Schisandrol A and gomisin N from Schisandra chinensis extract improve hypogonadism via anti-oxidative stress in TM3 Leydig cells

BACKGROUND/OBJECTIVES@#Male hypogonadism is a condition where the body does not produce enough testosterone and significantly impacts health. Age, obesity, genetics, and oxidative stress are some physiological factors that may contribute to testosterone deficiency.Previous studies have shown many pharmacological benefits of Schisandra chinensis (S. chinensis) Baillon as an anti-inflammatory and antioxidant. However, the molecular mechanism of attenuating hypogonadism is yet to be well established. This research was undertaken to study the effects of S. chinensis extract (SCE) on testosterone deficiency.MATERIALS/METHODS: S. chinensis fruit was pulverized and extracted using 60% aqueous ethanol. HPLC analysis was performed to analyze and quantify the lignans of the SCE. @*RESULTS@#The 2,2-diphenyl-2-picrylhydrazyl and 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) scavenging assays confirmed that the SCE and its major lignans (schisandrol A and gomisin N) inhibit oxidative stress. Effects of SCE analysis on the testosterone level under oxidative stress conditions revealed that both schisandrol A and gomisin N were able to recover the lowered testosterone levels. Through mRNA expression of TM3 Leydig cell, we observed that the SCE lignans were able to induce the enzymes involved in testosterone biosynthesis-related genes such as 3β-HSD4 (P < 0.01 for SCE, and P < 0.001 for schisandrol A and gomisin N), 17β-HSD3 (P < 0.001 for SCE, schisandrol A and gomisin N), and 17, 20-desmolase (P < 0.01 for schisandrol A, and P < 0.001 for SCE and gomisin N). @*CONCLUSIONS@#These results support that SCE and its active components could be potential therapeutic agents for regulating and increasing testosterone production.

Clinical outcomes of submucosal colorectal cancer diagnosed after endoscopic resection: a focus on the need for surgery

Background/Aims@#We aimed to investigate the proportion of and risk factors for residual cancer and/or lymph node metastasis after surgery was performed because of high-risk pathological features in endoscopic resection specimen of suspected superficial submucosal colorectal cancer (SSMC). @*Methods@#We reviewed medical records of 497 patients (58.8 ± 9.8 years, 331 males) undergoing endoscopic resection of suspected SSMC. High-risk pathological features included: deep submucosal cancer invasion ≥ 1,000 μm; positive lymphovascular and/or perineural invasion; poorly differentiated adenocarcinoma; and positive resection margin. We investigated the occurrence of additional surgery and residual cancer and/or lymph node involvement in the surgical specimen. @*Results@#En bloc resection was performed in 447 patients (89.9%). High-risk pathological features were detected in 372 patients (74.8%). Additional surgery was performed in 336 of 372 patients with high-risk pathological features. Of these, 47 surgical specimens (14.0%) showed residual cancer and/or lymph node metastasis. Piecemeal resection was more common in those with residual cancer and/or lymph node involvement than those without (9/47 [19.1%] vs. 24/289 [8.3%], P= 0.032). Positive resection margin was also significantly associated with positive residual cancer and/or lymph node involvement. As the number of high-risk pathological features increased, the risk of regional lymph node metastasis increased proportionally (P= 0.002). @*Conclusions@#High-risk pathological features were frequently detected after endoscopic resection of suspected SSMC while residual cancer and/or lymph node metastasis were not commonly present in the additional surgical specimen. Further optimized strategy for proper endoscopic management of suspected SSMC is necessary.

