Biomedical subjects

T Araki

Publications and source records attributed to T Araki.

At least 37 records · Page 2Linked to original sources

PubMed2003

Effects of extracellular Na+ and Ca2+ ions and Ca2+ channel modulators on the cell-associated activity of 99mTc-MIBI and 99mTc-tetrofosmin in tumour cells.

Our aim was to determine whether the Ca2+ ion or cell membrane Ca2+ and Na+/Ca2+ ion transport systems are involved in maintaining the cell-associated activity of technetium-99m-hexakis-methoxy-isobutyl-isonitrile (99mTc-MIBI) and technetium-99m-ethylene-bis[bis(2-ethoxyethyl)phosphin] (99mTc-tetrofosmin) in tumour cell lines. The cell-associated activities of 99mTc-MIBI and 99mTc-tetrofosmin were assessed in various buffers, with or without Na+ and/or with different concentrations of Ca2+, in Lewi's murine lung cell carcinoma and human glioma cell lines. Different Ca2+ channel modulators, such as verapamil, flunarizine and 3,4-dichlorobenzamil (DCB), were used to assess the effect of Ca2+ channels on the cell-associated activity of 99mTc-MIBI and 99mTc-tetrofosmin. Despite significant differences between cell lines, the cell-associated activity of 99mTc-MIBI was higher in buffers without extracellular Ca2+ and Na+. The cell-associated activity of 99mTc-MIBI was significantly lower in all buffers containing high concentrations of Ca2+ in both cell lines. The cell-associated activity of Tc-tetrofosmin was also significantly higher in buffers without Ca2+, and was significantly decreased in buffers with high concentrations of Ca2+. All modulators significantly increased the cell-associated activity of 99mTc-MIBI in both cell lines in all buffers. All modulators increased the cell-associated activity of 99mTc-tetrofosmin, particularly in buffers containing Ca2+. The cell-associated activities of both 99mTc-MIBI and 99mTc-tetrofosmin may be dependent on verapamil-, flunarizine- and DCB-sensitive Ca2+ channels.

Amiloride↗

PubMed2003

A novel therapeutic approach combining human plasma-derived Factors VIIa and X for haemophiliacs with inhibitors: evidence of a higher thrombin generation rate in vitro and more sustained haemostatic activity in vivo than obtained with Factor VIIa alone.

BACKGROUND AND OBJECTIVES: Therapy with recombinant Factor VIIa (rFVIIa) for haemophiliacs with inhibitors still has some unresolved problems, such as the requirement for frequent infusions of rFVIIa every 2-3 h to sustain haemostatic activity for an extended time-period and that the therapeutic dose of rFVIIa is not always predictable. In the present study, we searched for an effective combination of plasma-derived FVIIa with other blood coagulation factors, and demonstrated that a therapeutic approach combining plasma-derived FVIIa and Factor X (FX) was more useful for treating haemophiliacs with inhibitors than FVIIa alone. MATERIALS AND METHODS: The haemostatic effects of FVIIa and FX were evaluated in vitro and in vivo. In in vitro experiments we assessed the following: the ability to enhance the thrombin generation rate in a reconstituted blood coagulation model without Factor VIII (FVIII) or Factor IX (FIX); the ability to correct the activated partial prothrombin time (APTT) of FVIII-depleted plasma or FIX-depleted plasma; and the ability to correct the clotting time of haemophilia-like whole blood using thromboelastography (TEG). In in vivo experiments, the haemostatic activity of the combination treatment of FVIIa and FX was determined by measuring the bleeding time and TEG using a monkey haemophilia B model produced by the injection of anti-human FIX polyclonal antibodies. The degree of thrombogenicity of the combination was evaluated using the rabbit stasis model. RESULTS: The addition of FX to FVIIa dramatically enhanced the thrombin generation rate in the reconstituted blood coagulation model and corrected the prolonged APTTs of FVIII- and FIX-depleted plasmas to levels achieved by the replacement therapies. In contrast, the addition of prothrombin to FVIIa did not show such enhancing activity. Furthermore, FVIIa-induced whole blood clotting times in the FVIII- and FIX-inhibited states were also shortened by the addition of FX in a concentration-dependent manner. Finally, the co-administration of FVIIa (80 microg/kg) and FX (800 microg/kg) in a monkey haemophilia B model resulted in a more robust and persistent haemostatic effect on the secondary bleeding time and whole-blood clotting time of TEG than that of FVIIa alone. The results of rabbit stasis tests for evaluating the risk of thrombogenicity showed that the combination of FVIIa and FX was less thrombogenic than FEIBA. CONCLUSIONS: The present study demonstrated that the combination of FVIIa and FX appeared to have a higher and more sustainable haemostatic potential than FVIIa alone, and less thrombogenicity than FEIBA. A therapeutic approach combining FVIIa and FX could be a promising and novel approach to compensate for the disadvantages of rFVIIa and FEIBA for haemophiliacs with inhibitors.

