Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with 30 microg of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.
Animals ; Blood Glucose* ; Brain ; Corticosterone ; Glipizide ; Glyburide ; Immobilization* ; Insulin ; Mice ; Mice, Inbred ICR ; Plasma ; Tolazamide

BACKGROUND: The purposes of this study were (1) to investigate the abilities of word definition in patients with Alzheimer's disease (AD) according to the severity, and (2) to examine the error patterns in patients with Alzheimer's disease. METHODS: Eight individuals with MCI (CDR=0.5) and 16 patients with AD (eight for probable AD mild group of CDR=1 and eight for probable AD moderate group of CDR=2) participated in the study. Eight normal age-, gender-, and education-matched elderly adults served as a control group for the MCI and AD groups. As stimuli for the word definition, eleven semantic categories were used, and two concrete words were selected from each category, resulting in a total of 22 items. Prior to the task, four definition categories were provided: 1) functional, 2) relational, 3) perceptual, and 4) categorical. Statistical analyses were performed using Kruskal-Wallis test, and Bonferroni analyses were used as a post-hoc comparison for any significant results. RESULTS: There were significant differences in word definition scores among four groups. The probable AD moderate group showed the lower definition score than the probable AD mild group. And the probable AD moderate group showed the lower definition score than MCI group. Each group defined words in different ways. While the control group employed four definition different categories equally, the probable AD moderate group used a functional definition category mainly. However, relational and categorical definition categories were rarely observed in the probable AD moderate group. The analysis of error pattern showed that inadequate definition was frequently observed in all groups. CONCLUSIONS: The results from this study suggest that word definition task could be a sensitive indicator of the impairment of semantic knowledge in patients with AD.
Adult ; Aged ; Alzheimer Disease* ; Humans ; Mild Cognitive Impairment ; Semantics

The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (alpha-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with alpha-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, alpha-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.
Animals ; Blood Glucose* ; Cetirizine ; Dimaprit ; Down-Regulation ; Glucose ; Histamine* ; Mice* ; Mice, Inbred ICR ; Ranitidine ; Receptors, Histamine H2 ; Receptors, Histamine H3 ; Receptors, Histamine* ; Spinal Cord ; Up-Regulation

In the present study, the effect of intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration with cholera toxin (CTX) on the blood glucose level was examined in ICR mice. The i.t. treatment with CTX alone for 24 h dose-dependently increased the blood glucose level. However, i.c.v. treatment with CTX for 24 h did not affect the blood glucose level. When mice were orally fed with D-glucose (2 g/kg), the blood glucose level reached to a maximum level at 30 min and almost returned to the control level at 120 min after D-glucose feeding. I.c.v. pretreatment with CTX increased the blood glucose level in a potentiative manner, whereas i.t. pretreatment with CTX increased the blood glucose level in an additive manner in a D-glucose fed group. In addition, the blood glucose level was increased in formalin-induced pain animal model. I.c.v. pretreatment with CTX enhanced the blood glucose level in a potentiative manner in formalin-induced pain animal model. On the other hand, i.t. pretreatment with CTX increased the blood glucose level in an additive manner in formalin-induced pain animal model. Our results suggest that CTX administered supraspinally or spinally differentially modulates the regulation of the blood glucose level in D-glucose fed model as well as in formalin-induced pain model.
Animals ; Blood Glucose ; Brain ; Cholera ; Cholera Toxin ; Glucose ; Hand ; Mice ; Mice, Inbred ICR ; Models, Animal ; Spinal Cord

We have recently demonstrated that some anti-diabetic drugs such as biguanide and thizolidinediones administered centrally modulate the blood glucose level, suggesting that orally administered anti-diabetic drugs may modulate the blood glucose level by acting on central nervous system. The present study was designed to explore the possible action of another class of anti-diabetic drugs, glinidies, administered centrally on the blood glucose level in ICR mice. Mice were administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with 5 to 30 microg of repaglinide or nateglinide in D-glucose-fed and streptozotocin (STZ)-treated models. We found that i.c.v. or i.t. injection with repaglinide dose-dependently attenuated the blood glucose level in D-glucose-fed model, whereas i.c.v. or i.t. injection with nateglinide showed no modulatory action on the blood glucose level in D-glucose-fed model. Furthermore, the effect of repaglinide administered i.c.v. or i.t. on the blood glucose level in STZ-treated model was studied. We found that repaglinide administered i.c.v. slightly enhanced the blood glucose level in STZ-treated model. On the other hand, i.t. injection with repaglinide attenuated the blood glucose level in STZ-treated model. The plasma insulin level was enhanced by repaglinide in D-glucose-fed model, but repaglinide did not affect the plasma insulin level in STZ-treated model. In addition, nateglinide did not alter the plasma insulin level in both D-glucose-fed and STZ-treated models. These results suggest that the anti-diabetic action of repaglinide appears to be, at least, mediated via the brain and the spinal cord as revealed in both D-glucose fed and STZ-treated models.
Animals ; Blood Glucose ; Brain ; Carbamates ; Central Nervous System ; Cyclohexanes ; Glucose* ; Hand ; Insulin ; Mice* ; Mice, Inbred ICR ; Phenylalanine ; Piperidines ; Plasma ; Spinal Cord ; Streptozocin

