Seok Jai Kim

Curcumin protects against regional myocardial ischemia/reperfusion injury through activation of RISK/GSK-3β and inhibition of p38 MAPK and JNK.

Background: Curcumin, the active ingredient of turmeric (Curcuma longa), is known to have anti-inflammatory and antioxidative properties. The present study was aimed to determine the effect of curcumin in regional myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms involving the role of prosurvival kinases and apoptotic kinases. Methods: Sprague-Dawley rats (n = 109) subjected to a 30-minute left anterior descending coronary artery (LAD) occlusion followed by reperfusion were assigned to receive saline (control), curcumin (100 mg/kg), wortmannin (inhibitor of phosphatidylinositol-3-OH kinase [PI3K]-Akt), wortmannin + curcumin, U0126 (inhibitor of extracellular signal-regulated kinase [ERK1/2]), U0126 + curcumin, SB216763 (inhibitor of glycogen synthase kinase [GSK-3β]), and SB216763 + curcumin 20 minutes before LAD occlusion. Infarct size was measured after 2 hours of reperfusion by triphenyl tetrazolium chloride staining. The phosphorylation of Akt, ERK1/2, GSK-3β, p38, and c-Jun N-terminal kinases (JNK) was determined by immunoblotting after 10 minutes of reperfusion. Results: Curcumin significantly reduced the infarct size compared with the control (33.1% ± 6.2% vs 50.1% ± 3.9%; P < .05). Wortmannin or U0126 alone did not affect the infarct size but abolished the curcumin-induced cardioprotective effect. Curcumin significantly enhanced the phosphorylation of Akt, ERK1/2, and GSK-3β, while it reduced that of p38 and JNK. Wortmannin or U0126 abolished enhanced phosphorylation of GSK-3β induced by curcumin. SB216763 alone or combined with curcumin reduced the infarct size and enhanced phosphorylation of GSK-3β compared with the control. Conclusions: Preconditioning by curcumin effectively protects against regional myocardial I/R injury through the activation of prosurvival kinases involving PI3K-Akt, ERK1/2, and GSK-3β, and attenuation of p38 and JNK.

Roles of Adenosine Receptor Subtypes in the Antinociceptive Effect of Intrathecal Adenosine in a Rat Formalin Test

The contributions of adenosine receptor subtypes to antinociception produced by adenosine were determined at the spinal level. There are 4 types of adenosine receptors, namely A₁, A_2A, A_2B and A₃. The authors investigated the properties of the subtypes of spinal adenosine receptors in terms of nociceptive modulation. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 µl) into the hind paws of male Sprague-Dawley rats. After observing the effect of intrathecal adenosine during the formalin test, the effects of intrathecal adenosine A₁(CPT), A_2A (CSC), A_2B (alloxazine) and A₃(MRS 1220) receptor antagonists on the action of adenosine were examined. Intrathecal adenosine inhibited phase 2 flinching response without affecting phase 1 response. CPT, CSC, alloxazine and MRS 1220 antagonized the antinociceptive action of adenosine during phase 2 of the formalin test. These results suggest that spinal adenosine A₁, A_2A, A_2B and A₃receptors may play an important role in the antinociception of adenosine in the formalin-induced facilitated state.

Neuroprotective effects of remifentanil against transient focal cerebral ischemia in rats.

Background: Opioid agonists have been implicated in neuroprotection from hypoxic injury through regulating mitogen-activated protein kinases and cytokines. We determined the effects of remifentanil in focal brain ischemia and reperfusion (I/R) injury. Mechanisms linked to mitogen-activated protein kinases, including extracellular signaling-regulated kinase (ERK) 1/2, p38 kinases, and c-Jun N-terminal kinase (JNK), and various cytokines were also examined. Methods: Male Sprague-Dawley rats were subjected to an I/R insult consisting of 90 minutes’ middle cerebral artery occlusion (MCAO) followed by reperfusion under general anesthesia. Neurological deficit scores and infarct volume were determined after 24 hours of reperfusion. Remifentanil (5 &mgr;g/kg/min) was given alone or combined with naltrindole (&dgr;-opioid receptor antagonist; 1 mg/kg), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (&mgr;-opioid receptor antagonist; 1 mg/kg), or 5′-guanidinonaltrindole (&kgr;-opioid receptor antagonist; 1 mg/kg). Opioid antagonists were administered 20 minutes before MCAO. Remifentanil infusion was started 10 minutes before MCAO and continued throughout. The control group was without drugs. The expression levels of ERK1/2, p38, and JNK, and also those of tumor necrosis factor-&agr; (TNF-&agr;) and interleukin-6, were determined after 1, 3, and 24 hours of reperfusion. Results: Remifentanil significantly improved the functional outcome and reduced the infarct volumes (69.0±24.3 mm3 vs. 108.9±24.8 mm3), which were not affected by D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 or 5′-guanidinonaltrindole, but were abolished by naltrindole. The I/R insult enhanced the phosphorylation of ERK 1/2 and the expression of TNF-&agr;, which were significantly reduced by remifentanil. Neither the phosphorylation of p38 and JNK nor the production of interleukin-6 was altered throughout the experiment. Conclusions: Remifentanil may be neuroprotective against focal I/R injury, possibly through the activation of &dgr;-opioid receptors and attenuation of ERK 1/2 activity and TNF-&agr; production, in the rat brain.