Estrogen reinforces barrier formation and protects against tumor necrosis factor alpha-induced barrier dysfunction in oral epithelial cells

PURPOSE: Epithelial barrier dysfunction is involved in the pathophysiology of periodontitis and oral lichen planus. Estrogens have been shown to enhance the physical barrier function of intestinal and esophageal epithelia, and we aimed to investigate the effect of estradiol (E2) on the regulation of physical barrier and tight junction (TJ) proteins in human oral epithelial cell monolayers. METHODS: HOK-16B cell monolayers cultured on transwells were treated with E2, an estrogen receptor (ER) antagonist (ICI 182,780), tumor necrosis factor alpha (TNFα), or dexamethasone (Dexa), and the transepithelial electrical resistance (TER) was then measured. Cell proliferation was measured by the cell counting kit (CCK)-8 assay. The levels of TJ proteins and nuclear translocation of nuclear factor (NF)-κB were examined by confocal microscopy. RESULTS: E2 treatment increased the TER and the levels of junctional adhesion molecule (JAM)-A and zonula occludens (ZO)-1 in a dose-dependent manner, without affecting cell proliferation during barrier formation. Treatment of the tight-junctioned cell monolayers with TNFα induced decreases in the TER and the levels of ZO-1 and nuclear translocation of NF-κB. These TNFα-induced changes were inhibited by E2, and this effect was completely reversed by co-treatment with ICI 182,780. Furthermore, E2 and Dexa presented an additive effect on the epithelial barrier function. CONCLUSIONS: E2 reinforces the physical barrier of oral epithelial cells through the nuclear ER-dependent upregulation of TJ proteins. The protective effect of E2 on the TNFα-induced impairment of the epithelial barrier and its additive effect with Dexa suggest its potential use to treat oral inflammatory diseases involving epithelial barrier dysfunction.

Neuroprotective effect of lithium after pilocarpine-induced status epilepticus in mice

Status epilepticus is the most common serious neurological condition triggered by abnormal electrical activity, leading to severe and widespread cell loss in the brain. Lithium has been one of the main drugs used for the treatment of bipolar disorder for decades, and its anticonvulsant and neuroprotective properties have been described in several neurological disease models. However, the therapeutic mechanisms underlying lithium's actions remain poorly understood. The muscarinic receptor agonist pilocarpine is used to induce status epilepticus, which is followed by hippocampal damage. The present study was designed to investigate the effects of lithium post-treatment on seizure susceptibility and hippocampal neuropathological changes following pilocarpine-induced status epilepticus. Status epilepticus was induced by administration of pilocarpine hydrochloride (320 mg/kg, i.p.) in C57BL/6 mice at 8 weeks of age. Lithium (80 mg/kg, i.p.) was administered 15 minutes after the pilocarpine injection. After the lithium injection, status epilepticus onset time and mortality were recorded. Lithium significantly delayed the onset time of status epilepticus and reduced mortality compared to the vehicle-treated group. Moreover, lithium effectively blocked pilocarpine-induced neuronal death in the hippocampus as estimated by cresyl violet and Fluoro-Jade B staining. However, lithium did not reduce glial activation following pilocarpine-induced status epilepticus. These results suggest that lithium has a neuroprotective effect and would be useful in the treatment of neurological disorders, in particular status epilepticus.

Detection of Autoantibodies against Aquaporin-1 in the Sera of Patients with Primary Sjögren's Syndrome

The pathophysiology of glandular dysfunction in Sjögren's syndrome (SS) has not been fully elucidated. Previously, we reported the presence of autoantibodies to AQP-5 in patients with SS, which was associated with a low resting salivary flow. The purpose of this study was to investigate the presence of anti-AQP1 autoantibodies. To detect anti-AQP1 autoantibodies, cell-based indirect immunofluorescence assay was developed using MDCK cells that overexpressed human AQP1. By screening 112 SS and 52 control sera, anti-AQP1 autoantibodies were detected in 27.7% of the SS but in none of the control sera. Interestingly, the sera that were positive for anti-AQP1 autoantibodies also contained anti-AQP5 autoantibodies in the previous study. Different from anti-AQP5 autoantibodies, the presence of anti-AQP1 autoantibodies was not associated with the salivary flow rate. Although anti-AQP1 autoantibodies are not useful as a diagnostic marker, the presence of autoantibodies to AQP1 may be an obstacle to AQP1 gene therapy for SS.

The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia

Ampicillin, a beta-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G signifi cantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus.

