Kozue Kubo

Possible link between cyclooxygenase-inhibiting and antitumor properties of propofol

The intravenous anesthetic propofol has a number of well-known nonanesthetic effects, including anti-oxidation and anti-emesis. Another interesting nonanesthetic effect of propofol may be its cyclooxygenase (COX)-inhibiting activity. This activity may have important clinical implications, as propofol could have antitumor properties through COX inhibition. Propofol could counteract the activity of COX, which elicits, via its major product prostaglandin E2, (1) tumor growth stimulation, (2) increased tumor survival, (3) enhanced tumor invasiveness, (4) stimulation of new vessel formation, and (5) tumor evasion of host immune surveillance through suppression of immune cell functions. Indeed, accumulated evidence indicates that propofol suppresses the proliferation, motility, and invasiveness of tumors in vitro and in vivo. Therefore, propofol could be a particularly suitable anesthetic for use during the perioperative period for cancer surgery. However, whether the COX-inhibiting activity of propofol is related to the reported antitumor properties of propofol is not known. Definitive evidence remains to be provided.

Edaravone, a free radical scavenger, mitigates both gray and white matter damages after global cerebral ischemia in rats.

Recent studies have shown that similar to cerebral gray matter (mainly composed of neuronal perikarya), white matter (composed of axons and glias) is vulnerable to ischemia. Edaravone, a free radical scavenger, has neuroprotective effects against focal cerebral ischemia even in humans. In this study, we investigated the time course and the severity of both gray and white matter damage following global cerebral ischemia by cardiac arrest, and examined whether edaravone protected the gray and the white matter. Male Sprague-Dawley rats were used. Global cerebral ischemia was induced by 5 min of cardiac arrest and resuscitation (CAR). Edaravone, 3 mg/kg, was administered intravenously either immediately or 60 min after CAR. The morphological damage was assessed by cresyl violet staining. The microtubule-associated protein 2 (a maker of neuronal perikarya and dendrites), the beta amyloid precursor protein (the accumulation of which is a maker of axonal damage), and the ionized calcium binding adaptor molecule 1 (a marker of microglia) were stained for immunohistochemical analysis. Significant neuronal perikaryal damage and marked microglial activation were observed in the hippocampal CA1 region with little axonal damage one week after CAR. Two weeks after CAR, the perikaryal damage and microglial activation were unchanged, but obvious axonal damage occurred. Administration of edaravone 60 min after CAR significantly mitigated the perikaryal damage, the axonal damage, and the microglial activation. Our results show that axonal damage develops slower than perikaryal damage and that edaravone can protect both gray and white matter after CAR in rats.

Propofol Suppresses Prostaglandin E 2 Production in Human Peripheral Monocytes

Prostaglandin E2 secreted from monocytes/macrophages plays important roles in immunity and in inflammation. Currently, propofol, an intravenous anesthetic, is the most widely used drug for the anesthesia and sedation of patients, including those who are vulnerable to infection and/or immunosuppression. Here we report that propofol suppressed prostaglandin E2 production in lipopolysaccharide-activated human peripheral monocytes. The suppressive effects of propofol were ascribed to its inhibition of cyclooxygenase-2 activity rather than to effects on cyclooxygenase protein expression or substrate availability. Thus, propofol seems to have a prominent effect on immunity and inflammation.

Promotion of interferon-gamma production by natural killer cells via suppression of murine peritoneal macrophage prostaglandin E2 production using intravenous anesthetic propofol

Propofol is an intravenous anesthetic, widely used for general anesthesia during surgery, which inevitably involves tissue trauma with inflammation. At sites of inflammation, prostanoids, especially prostaglandin E₂ (PGE₂), are abundant. This study addresses the effect of propofol on macrophage PGE₂ production. Using thioglycollate-elicited murine peritoneal macrophages, propofol (7.5-30 μM) suppressed lipopolysaccharide-induced PGE₂ production. The suppression was via the direct inhibition of cyclooxygenase (COX) enzyme activity and due neither to the downregulation of COX expression nor the inhibition of arachidonic acid release from plasma membranes. In macrophage:natural killer (NK) cell co-culture, propofol dramatically increased interferon-gamma (IFN-γ) production, and the actions of propofol were mimicked by a selective COX-2 inhibitor, NS-398, as well as the selective EP4 receptor antagonist L-161,982, suggesting a role of PGE₂ suppression in the upregulation of IFN-γ production. Furthermore, in purified NK cell culture, PGE₂ directly suppressed the production of IFN-γ by activated NK cells, which was reversed by selective inhibition of EP4 activity. Taken together, our results show that, in macrophage:NK cell co-culture, propofol, through the suppression of macrophage PGE₂ production, upregulates NK cell IFN-γ production by alleviating EP4 receptor-mediated suppression of IFN-γ production. Propofol may potentially exert considerable influence on inflammation and immunity by suppressing PGE₂ synthesis.

Successful management of cesarean section in a patient with Romano-Ward syndrome using landiolol, a selective and short-acting β1 receptor antagonist

Romano–Ward (R-W) syndrome is an autosomal dominant hereditary disorder and is characterized by a prolonged QT interval on the electrocardiogram (ECG), syncope, and sudden death. We report here a case of cesarian section in a patient with R-W syndrome whose QT prolongation was successfully managed with landiolol, a selective β1 receptor blocker. A 25-year-old woman with R-W syndrome was scheduled for cesarean section. In the operating room, the patient’s ECG showed tachycardia (102 beats·min−1) and marked QT prolongation (QTc = 0.56 s). After spinal anesthesia, the patient’s heart rate (HR) increased to 130 beats/min accompanied by a slight decrease in arterial blood pressure to 97/57 mmHg and the QTc was prolonged to 0.57 s. Landiolol was continuously infused at a rate of 0.04 mg·kg−1·min−1 and the HR gradually decreased to 80–90 beats·min−1 accompanied by the normalization of QTc to 0.48 s. We thought that the use of landiolol was more rational and was preferable to a nonselective β receptor blocker for a term-pregnant woman because blockade of the β2 receptor might cause uterine contraction. After the use of landiolol, intraoperative and postoperative courses in both the patient and the baby were uneventful.