Animals↗

PubMed2003

Scanning transmission X-ray, laser scanning, and transmission electron microscopy mapping of the exopolymeric matrix of microbial biofilms.

Confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM), and soft X-ray scanning transmission X-ray microscopy (STXM) were used to map the distribution of macromolecular subcomponents (e.g., polysaccharides, proteins, lipids, and nucleic acids) of biofilm cells and matrix. The biofilms were developed from river water supplemented with methanol, and although they comprised a complex microbial community, the biofilms were dominated by heterotrophic bacteria. TEM provided the highest-resolution structural imaging, CLSM provided detailed compositional information when used in conjunction with molecular probes, and STXM provided compositional mapping of macromolecule distributions without the addition of probes. By examining exactly the same region of a sample with combinations of these techniques (STXM with CLSM and STXM with TEM), we demonstrate that this combination of multimicroscopy analysis can be used to create a detailed correlative map of biofilm structure and composition. We are using these correlative techniques to improve our understanding of the biochemical basis for biofilm organization and to assist studies intended to investigate and optimize biofilms for environmental remediation applications.

Bacteria↗

PubMed2002

Changes in the proportion of T helper 1 and T helper 2 cells in cord blood after premature rupture of membranes.

This study investigated changes in the proportion of T helper (Th)1 and Th2 cells in cord blood after premature rupture of membranes (PROM), and evaluate the effects of PROM on the intrauterine fetal immune status. The proportion of CD3-positive T cells secreting interferon (IFN)-gamma as an index of Th1 cells, and interleukin (IL)-4 as an index of Th2 cells in cord blood of 12 newborns with and without PROM, were analyzed by flow cytometry. In cord blood of newborns with PROM, the proportion of IFN-gamma secreting cells significantly increased, and the proportion of IL-4 secreting cells was rather high but not significantly higher than that of newborns without PROM. These changes eventually caused a shift in the Th1/Th2 ratio to Th1 dominance in PROM. There was no significant correlation between the proportion of IFN-gamma secreting cells and the duration of PROM before the onset of labor. These results suggest that the increase in the proportion of IFN-gamma secreting cells after PROM, which eventually cause the Th1/Th2 ratios to show the Th1 predominance, may reflect in part intrauterine fetal immune responses to PROM.

Adult↗

PubMed2002

Serum adenosine deaminase activity and its isoenzyme pattern in women with normal pregnancies.

Adenosine deaminase (ADA) is a purine enzyme which is essential for the proliferation, maturation and function of lymphoid cells, and congenital deficiency of this enzyme is associated with severe combined immunodeficiency disease. The activity of ADA has changed in diseases characterized by the alteration of cell-mediated immunity such as rheumatoid arthritis, systemic lupus erythematosus and tuberculosis, so ADA has been considered as a nonspecific marker of cell-mediated immunity. In this study we examined changes in serum total ADA activity and the patterns of two ADA isoenzymes, ADA1 and ADA2 in normal pregnant women, and evaluated the possible role of the alteration of cell-mediated immunity during normal pregnancy as causes of changes in ADA activity. We measured serum activities of total ADA, ADA1 and ADA2 in normal pregnant women in the third trimester (n=24) and age-matched healthy nonpregnant women (n=24). Peripheral blood lymphocytes and monocytes were also measured. In normal pregnant women, serum total ADA activity averaged 10.5 +/- 0.5 U/L, which was significantly lower than in nonpregnant women (14.0 +/- 0.5 U/L ) (p<0.05), and mean serum ADA2 activity also significantly reduced that of nonpregnant women (p<0.05). There was no significant difference in ADA1 activity in normal pregnant and nonpregnant women. The decrease in total ADA activity was accompanied by the decrease in lymphocyte count. These results suggest that reduced serum total ADA activity reflects decrease in ADA2 activity, and which may be in part associated with depressed cell-mediated immunity during normal pregnancy.