Neuroprotective effect of caffeic acid phenethyl ester in 3-nitropropionic acid-induced striatal neurotoxicity

Caffeic acid phenethyl ester (CAPE), derived from honeybee hives, is a bioactive compound with strong antioxidant activity. This study was designed to test the neuroprotective effect of CAPE in 3-nitropropionic acid (3NP)-induced striatal neurotoxicity, a chemical model of Huntington's disease (HD). Initially, to test CAPE's antioxidant activity, a 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) antioxidant assay was employed, and CAPE showed a strong direct radical-scavenging eff ect. In addition, CAPE provided protection from 3NP-induced neuronal cell death in cultured striatal neurons. Based on these observations, the in vivo therapeutic potential of CAPE in 3NP-induced HD was tested. For this purpose, male C57BL/6 mice were repeatedly given 3NP to induce HD-like pathogenesis, and 30 mg/kg of CAPE or vehicle (5% dimethyl sulfoxide and 95% peanut oil) was administered daily. CAPE did not cause changes in body weight, but it reduced mortality by 29%. In addition, compared to the vehicle-treated group, robustly reduced striatal damage was observed in the CAPE-treated animals, and the 3NP-induced behavioral defi cits on the rotarod test were signifi cantly rescued after the CAPE treatment. Furthermore, immunohistochemical data showed that immunoreactivity to glial fibrillary acidic protein (GFAP) and CD45, markers for astrocyte and microglia activation, respectively, were strikingly reduced. Combined, these data unequivocally indicate that CAPE has a strong antioxidant eff ect and can be used as a potential therapeutic agent against HD.

A Needle Penetrating the Stomach Cavity after Acupuncture

Although acupuncture is known as a safe procedure that is widely used in many countries, complications including infection, hemorrhage, hematoma, pneumothorax, nerve damage, and cardiac tamponade have been reported. A needle penetrating the stomach after acupuncture, however, is very rare. Here, we report the case of 47-year-old woman who experienced abdominal pain 2 days after receiving acupuncture. Upper gastrointestinal endoscopy identified an approximately 2.5-cm long needle in the posterior wall of the antrum. The needle was removed endoscopically using rat tooth forceps with no complications.

A Case of Primaquine-Induced Acute Liver Failure / 대한내과학회지

Primaquine was approved for treatment of malaria in 1952 by the United States Food and Drug Administration (FDA). It has remained the only FDA-licensed drug capable of clearing the intra-hepatic schizonts and hypnozoites of Plasmodium vivax. It is associated with serious hazards and side effects, such as hemolytic anemia and methemoglobinemia. However, there is no report of primaquine causing liver injury in Korea. We describe a case of acute liver failure following primaquine overdose in a 19-year-old man.

N-acetylcysteine and the human serum components that inhibit bacterial invasion of gingival epithelial cells prevent experimental periodontitis in mice

PURPOSE: We previously reported that human serum significantly reduces the invasion of various oral bacterial species into gingival epithelial cells in vitro. The aims of the present study were to characterize the serum component(s) responsible for the inhibition of bacterial invasion of epithelial cells and to examine their effect on periodontitis induced in mice. METHODS: Immortalized human gingival epithelial (HOK-16B) cells were infected with various 5- (and 6-) carboxy-fluorescein diacetate succinimidyl ester-labeled oral bacteria, including Fusobacterium nucleatum, Provetella intermedia, Porphyromonas gingivalis, and Treponiema denticola, in the absence or presence of three major serum components (human serum albumin [HSA], pooled human IgG [phIgG] and alpha1-antitrypsin). Bacterial adhesion and invasion were determined by flow cytometry. The levels of intracellular reactive oxygen species (ROS) and activation of small GTPases were examined. Experimental periodontitis was induced by oral inoculation of P. gingivalis and T. denticola in Balb/c mice. RESULTS: HSA and phIgG, but not alpha1-antitrypsin, efficiently inhibited the invasion of various oral bacterial species into HOK-16B cells. HSA but not phIgG decreased the adhesion of F. nucleatum onto host cells and the levels of intracellular ROS in HOK-16B cells. N-acetylcysteine (NAC), a ROS scavenger, decreased both the levels of intracellular ROS and invasion of F. nucleatum into HOK-16B cells, confirming the role of ROS in bacterial invasion. Infection with F. nucleatum activated Rac1, a regulator of actin cytoskeleton dynamics. Not only HSA and NAC but also phIgG decreased the F. nucleatum-induced activation of Rac1. Furthermore, both HSA plus phIgG and NAC significantly reduced the alveolar bone loss in the experimental periodontitis induced by P. gingivalis and T. denticola in mice. CONCLUSIONS: NAC and the serum components HSA and phIgG, which inhibit bacterial invasion of oral epithelial cells in vitro, can successfully prevent experimental periodontitis.