Intravenous anesthetic propofol suppresses prostaglandin E2 production in murine dendritic cells

Propofol is an intravenous anesthetic that is widely used for anesthesia and sedation. Dendritic cells (DC) are one of the crucial immune cells that bridge innate and adaptive immunity, in which DC process antigens during innate immune responses to present them to naïve T-cells, leading to an establishment of adaptive immunity. Prostaglandin (PG)-E2 may be secreted by DC into the microenvironment, considerably influencing DC phenotype and function, and thus determining the fate of adaptive immunity. Since propofol suppresses PGE2 production in murine macrophages, the primary purpose of the present study was to determine whether propofol also suppresses PGE2 production in DC. Assuming a positive finding of such suppression, we tested whether this also leads to alterations of interleukin (IL)-12 and IL-10 production and DC surface marker expression, both of which can be modulated by PGE2. In bone marrow-derived DC, propofol significantly suppressed the PGE2 production after lipopolysaccharide stimulation. Cyclo-oxygenase (COX) protein expression and arachidonic acid release were unaffected, while COX enzyme activity was significantly inhibited by propofol. The propofol-induced COX inhibition did not lead to the increased production of cysteinyl leukotrienes and leukotriene-B4. Endogenous COX inhibition with propofol, as well as with the selective COX-2 inhibitor, NS-398, did not affect IL-12 and IL-10 production from DC. The surface expression of I-Ab and CD40 on DC was not changed, while that of CD86 slightly increased, with both propofol and NS-398; expression of CD80 was not affected with propofol, but increased slightly with NS-398. Finally, endogenous COX inhibition with either propofol or NS-398 did not significantly affect the ability of DC to induce allogeneic T-cell proliferation. It is concluded that the intravenous anesthetic propofol suppresses COX enzyme activity in DC, with no consequences with respect to IL-12/IL-10 production and allogeneic T-cell proliferation, while minimal consequences were observed in surface molecule expression.

Possible role of propofol's cyclooxygenase-inhibiting property in alleviating dopaminergic neuronal loss in the substantia nigra in an MPTP-induced murine model of Parkinson's disease.

Propofol is an intravenous anesthetic widely used for sedation and general anesthesia. We investigated the effect of propofol on prostanoid production by activated microglia. Primary microglial culture was obtained from the brains of neonatal C57BL/6 mice. The microglia were stimulated with lipopolysaccharide (LPS) in the presence of propofol. Propofol suppressed the LPS-induced production of prostaglandin E(2) and thromboxane B(2). Cyclooxygenase (COX) protein expression and arachidonic acid release were not affected by propofol, while COX enzyme activity was significantly inhibited by propofol. The COX-inhibiting activity was also observed with purified enzymes, with COX-2 inhibition being significantly greater than COX-1 inhibition. Next, we studied whether the COX-inhibiting activity of propofol resulted in dopaminergic neuroprotection in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinsons disease, in which COX inhibitors, such as non-steroidal anti-inflammatory drugs, are reported to be neuroprotective. C57BL/6 mice received intraperitoneal injections of MPTP with or without propofol treatment, and the dopaminergic neurons in the substantia nigra pars compacta (SNpc) were examined immunohistochemically by observing the tyrosine hydroxylase-positive cells. The number of dopaminergic neurons in the SNpc was significantly reduced by MPTP treatment, while the MPTP-induced neuronal loss was minimal upon treatment with propofol or the selective COX-2 inhibitor, NS-398. These results indicate that propofol might be beneficial in mitigating MPTP-induced dopaminergic neurons, possibly via its COX-inhibiting activity.

Vaccines using dendritic cells, differentiated with propofol, enhance antitumor immunity in mice.

Dendritic cell-based vaccines are useful for enhancing antitumor immunity. It has been suggested that propofol, an intravenous anesthetic, can enhance antitumor immunity in mice. We tested vaccine efficacy for eliciting antitumor immunity, using dendritic cells differentiated from bone marrow cells in the presence of propofol. Propofol-differentiated (but not control vehicle-differentiated) dendritic cells significantly delayed the growth of B16 melanoma in vivo. In vitro cytotoxic T cell activity was not affected by propofol. However, natural killer cell activity in mice vaccinated with dendritic cells differentiated in propofol was significantly upregulated, compared to unvaccinated mice.

An unusual case of airway obstruction at the tip of an endotracheal tube caused by insertion of a nasogastric tube

We report an unusual case of ventilatory impediment caused by the obstruction of an endotracheal tube (ETT) by a nasogastric (NG) tube. A 72-year-old woman with bronchial asthma was scheduled for colostomy closure. An ETT of 7.5-mm internal diameter (ID) could not be advanced, and finally a 5.0-mm ID ETT was placed, because she had post-intubation tracheal stenosis. When an NG tube was inserted after endotracheal intubation, ventilation suddenly became nearly impossible. She was treated for an asthmatic attack, but her respiratory condition did not recover. We then exchanged the ETT for a laryngeal mask airway (LMA) and removed the NG tube. It was suspected that the cause of the airway obstruction was that the NG tube in the esophagus compressed the membranous portion of the stenotic trachea and the tip of the ETT was obstructed.