Here we have investigated how lactosylceramide (LacCer) modulates gene expression of adhesion molecules in TNF-alpha and IFNgamma (CM)-stimulated astrocytes. We have observed that stimulation of astrocytes with CM increased the gene expression of ICAM-1 and VCAM-1. D-Threo-1-phenyl- 2-decanoylamino-3-morpholino-1-propanol (PDMP) and N-butyldeoxynojirimycin (NBDNJ), inhibitors of glucosylceramide synthase (GLS) and LacCer synthase (galactosyltransferase, GalT-2), inhibited the gene expression of ICAM-1 and VCAM-1 and activation of their gene promoter induced by CM, which were reversed by exogenously supplied LacCer. Silencing of GalT-2 gene using its antisense oligonucleotides also attenuated CM-induced ICAM-1 and VCAM-1 expression, which were reversed by LacCer. PDMP treatment and silencing of GalT-2 gene significantly reduced CM-induced luciferase activities in NF-KB, AP-1, GAS, and STAT-3 luciferase vectors-transfected cells. In addition, LacCer reversed the inhibition of NF-KB and STAT-1 luciferase activities by PDMP. Taken together, our results suggest that LacCer may play a crucial role in the expression of ICAM-1 and VCAM-1 via modulating transcription factors, such as NF-KB, AP-1, STAT-1, and STAT-3 in CM-stimulated astrocytes.
1-Deoxynojirimycin ; Antigens, CD ; Astrocytes ; Galactosyltransferases ; Gene Expression ; Glucosyltransferases ; Intercellular Adhesion Molecule-1 ; Lactosylceramides ; Luciferases ; Morpholines ; NF-kappa B ; Oligonucleotides, Antisense ; Transcription Factor AP-1 ; Transcription Factors ; Tumor Necrosis Factor-alpha ; Vascular Cell Adhesion Molecule-1

Visnagin (4-methoxy-7-methyl-5H-furo[3,2-g][1]-benzopyran-5-one), which is an active principle extracted from the fruits of Ammi visnaga, has been used as a treatment for low blood-pressure and blocked blood vessel contraction by inhibition of calcium influx into blood cells. However, the neuroprotective effect of visnagin was not clearly known until now. Thus, we investigated whether visnagin has a neuroprotective effect against kainic acid (KA)-induced neuronal cell death. In the cresyl violet staining, pre-treatment or post-treatment visnagin (100 mg/kg, p.o. or i.p.) showed a neuroprotective effect on KA (0.1 microgram) toxicity. KA-induced gliosis and proinflammatory marker (IL-1beta, TNF-alpha, IL-6, and COX-2) inductions were also suppressed by visnagin administration. These results suggest that visnagin has a neuroprotective effect in terms of suppressing KA-induced pathogenesis in the brain, and that these neuroprotective effects are associated with its anti-inflammatory effects.
Ammi ; Animals ; Benzoxazines ; Blood Cells ; Blood Vessels ; Brain ; Calcium ; Cell Death ; Contracts ; Cytokines ; Fruit ; Gliosis ; Glycosaminoglycans ; Hippocampus ; Interleukin-6 ; Kainic Acid ; Khellin ; Mice ; Neurons ; Neuroprotective Agents ; Tumor Necrosis Factor-alpha ; Viola

The present study demonstrates the effect of fibrates, agonists of PPARalpha on cytokines-induced proliferation in primary cultured astrocytes. Alone or combination treatment with cytokines, such as IL-1beta (10 ng/ml), IFNgamma (10 ng/ml), and TNF-alpha (10 ng/ml) cause a significant increase of cell proliferation in a time-dependent manner. Treatment of astrocytes with bezafibrate and fenofibrate (0, 5, and 10 micrometer) reduced the IFNgamma and IL-1beta-induced cell proliferation in a dose-dependent manner. To address the involvement of IL-6 on the IFNgamma and IL-1beta-induced cell proliferation, released IL-6 level was measured. IFNgamma and IL-1beta cause an increase of released IL-6 protein level in a time-dependent manner. Furthermore, pretreatment with IL-6 antibody (0, 0.1, 1, 2.5, and 5 ng/ml) dose-dependently inhibited the IFNgamma and IL-1beta-induced cell proliferation. However, bezafibrate and fenofibrate did not affect increased mRNA and protein levels of IL-6 in IFNgamma and IL-1beta-stimulated astrocytes. Taken together, these results clearly suggest that activation of PPARalpha attenuates the IFNgamma and IL-1beta-induced cell proliferation through IL-6 independent pathway.
Astrocytes ; Bezafibrate ; Cell Proliferation ; Cytokines ; Fenofibrate ; Fibric Acids ; Interleukin-6 ; PPAR alpha ; RNA, Messenger ; Tumor Necrosis Factor-alpha