Influence of Aspirin on Pilocarpine-Induced Epilepsy in Mice

Aspirin (acetylsalicylic acid) is one of the most widely used therapeutic agents based on its pharmacological actions, including anti-inflammatory, analgesic, anti-pyretic, and anti-thrombotic effects. In this study, we investigated the effects of aspirin on seizure susceptibility and hippocampal neuropathology following pilocarpine-induced status epilepticus (SE). SE was induced by pilocarpine hydrochloride (280 mg/kg, i.p.) administration in C57BL/6 mice (aged 8 weeks). Aspirin was administered daily (15 mg/kg or 150 mg/kg, i.p.) for 10 days starting 3 days before SE, continuing until 6 days after SE. After pilocarpine injection, SE onset time and mortality were recorded. Neuronal cell death was examined using cresyl violet and Fluoro-Jade staining, and glial responses were observed 7 days post SE using immunohistochemistry. In the aspirin-treated group, the onset time of SE was significantly shortened and mortality was markedly increased compared to the control group. However, in this study, aspirin treatment did not affect SE-induced neuronal cell death or astroglial and microglial responses in the hippocampus. In conclusion, these results suggest that the safety of aspirin should be reevaluated in some patients, especially with neurological disorders such as temporal lobe epilepsy.

A Case of Inferior Mesenteric Arterial Thrombosis with Bowel Infarction Successfully Treated by Conservative Treatment / 대한내과학회지

Acute mesenteric thrombosis accounts for 25-30% of acute mesenteric ischemia and occurs usually alongside severe atherosclerotic disease. Acute mesenteric thrombosis primarily affects the superior mesenteric artery; thus, inferior mesenteric arterial thrombosis is an extremely rare form of the condition. Surgical treatment is mandatory to resolve impending or overt bowel infarction in acute mesenteric ischemia patients. However, here we report a case of colonic infarction caused by acute inferior mesenteric thrombosis successfully treated by conservative management.

Intrathecal Lamotrigine Attenuates Mechanical Allodynia and Suppresses Microglial and Astrocytic Activation in a Rat Model of Spinal Nerve Ligation

PURPOSE: Lamotrigine, a novel anticonvulsant, is a sodium channel blocker that is efficacious in certain forms of neuropathic pain. Recently, microglial and astrocytic activation has been implicated in the development of nerve injury-induced neuropathic pain. We have assessed the effects of continuous intrathecal administration of lamotrigine on the development of neuropathic pain and glial activation induced by L5/6 spinal-nerve ligation in rats. MATERIALS AND METHODS: Following left L5/6 spinal nerve ligation (SNL), Sprague-Dawley male rats were intrathecally administered lamotrigine (24, 72, or 240 microg/day) or saline continuously for 7 days. Mechanical allodynia of the left hind paw to von Frey filament stimuli was determined before surgery (baseline) and once daily for 7 days postoperatively. On day 7, spinal activation of microglia and astrocytes was evaluated immunohistochemically, using antibodies to the microglial marker OX-42 and the astrocyte marker glial fibrillary acidic protein (GFAP). RESULTS: Spinal-nerve ligation induced mechanical allodynia in saline-treated rats, with OX-42 and GFAP immunoreactivity being significantly increased on the ipsilateral side of the spinal cord. Continuously administered intrathecal lamotrigine (240 microg/day) prevented the development of mechanical allodynia, and lower dose of lamotrigine (72 microg/day) ameliorated allodynia. Intrathecal lamotrigine (72 and 240 microg/day) inhibited nerve ligation-induced microglial and astrocytic activation, as evidenced by reduced numbers of cells positive for OX-42 and GFAP. CONCLUSION: Continuously administered intrathecal lamotrigine blocked the development of mechanical allodynia induced by SNL with suppression of microglial and astrocytic activation. Continuous intrathecal administration of lamotrigine may be a promising therapeutic intervention to prevent neuropathy.