Antinociceptive effects and synergistic interaction with morphine of intrathecal metabotropic glutamate receptor 2/3 antagonist in the formalin test of rats.

Spinal metabotropic glutamate receptors (mGluRs) have been known to be involved in the modulation of nociception. While the antinociceptive effects of the mGluR1/5 have been demonstrated, the role of mGluR2/3 for nociception is less clear. This study investigated the effects of an intrathecal mGluR2/3 agonist, APDC, and a mGluR2/3 antagonist, LY341495, for inflammatory and acute pain in the formalin test and thermal stimulation test. We also examined their interaction with intrathecal morphine for the antinociceptive effect. APDC had little effect on the formalin-induced nociception. In contrast, LY341495 caused a dose-dependent suppression of the phase 2 flinching response to the formalin stimulus without affecting phase 1 flinching response. Furthermore, the suppression of pain behavior by LY341495 during phase 2 was reduced significantly by pretreatment with APDC. LY341495 and morphine also showed synergistic drug interaction for antinociception during phase 2 in the formalin test.

Effect of ulinastatin on cytokine reaction during gastrectomy

Background Inflammation plays an important role in the postoperative morbidity of organs, which is related to the activation of pro-inflammatory and anti-inflammatory cytokines. Ulinastatin (Urinary trypsin inhibitor, UTI) is a serine protease inhibitor found in human urine or serum that inhibits the activation of human leukocyte elastase. This study examined the effect of UTI on the inflammation response in patients undergoing a gastrectomy. Methods Thirty patients scheduled to undergo a gastrectomy were divided into two groups as follows: Control group (untreated, n = 15) and UTI group (100,000 units of UTI were continuously injected intravenously for 2 hours, n = 15). Arterial blood was sampled before surgery (T0), 10 minutes after its onset (T1), at its end (T2), and 1 hour after surgery (T3) to measure the level of cytokines. Results Both the control and treatment groups had higher interleukin (IL)-6 levels at T2 and T3 than T0, and the level increased with time. However, the increase was smaller in the treatment group. The IL-8 levels were not activated significantly in any of the groups. Conclusions UTI inhibits the secretion of IL-6, which is an inflammatory cytokine produced after a gastrectomy. This shows that UTI can decrease the inflammation reaction caused by surgical stress.

Fatal pulmonary embolism caused by thrombosis of contralateral axillary vein after arthroscopic right rotator cuff repair -A case report-

A clinically apparent thromboembolism associated with arthroscopic shoulder surgery is extremely rare. We report a case of a fatal pulmonary embolism developed after an arthroscopic rotator cuff repair in a 45-year-old woman. On the first day after surgery, she experienced syncope that was complicated by cardiac arrest. No hemostasis impairment was noted. A computed tomography scan revealed a pulmonary embolism, and Doppler ultrasound revealed thrombosis of the axillary vein on the contralateral shoulder. She died from multiple organ failure 13 days after surgery. This case shows that clinicians must be aware of the potential occurrence of a pulmonary thromboembolism in patients undergoing prolonged arthroscopic shoulder surgery.

Protective Effect of Sauchinone Against Regional Myocardial Ischemia/Reperfusion Injury: Inhibition of p38 MAPK and JNK Death Signaling Pathways

Sauchinone has been known to have anti-inflammatory and antioxidant effects. We determined whether sauchinone is beneficial in regional myocardial ischemia/reperfusion (I/R) injury. Rats were subjected to 20 min occlusion of the left anterior descending coronary artery, followed by 2 hr reperfusion. Sauchinone (10 mg/kg) was administered intraperitoneally 30 min before the onset of ischemia. The infarct size was measured 2 hr after resuming the perfusion. The expression of cell death kinases (p38 and JNK) and reperfusion injury salvage kinases (phosphatidylinositol-3-OH kinases-Akt, extra-cellular signal-regulated kinases [ERK1/2])/glycogen synthase kinase (GSK)-3β was determined 5 min after resuming the perfusion. Sauchinone significantly reduced the infarct size (29.0% ± 5.3% in the sauchinone group vs 44.4% ± 6.1% in the control, P < 0.05). Accordingly, the phosphorylation of JNK and p38 was significantly attenuated, while that of ERK1/2, Akt and GSK-3β was not affected. It is suggested that sauchinone protects against regional myocardial I/R injury through inhibition of phosphorylation of p38 and JNK death signaling pathways.

