and caudal directions with the aim being to facilitate catheterization of the IJV. We examined whether this method increased the compressive force required to collapse the IJV.MethodsIn ten volunteers, the compressive force required to collapse the right IJV, and the cross-sectional area and anteroposterior and transverse diameters of the IJV were measured with ultrasound imaging in the supine position (SP) with or without the STM or in the Trendelenburg position of 10° head-down (TP) without the STM.ResultsThe compressive force to required to collapse the vein was increased significantly with the STM, while the crosssectional area and anteroposterior diameter of the vein in the SP with STM were similar to those in the TP without the STM.ConclusionWith the STM, not only the cross-sectional area but also the compressive force required to collapse the IJV increased. Thus, the STM may facilitate real-time ultrasoundassisted guidance for catheterization of the IJV by maintaining the cross-sectional area of the vein during the guidance.

Orotracheal intubation with an AirWay Scope in a patient with Treacher Collins syndrome

Treacher Collins syndrome (TCS) is a congenital malformation of craniofacial development; in these patients conventional direct laryngoscopy is very difficult and often unsuccessful because of the upper airway malformation. A 20-year-old man with TCS was scheduled for elective tympanoplasty. The patient showed the characteristic facial appearance of TCS, and a difficult airway was anticipated. After careful anesthesia induction, direct laryngoscopy with Macintosh blade no. 4 of a direct laryngoscope failed to visualize the epiglottis, even with cricoid pressure, resulting in a grade 4 Cormack and Lehane view. Next, the AirWay Scope was easily inserted, and his glottic opening was clearly visualized. An 8.0-mm-internal-diameter tracheal tube was then advanced into the trachea without any difficulty. The AirWay Scope is a very useful airway device for orotracheal intubation; it provides an excellent view of the glottis without requiring alignment of the oral, pharyngeal, and laryngeal axes, and appears to be promising for use in patients with a difficult airway.

Midazolam inhibits the formation of amyloid fibrils and GM1 ganglioside-rich microdomains in presynaptic membranes through the gamma-aminobutyric acid A receptor

Recent studies have suggested that a positive correlation exists between surgical interventions performed under general anesthesia and the risk of developing Alzheimers disease (AD) in the late postoperative period. It has been reported that amyloid β-protein (Αβ) fibrillogenesis, which is closely related to AD, is accelerated by exposure to anesthetics. However, the mechanisms underlying these effects remain uncertain. This study was designed to investigate whether the anesthetic midazolam affects Αβ fibrillogenesis, and if so, whether it acts through GM1 ganglioside (GM1) on the neuronal surface. Midazolam treatment decreased GM1 expression in the detergent-resistant membrane microdomains of neurons, and these effects were regulated by the gamma-aminobutyric acid-A receptor. Midazolam inhibited Αβ fibril formation from soluble Αβ on the neuronal surface. In addition, midazolam suppressed GM1-induced fibril formation in a cell-free system. Moreover, midazolam inhibited the formation of Αβ assemblies in synaptosomes isolated from aged mouse brains. These finding suggested that midazolam has direct and indirect inhibitory effects on Αβ fibrillogenesis.

Use of landiolol in the perioperative management of supraventricular tachycardia

was stable. Her blood pressure then dropped, although the IABP worked well. The vasoconstrictive effect of dopamine appeared to be required for maintaining a stable hemodynamic status. Landiolol was discontinued 10 h after her admission to the intensive care unit. The SVT recurred immediately, resulting in failure of IABP synchronization. Landiolol infusion was recommenced. As a result, her HR decreased to 90– 100 bpm and her hemodynamic status improved again. The landiolol infusion was continued for another 50 h, at the same rate. She remained stable and was discharged from the intensive care unit on the tenth postoperative day. We believe that landiolol is useful for the HR control of perioperative SVT in patients undergoing cardiac surgery and that the resultant slow cardiac rhythm aids the synchronization of IABP with the patient’s heartbeat. In this patient, landiolol was safely administered not only intraoperatively but also postoperatively for as long as 3 days. Landiolol is considered to be effective in treating perioperative SVT because of its similarity to esmolol, another cardioselective and ultra-shortacting β-blocker, which, it is claimed, is safe and efficacious [4,5]. Further, landiolol has been shown to have a less depressive effect on the cardiovascular system than esmolol in animals [6,7]. In humans, it appears that the blood pressure does not significantly decrease at the optimal dose of landiolol required for HR control [8]. This characteristic would be advantageous for administration to a patient with hypotension.

Intra-operative monitoring of vagal nerve activity with wire electrodes.

A monitoring system for tracking the electromyogram (EMG) of the vocal cords with wire electrodes embedded in an endotracheal tube was designed to identify the recurrent laryngeal nerve during thyroidectomy. Our recent experience in two cases suggests that vagal nerve activity can be correctly detected by recording of the EMG of the vocal cords using a special endotracheal tube embedded with wire electrodes.