A Hyperactive Neutrophil Phenotype in Aggressive Periodontitis

Although neutrophils function in both defense and tissue destruction, their defensive roles have rarely been studied in association with periodontitis. We hypothesized that peripheral neutrophils are pre-activated in vivo in periodontitis and that hyperactive neutrophils would show enhanced phagocytic ability as well as an increased production of reactive oxygen species (ROS). Peripheral blood neutrophils from patients with aggressive periodontitis and age/gender-matched healthy subjects (10 pairs) were isolated. The levels of CD11b and CD64 expression on the neutrophils and the level of plasma endotoxin were determined by flow cytometry and a limulus amebocyte lysate test, respectively. In addition, neutrophils were subjected to a flow cytometric phagocytosis assay and luminol-enhanced chemiluminescence for non-opsonized Fusobacterium nucleatum in parallel. The neutrophilsfrom most patients expressed increased levels of both CD11b and CD64. In addition, the plasma from these patients tended to contain a higher level of endotoxin than the healthy controls. In contrast, no differences were found between the two groups with regard to phagocytosis or ROS generation by F. nucleatum. The ability to phagocytose F. nucleatum was found to positively correlate with the ability to produce ROS. In conclusion, peripheral neutrophils from patients with aggressive periodontitis are hyperactive but not hyperreactive to F. nucleatum.

Intrathecal lamotrigine blocks and reverses antinociceptive morphine tolerance in rats / 대한마취과학회지

BACKGROUND: Chronic administration of morphine leads to the development of tolerance. We investigated the effects of intrathecal lamotrigine on the spinal morphine tolerance in rats that are undergoing tail flick tests. METHODS: Sprague-Dawley rats were given intrathecal injections of saline 10 microl, lamotrigine 300 microg, morphine 15 microg or lamotrigine plus morphine combinations for 7 days (lamotrigine was given for days 1-7, days 1-3 or days 5-7). The acute and chronic nociceptive sensitivities were assessed using a tail flick test in which the distal 5 cm of the tail was dipped into warm water before and 30 minutes after the drug injection. With successive injections of morphine on day 8, a cumulative antinociceptive dose-response curve was constructed and the 50% effective dose (ED50) was calculated for each study group. RESULTS: The coinjection group of lamotrigine with morphine blocked the development of tolerance, as was shown by the preservation of morphine antinociception over 7 days and the concomitant decrease in the ED50 values on day 8, as compared with the morphine-alone group. Coinjection of lamotrigine blocked the development of morphine tolerance, as shown by the preservation of morphine antinociception over 7 days and the concomitant decrease in the ED50 values on day 8, as compared with the morphine-alone group. CONCLUSIONS: This study suggests that lamotrigine augments the antinociceptive action of both acute and chronic morphine therapy, and it also attenuates the antinociceptive morphine tolerance in rats.