Lack of Reciprocity between Opioid and 5-HT3 Receptors for Antinociception in Rat Spinal Cord

We examined the properties of the drug interaction between morphine and 5-HT3 receptor antagonist at the spinal level. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 µl) into the hindpaw of the rats. Intrathecal morphine and m-CPBG (5-HT3 receptor agonist) dose-dependently decreased the flinching response during phase 1 and phase 2 in the formalin test. Intrathecal 5-HT3 receptor antagonists (LY-278,584 and ondansetron) did not reverse the antinociceptive effect of intrathecal morphine. Intrathecal naloxone had little effect on attenuation of the antinociception of intrathecal m-CPBG. Taken together, no reciprocal interaction was noted between 5-HT3 receptor and opioid receptors at the spinal level. Thus, the 5-HT3 receptor antagonist may be useful to manage opioid-induced emesis at the spinal level.

Anesthetic requirements and stress hormone responses in chronic spinal cord-injured patients undergoing surgery below the level of injury: nitrous oxide vs remifentanil

Background Nitrous oxide (N2O) and remifentanil both have anesthetic-reducing and antinociceptive effects. We aimed to determine the anesthetic requirements and stress hormone responses in spinal cord-injured (SCI) patients undergoing surgery under sevoflurane anesthesia with or without pharmacodynamically equivalent doses of N2O or remifentanil. Methods Forty-five chronic, complete SCI patients undergoing surgery below the level of injury were randomly allocated to receive sevoflurane alone (control, n = 15), or in combination with 67% N2O (n = 15) or target-controlled infusion of 1.37 ng/ml remifentanil (n = 15). Sevoflurane concentrations were titrated to maintain a Bispectral Index (BIS) value between 40 and 50. Measurements included end-tidal sevoflurane concentrations, mean arterial blood pressure (MAP), heart rate (HR), and plasma catecholamine and cortisol concentrations. Results During surgery, MAP, HR, and BIS did not differ among the groups. Sevoflurane concentrations were lower in the N2O group (0.94 ± 0.30%) and the remifentanil group (1.06 ± 0.29%) than in the control group (1.55 ± 0.34%) (P < 0.001, both). Plasma concentrations of norepinephrine remained unchanged compared to baseline values in each group, with no significant differences among groups throughout the study. Cortisol levels decreased during surgery as compared to baseline values, and returned to levels higher than baseline at 1 h after surgery (P < 0.05) without inter-group differences. Conclusions Remifentanil (1.37 ng/ml) and N2O (67%) reduced the sevoflurane requirements similarly by 31-39%, with no significant differences in hemodynamic and neuroendocrine responses. Either remifentanil or N2O can be used as an anesthetic adjuvant during sevoflurane anesthesia in SCI patients undergoing surgery below the level of injury.

Comparison of intubating conditions and hemodynamic responses to tracheal intubation with different effect-site concentrations of remifentanil without muscle relaxants during target-controlled infusion of propofol

BACKGROUND We compared the effects of different remifentanil effect-site concentrations on intubating conditions, and cardiovascular and bispectral index score (BIS) responses to intubation at a fixed effect-site concentration of propofol without muscle relaxants. METHODS Sixty-four patients were randomly assigned to one of three groups: remifentanil 2 (group R2, n = 22), 4 (group R4, n = 21), or 6 ng/ml (group R6, n = 21). Anesthesia was induced using target-controlled infusion of propofol 5 microgram/ml and each concentration of remifentanil. Laryngoscopy and intubation was attempted at 2.5 min following induction. Intubating conditions were assessed as excellent, good or poor using a standard scoring system. Mean arterial pressure (MAP), heart rate (HR), and BIS values were assessed. RESULTS Excellent or good intubating conditions were obtained in 91% of group R4 and 95% of R6, both of which are higher compared with 32% of R2 (P < 0.01). MAP and HR decreased significantly after induction in all groups. After intubation, they recovered to baseline value in group R2 and R4 but were significantly less than baseline values in R6. BIS response to intubation was attenuated in group R4 and R6 but not R2. Hypotension was more frequent in group R6 than R2. CONCLUSIONS Remifentanil target concentrations of 4 or 6 ng/ml combined with 5 microgram/ml propofol provided good or excellent conditions for tracheal intubation and prevented cardiovascular and BIS response during induction without muscle relaxants. However, the use of 6 ng/ml dose was associated with frequent occurrence of hypotension and bradycardia requiring treatment.