Adenosine Deaminase↗

PubMed2002

Assessment of the hepatic arterial and portal venous blood flows during pregnancy with Doppler ultrasonography.

PURPOSE: The aim of this study was to evaluate whether the dual hepatic blood supply is altered in healthy pregnant women compared with that in nonpregnant women. MATERIALS AND METHODS: Flow wave-forms in common hepatic artery and portal vein were obtained in 67 healthy pregnant women at 10-40 weeks gestation and 22 nonpregnant women by using Doppler ultrasonography. RESULTS: In the nonpregnant group, the mean (SD) hepatic arterial blood flow, portal venous blood flow, and total liver blood flow were 0.57 (0.31) L/min, 1.25 (0.46) L/min, and 1.82 (0.63) L/min, respectively. In the healthy pregnant group, the portal venous blood flow and total liver blood flow significantly increased after 28 weeks gestation. However, the hepatic arterial blood flow remained unchanged during pregnancy. There was no relationship between the hepatic arterial blood flow and the portal venous blood flow. CONCLUSION: The results demonstrated that the hepatic perfusion increased during third trimester compared to nonpregnant level. Because the hepatic arterial blood flow remained unchanged during pregnancy, major determinant of the increase in the hepatic perfusion was the portal venous return. The data suggest that the hepatic arterial and portal venous vascular territories have regulatory mechanisms that allow for independent changes during pregnancy.

Adult↗

PubMed2002

Maternal plasma adenosine and endothelin-1 levels in twin gestation complicated by preeclampsia.

The aim of this study was to evaluate the relationship between the vascular resistance in uterine arteries and the maternal release of adenosine and endothelin-1 in twin gestations with and without preeclampsia. Uterine artery Doppler velocimetry and maternal arterial blood sampling were performed in 14 women with normal singleton gestation, nine women with singleton gestation with preeclampsia, eight women with dichorionic twin gestation without preeclampsia and six women with dichorionic twin gestation with preeclampsia at 28-34 weeks' gestation. In normal singleton gestations, the average maternal uterine arteries pulsatility index (PI), plasma adenosine and endothelin-1 levels were 0.64+/-0.07, 0.34+/-0.11 micromol/l and 1.29+/-0.31 pg/ml, respectively. In preeclamptic singleton gestations, increased vascular resistance in the uterine arteries (PI: 0.85+/-0.14, P<0.05) and the elevation of maternal arterial plasma adenosine (0.48+/-0.14 micromol/l, P<0.05) and endothelin-1 levels (1.91+/-0.55 pg/ml, P<0.05) were observed. In the normal twin gestation group, the average maternal vascular resistance of the uterine arteries (PI: 0.55+/-0.09) was lower than that in the normal singleton gestation group, while the average plasma adenosine levels (0.47+/-0.12 micromol/l) were higher than that in normal singleton gestation. On the other hand, significant increased plasma endothelin-1 concentrations (1.87+/-0.42 pg/ml) were observed in the preeclamptic twin gestation groups without changes in plasma adenosine levels or vascular resistance of uterine arteries. Our results indicate the presence of different mechanisms for the pathogenesis of preeclampsia between twin and singleton gestations.

Adenosine↗

PubMed2002

Therapeutic effect of neuronal nitric oxide synthase inhibitor (7-nitroindazole) against MPTP neurotoxicity in mice.