Effect of intrathecal oxcarbazepine on rat tail flick test-determined morphine tolerance / 대한마취과학회지

BACKGROUND: Repeated administration of morphine leads to characteristic tolerance. We tested the effects of intrathecal oxcarbazepine (OXC) on spinal morphine tolerance in rats using the tail flick test. METHODS: Sprague-Dawley rats received intrathecal injections of 10 microliter saline alone, or 10 microliter of solutions containing 100 microgram OXC, 15 microgram morphine, or OXC + morphine for 7 days. Different groups of rats received OXC on days 1-7, 1-3, or 5-7. The tail-flick assay was used to measure acute and chronic nociception. The nociceptive stimulus consisted of dipping the distal 5 cm of the tail into warm water before and 30 min after drug injection. On day 8, an antinociceptive dose-response curve was plotted, and the 50% effective dose for morphine (given alone) was determined for all groups. RESULTS: Morphine or OXC both produced acute antinociception; OXC + morphine resulted in a significantly larger response than obtained with morphine alone. Morphine tolerance was produced by intrathecal injection of morphine over 7 days. Co-administration of morphine and OXC completely blocked morphine tolerance, but tolerance developed when OXC injection was stopped, and morphine potency was partially restored by co-administration of OXC in tolerant rats. CONCLUSIONS: The antinociceptive effect of both acute and chronic morphine therapy is increased with intrathecal OXC, and antinociceptive morphine tolerance is attenuated in rats.

The Antiallodynic Effects of Intrathecal Zaprinast in Rats with Chronic Constriction Injury of the Sciatic Nerve

BACKGROUND: Zaprinast is an inhibitor of phosphodiesterase 5, 6 and 9. Phosphodiesterase inhibitors could produce anti-nociceptive effects by promoting the accumulation of cGMP. We hypothesized that intrathecal zaprinast could attenuate the allodynia induced by chronic constriction injury of the sciatic nerve in rat. METHODS: Sprague-Dawley rats were prepared with four loose ligations of the left sciatic nerve just proximal to the trifurcation into the sural, peroneal and tibial nerve branches. Tactile allodynia was measured by applying von Frey filaments to the lesioned hindpaw. The thresholds for the withdrawal responses were assessed. Zaprinast (3-100microg) was administered intrathecally by the direct lumbar puncture method to obtain the dose-response curve and the 50% effective dose (ED50). Measurements were taken before and 15, 30, 45, 60, 90, 120, and 180 min after the intrathecal doses of zaprinast. The side effects were also observed. RESULTS: Intrathecal zaprinast resulted in a dose-dependent antiallodynic effect. The maximal effects occurred within 15-30 min and then they gradually decreased down to the baseline level over time in all the groups. There was a dose dependent increase in the magnitude and duration of the effect. The ED50 value was 17.4microg (95% confidence intervals; 14.7-20.5microg). No severe motor weakness or sedation was observed in any of the rats. CONCLUSIONS: Intrathecally administered zaprinast produced a dose-dependent antiallodynic effect in the chronic constriction injury neuropathic pain model. These findings suggest that spinal phosphodiesterase 5, 6 and 9 may play an important role in the modulation of neuropathic pain.

Changes of the Lipoprotein Profiles with Time after Discontinuation of Statin Therapy

BACKGROUND AND OBJECTIVES: Some patients stop statin therapy in spite of their doctors' advice. This study was designed to assess the pattern of lipoprotein profile changes and clinical characteristics of the patients who discontinued statin therapy. SUBJECTS AND METHODS: 69 patients (male 42.0%) were enrolled. The clinical characteristics and laboratory data on the lipoprotein levels were obtained from the medical records. RESULTS: The coexistence of diabetes mellitus (DM) was seen in 28% of the patients, hypertension was noted in 72% and coronary artery disease (CAD) was noted in 42%. The average lipoprotein levels during statin therapy were total cholesterol (TC)=163.8 mg/dL, triglycerides (TG)=174.3 mg/dL, high-density lipoprotein cholesterol (HDL-C)=34.8 mg/dL and low-density lipoprotein cholesterol (LDL-C)=94.2 mg/dL. LDL-C level increased by 44.9% at 2-3 months after ceasing statin therapy and by 54.6% at 4-6 months after ceasing statin therapy (p<0.01). The changes of the lipoprotein levels from baseline to 2-3 months and 4-6 months after discontinuation were +22.6% and +30.0% for the TC level, +20.8% and +24.0% for the TG level, and 0.06% and -0.65% for the HDL-C level respectively (p<0.01 for TC and TG, p=not significant (NS) for HDL-C). The achievement rate of target LDL-C level as suggested by the Adult Treatment Panel III (ATP III) of National Cholesterol Education Program (NCEP) was decreased 62.7% at 2-3 months and then it was decreased to 61.8% at 4-6 months after statin discontinuation. DM and CAD were more frequent in the patients who did not achieve the target LDL-C level even with life style modification. CONCLUSION: After statin discontinuation, TC and LDL-C were increased within 3 months. DM and CAD were highly prevalent in patients who didn't achieve their treatment goal.