PURPOSE: To explore the role of cell cycle and apoptosis regulators during hepatocarcinogenesis, the expression of cell cycle-related proteins (cyclin D1 and p27kip1) and apoptosis-related proteins (p53, survivin, caspase 3). METHODS: Sprague-Dawley rats were given 120 ppm diethylnitrosamine (DEN) as a carcinogen and sequentially sacrificed. The expression of cell cycle and apoptotic related proteins were examined by light microscopy and immunohistochemistry. RESULTS: During the DEN-induced hepatocarcinogenesis, sequential histologic changes from preneoplastic lesions (altered hepatic cellular foci, hyperplastic nodules, and hepatocellular adenomas) and ultimately overt hepatocellular carcinomas and metastatic lesions were noted. The cyclin D1 were progressively increased from preneoplastic lesions to hepatocellular carcinomas. However, the p27kip1 and the survivine proteins did not show any other difference with the increasing degree of carcinogenesis. The p53 and caspase 3 proteins were more significantly increased in hepatocellular carcinomas than preneoplastic lesions. The cyclin D1 protein expression did not show any correlation with the expression of p27Kip1 protein, but the p53 expression was related to the expression of survivin and caspase 3. CONCLUSION: From the above results, over-expression of cyclin D1 plays a role in the early and late stages of hepatocarcinogenesis. In addition p53 and caspase 3 might be useful markers for evaluating the risk of malignant transformation.
Animals ; Apoptosis ; Carcinoma, Hepatocellular ; Caspase 3 ; Cell Cycle ; Cyclin D1 ; Cyclin-Dependent Kinase Inhibitor p27 ; Diethylnitrosamine ; Light ; Microscopy ; Proteins ; Rats ; Rats, Sprague-Dawley

BACKGROUND: Tricuspid regurgitation has been considered as a secondary lesion when it is combined with left valvular heart diseases. However, there have been some reports which show that tricuspid regurgitation keeps going and results in congestive heart failure even after a successful operation for left valvular heart disease. So far, there are no definite operation indications and predictive factors for the tricuspid regurgitation which is resulted from the left sided valvular heart disease. We designed this study to evaluate the effects of pulmonary artery pressure and left ventricular ejection fraction on the prognosis of tricuspid regurgitation, and to make an operation indication for the patients with secondary tricuspid regurgitation. MATERIAL AND METHOD: We reviewed the medical records of patients who underwent surgery for the left sided valvular heart disease with tricuspid regurgitation and were followed for more than 1 year with echocardiograms. There was a total of 114 cases. We compared the grades of tricuspid regurgitations and pulmonary artery pressures and left ventricular ejection fractions on the basis of echocardiograms which were checked preoperatively and on the last follow up. RESULT: There were 43 cases of tricuspid annuloplasty. In these patients, the grades of tricuspid regurgitations were improved in 42 cases (97.7%). But in 71 cases without annuloplasty, 29 cases (41%) were improved, 32 cases (45%) had no change, and 10 cases (14%) were aggravated. This finding shows significant differences in the prognoses of tricuspid regurgitations between the two groups (p<0.05). There was no difference in pulmonary artery pressures and ejection fractions between the patients who showed progression of tricuspid regurgitations and those who didn't (p>0.05). The improvements of tricuspid regurgitations are not statistically related to the changes of pulmonary artery pressures or left ventricular ejection fractions. CONCLUSION: This study shows that it is impossible to predict the prognoses of tricuspid regurgitations with preoperative pulmonary artery pressures or left ventricular ejection fractions. Also, the excellent results of tricuspid annuloplasty is proven in controlling the secondary tricuspid regurgitations. Therefore, when tricuspid regurgitation is detected preoperatively, the procedures to correct the tricuspid regurgitation at the time of the operation for the left-sided valvular heart disease must be considered positively, regardless of the grades of tricuspid regurgitations, to prevent significant tricuspid regurgitation that may develop later.
Follow-Up Studies ; Heart Failure ; Heart Valve Diseases* ; Humans ; Medical Records ; Prognosis* ; Pulmonary Artery ; Stroke Volume ; Tricuspid Valve Insufficiency*