Effects of neuronal nitric oxide synthase (nNOS) inhibitor (7-nitroindazole), nonselective NOS inhibitor (N(G)-nitro-L-arginine methyl ester; L-NAME), and monoamine oxidase inhibitor (pargyline) were studied on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The mice received four intraperitoneal injections of MPTP at 1-h intervals. A significant depletion in dopamine and DOPAC concentration was observed in the striatum from 1 day after MPTP treatment. The pretreatment of 7-nitroindazole and pargyline, but not L-NAME, dose-dependently protected against MPTP-induced depletion in dopamine content 3 days after MPTP treatment. Our histochemical study also showed that 7-nitroindazole and pargyline can prevent a marked decrease in the nigral cells and a marked increase in astrocytes in striatum 7 days after MPTP treatment. The protective effect of 7-nitroindazole against MPTP-induced dopamine and DOPAC depletion in the striatum was not attenuated by intraperitoneal pretreatment with L-arginine. Furthermore, the posttreatment of 7-nitroindazole or pargyline protected against MPTP-induced depletion of dopamine content. These results demonstrate that the protective mechanism by which 7-nitroindazole counteracts MPTP neurotoxicity in mice may be due not only to inhibition of nNOS, but also to MAO-B inhibition. Furthermore, our study suggests that the posttreatment of 7-nitroindazole and pargyline can prevent a significant decrease in dopamine levels in the striatum of MPTP-treated mice. These findings have important implications for the therapeutic time window and choice of nNOS or MAO inhibitors in patients with Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2002

Threshold values of visceral fat measures and their anthropometric alternatives for metabolic derangement in Japanese obese boys.

OBJECTIVE: To determine whether the direct measure of visceral adipose tissue (VAT) by computed tomography (CT) is a superior diagnostic criterion to the anthropometric surrogates and more classical criteria of obesity. DESIGN: Cross-sectional, clinical study. Obese boys were classified according to the occurrence of abnormal values in either serum triglyceride, alanine aminotransferase or insulin level. A threshold value of each criterion for such metabolic derangement was calculated, using the analysis of receiver operating characteristic (ROC) curve. SUBJECTS: Seventy-five consecutive outpatient Japanese obese boys, ranging in age from 6 to 14 y, were studied. MEASUREMENTS: Anthropometric indices measured were height, body weight, waist girth, hip girth, triceps and subscapular skinfold thicknesses. Classical criteria for obesity used were percentage overweight (POW), body mass index (BMI) and percentage body fat. Waist girth, sagittal diameter by CT and waist-hip ratio (WHR) were evaluated as anthropometric surrogates for VAT. The areas of total abdominal fat (TAF), VAT and subcutaneous adipose tissue (SAT) were measured by CT at the level of the umbilicus. Clinical blood biochemistry was analyzed in fasting blood samples of obese boys. RESULTS: Thirty-three boys were classified into a no-complication group, and 42 into a complication group. TAF, VAT and SAT areas were closely associated with age, body size and degree of overweight and adiposity, while VAT/SAT was not. VAT area, sagittal diameter, TAF area and waist girth were closely correlated with alanine aminotransferase, insulin, TG and HDL-C. VAT/SAT, BMI, SAT area, WHR, percentage body fat and POW were less closely associated with these biochemical indices. The descending order of the values of area under the curve for the ROC curves were as follows: VAT>sagittal diameter>TAF>VAT/SAT>waist girth>BMI>WHR>percentage body fat>POW. Both VAT area and VAT/SAT gave >80% of sensitivity and specificity. Among the anthropometric indices studied, the sagittal diameter was the best surrogate of visceral fat measure. The sensitivity and specificity for the rest of the anthropometric indices were in an unsatisfactory range. The threshold values for VAT area, VAT/SAT and sagittal diameter were 58.0 cm(2), 0.276 and 19.2 cm, respectively. CONCLUSION: The threshold values for VAT area, VAT/SAT and sagittal diameter for detecting biochemical complication in Japanese obese boys were lower than the respective values reported in adults. These values can be used for classifying the obese boys into two types: those with medical problem and those without.

Abdomen↗

PubMed2002

Reproducibility of pulsed Doppler measurements of the maternal renal circulation in normal pregnancies and those with pregnancy-induced hypertension.

OBJECTIVE: To assess the inter- and intraobserver reproducibilities of pulsed Doppler measurements of the maternal renal circulation in normal pregnancies and those affected by pregnancy-induced hypertension. MATERIALS AND METHODS: Color and pulsed Doppler ultrasound was used to measure acceleration time and resistance index in the renal segmental and interlobar arteries. For the investigation of interobserver reproducibility, two sonographers performed measurements blindly in six normal pregnant women and 14 women with pregnancy-induced hypertension between 28 and 36 weeks' gestation. A second group of 10 patients between 30 and 35 weeks' gestation were examined by one sonographer to assess the level of intraobserver reproducibility of measurements. For each patient in this group, the flow waveform was measured three times in succession. Calculations of the intraclass correlation coefficient Ri were used to determine the level of reproducibility. RESULTS: The interobserver Ri and intraobserver Ri for acceleration time in the segmental artery were 0.95 and 0.96 and for the interlobar artery they were 0.97 and 0.98, respectively. For the resistance index, these values were 0.01 and 0.01 in the segmental artery and 0.52 and 0.29 in the interlobar artery. CONCLUSION: Both the inter- and intraobserver reproducibility of acceleration time measurements in the renal segmental and interlobar arteries were clinically acceptable but the equivalent reproducibilities of resistance index measurements were poor.