Ischemic preconditioning in the rat hippocampus increases antioxidant activities but does not affect the level of hydroxyl radicals during subsequent severe ischemia

Several studies have demonstrated that ischemic preconditioning increases superoxide dismutase activity, but it is unclear how ischemic preconditioning affects events downstream of hydrogen peroxide production during subsequent severe ischemia and reperfusion in the hippocampus. To answer this question, we investigated whether ischemic preconditioning in the hippocampal CA1 region increases the activities of antioxidant enzymes glutathione peroxidase and catalase, resulting in a decrease in the level of hydroxyl radicals during subsequent severe ischemia-reperfusion. Transient forebrain ischemia was induced by four-vessel occlusion in rats. Ischemic preconditioning for 3 min or a sham operation was performed and a 15-min severe ischemia was induced three days later. Ischemic preconditioning preserved the CA1 hippocampal neurons following severe ischemia. The concentration of 2,3-dihydroxybenzoic acid, an indicator of hydroxyl radical, was measured using in vivo microdialysis technique combined with HPLC. The ischemia-induced increase in the ratio of 2,3-dihydroxybenzoic acid concentration relative to baseline did not differ significantly between preconditioned and control groups. On the other hand, activities of the antioxidant enzymes glutathione peroxidase-1 and catalase were significantly increased at 3 days after ischemic preconditioning in the hippocampus. Our results suggest that, in preconditioned rats, while hydrogen peroxide is generated from severe ischemia, the activity of catalase and glutathione peroxidase-1 is correspondingly increased to eliminate the excessive hydrogen peroxide. However, our results show that the enhanced activity of these antioxidant enzymes in preconditioned rats is not sufficient to decrease hydroxyl radical levels during subsequent severe ischemia-reperfusion.

Postischemic Treatment with Aminoguanidine Inhibits Peroxynitrite Production in the Rat Hippocampus Following Transient Forebrain Ischemia

Transient forebrain ischemia results in the delayed neuronal death in the CA1 area of the hippocampus. The present study was performed to determine effects of aminoguanidine, a selective iNOS inhibitor, on the generation of peroxynitrite and delayed neuronal death occurring in the hippocampus following transient forebrain ischemia. Transient forebrain ischemia was produced in the conscious rats by four-vessel occlusion for 10 min. Treatment with aminoguanidine (100 mg/kg or 200 mg/kg, i.p.) or saline (0.4 ml/100 g, i.p.) was started 30 min following ischemia-reperfusion and the animals were then injected twice daily until 12 h before sacrifice. Immunohistochemical method was used to detect 3-nitrotyrosine, a marker of peroxynitrite production. Posttreatment of aminoguanidine (200 mg/kg) significantly attenuated the neuronal death in the hippocampal CA1 area 3 days, but not 7 days, after ischemia-reperfusion. 3-Nitrotyrosine immunoreactivity was enhanced in the hippocampal CA1 area 3 days after reperfusion, which was prevented by the treatment of aminoguanidine (100 mg/kg and 200 mg/kg). Our findings showed that (1) the generation of peroxynitrite in the hippocampal CA1 area 3 days after ischemia-reperfusion was dependent on the iNOS activity; (2) the postischemic delayed neuronal death was attenuated in the early phase through the prevention of peroxynitrite generation by an iNOS inhibitor.