Adult↗

PubMed2002

Optically stimulated luminescence in an imaging plate using BaFi:Eu.

BaFI:Eu phosphors are fabricated using a new method of synthesis: liquid phase synthesis, in which the phosphor particles are formed through the association of Ba2+ ions, F-ions and Eu2+ ions in solution. An intense optically stimulated luminescence (OSL) peak at about 410 nm is observed by stimulating X ray irradiated BaFI:Eu phosphor with about 550-750 nm light. It is found that the peak wavelength of the optically stimulation spectrum is about 690 nm. This result suggests that the semiconductor laser can be used as the stimulating light source. It is also found that the OSL intensity is increased with increasing the X ray dose. The BaFI:Eu phosphor as a photostimulable material for the imaging plate of a computed radiography system provides the following advantages; (1) high X ray absorption coefficient, (2) high monodispersion in size which would contribute to sharp images, (3) high OSL and thus low luminescence mottle and (4) high DQE (detective quantum efficiency).

Barium Compounds↗

PubMed2002

Gamma-aminobutyric acidA and benzodiazepine receptor alterations in the rat brain after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle.

Gamma-aminobutyric acidA (GABA(A)) and benzodiazepine (BZ) receptors and dopamine uptake sites in 6-hydroxydopamine-treated rat brains were studied by receptor autoradiography using [3H]muscimol, [3H]flunitrazepam and [3H]mazindol binding, respectively. The rats were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks post-lesion. Degeneration of the nigrostriatal pathway after 6-hydroxydopamine treatment caused a significant loss of dopamine uptake sites in the ipsilateral striatum and substantia nigra (SN) in the lesioned animals. In the contralateral side, however, dopamine uptake sites showed no significant changes in the brain throughout the experiments. On the other hand, no significant changes in GABA(A) receptors were observed in the brain of both the ipsilateral and contralateral sides during post-lesion. In contrast, BZ receptors were observed significantly increased in the ventromedial part of striatum of the ipsilateral side from 2 to 4 weeks post-lesion. Furthermore, a transient increase in BZ receptors was found in the ipsilateral SN only at 2 weeks post-lesion. In contralateral side, most regions examined showed no significant changes in BZ receptors throughout the experiments except for a transient increase in the SN at 1 week post-lesion. These results demonstrate that 6-hydroxydopamine can cause severe functional damage in dopamine uptake sites in the nigrostriatal pathway. Our results also suggest that the change in BZ receptors is more pronounced than that in GABA(A) receptors in the brain after 6-hydroxydopamine treatment. Furthermore, our findings suggest that the increase in BZ receptors in the brain of 6-hydroxydopamine-treated model may be due to the additional disruption of the nigrostriatal dopamine system. Thus, investigations into possible changes in neurotransmitter receptors other than dopaminergic receptors appear to be important for the elucidation of pathogenesis of Parkinsons disease.

Animals↗

PubMed2002

Role of nitric oxide synthase against MPTP neurotoxicity in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway injury similar to that observed in Parkinson's disease. Many hypotheses have been proposed to explain the mechanisms underlying MPTP neurotoxicity. Previous work showed that the inhibitor of neuronal nitric oxide synthase (nNOS) might produce protection against MPTP-induced dopaminergic toxicity. To exactly test the role of NO in MPTP neurotoxicity, we examined the effect of nNOS inhibitor 7-nitroindazole, in comparison with that of nonselective NOS inhibitor (L-NAME), immunosuppressant (FK-506), monoamine oxidase (MAO) inhibitors (clorgyline and pargyline), N-methyl-D-aspartate receptor antagonist (MK-801) and Ca2+ antagonist (amlodipine). Among seven compounds, 7-nitroindazole produced dose-dependent protection against MPTP-induced depletion of striatal dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid (DOPAC) in mice. Clorgyline and pargyline also showed a significant effect on MPTP-induced dopamine depletion in the mouse striatum. However, both compounds did not protect against MPTP-induced depletion of striatal DOPAC Our immunohistological study with tyrosine hydroxylase (TH) and microtuble-associated protein 2 (MAP 2) showed that 7-nitroindazole or pargyline can protect against MPTP-induced depletion of TH and MAP 2 immunostained neurons in the substantia nigra. Furthermore, these compounds reduced a marked increase in GFAP-positive astrocytes of the mouse striatum after MPTP treatments. The present study demonstrates that nNOS inhibitor 7-nitroindazole as well as MAO inhibitors clorgyline and pargyline can produce dose-dependent neuroprotection against the dopaminergic neurotoxicity of MPTP. However, nonselective NOS inhibitor L-NAME, immunosuppressant FK-506, NMDA receptor antagonist MK-801 and Ca2+ antagonist amlodipine did not show a beneficial effect on MPTP neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2001

Endothelin-1 gene variant associates with blood pressure in obese Japanese subjects: the Ohasama Study.

A recent report based on the results of 2 epidemiological studies, the Etude Cas-Temoin de l'Infarctus Myocarde (ECTIM) and the Glasgow Heart Scan Study, revealed that a G/T polymorphism with an amino acid substitution (Lys-->Asn) at codon 198 in exon 5 of the endothelin-1 gene (ET-1) is associated with blood pressure in overweight people. They suggested that G/T polymorphism of ET-1 strongly interacted with body mass index (BMI) in the determination of BP levels. To examine interaction among G/T polymorphism of ET-1, BMI, and BP, we performed an association study in a general Japanese population. Subjects (n=1250) were recruited from Ohasama, a cohort in a rural community of northern Japan. DNA was extracted from buffy coat of participants, and G/T polymorphism of ET-1 was determined by the TaqMan probe polymerase chain reaction method, a powerful tool for semiautomatic genotype determination of a large number of samples. Frequency of T (Asn 198) allele in Japanese (27%) was slightly but significantly higher than in whites (24%). Baseline characteristics (age, BMI, systolic and diastolic BP, and antihypertensive treatment) of all subjects were not significantly different according to the genotype of G/T polymorphism. However, in obese subjects (> or =25 kg/m(2)) diastolic BPs were significantly associated with G/T polymorphism of ET-1. After adjustment for confounding factors, significant association remained; for overweight subjects, diastolic BP level in those with T allele (GT + TT) was 1.8 mm Hg (P=0.04) higher than in those with GG genotype. That similar results were obtained from subjects of different races suggests that the Lys198Asn polymorphism of ET-1 is involved in determination of BP levels in obese subjects.

Asian People↗

PubMed2001

Neuroprotective effect of riluzole in MPTP-treated mice.

The neuroprotective effects of riluzole, a Na(+) channel blocker with antiglutamatergic activity, and MK-801, a blocker of N-methyl-D-aspartate (NMDA) receptors, were compared in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in mice. The mice were injected intraperitoneally (i.p.) with four administrations of MPTP (10 mg/kg) at 1 h intervals and then the brains were analyzed 1, 3 and 7 days after the treatment. Dopamine and DOPAC levels were significantly decreased in the striatum from 1 day after MPTP treatment. A severe depletion in dopamine and DOPAC levels was found in the striatum 3 and 7 days after MPTP treatment. Riluzole antagonized the MPTP-induced decrease in dopamine, DOPAC and HVA levels in the striatum. On the other hand, MK-801 prevented the MPTP-induced decrease in DOPAC levels, but not in dopamine levels in the striatum. An immunohistochemical study indicated that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra. These results suggest that riluzole is effective against MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2001

Riluzole (2-amino-6-trifluoromethoxy benzothiazole) attenuates MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice.

The protective effects of 2-amino-6-trifluoromethoxy benzothiazole (riluzole), a Na(+) channel blocker with antiglutamatergic activity were investigated in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in mice. The mice were injected intraperitoneally (i.p.) with four administrations of MPTP (10 mg/kg) at 1 h intervals and then the brains were analyzed at 3 and 7 days after the treatments. Dopamine, DOPAC and HVA levels were significantly decreased in the striatum 3 days after MPTP treatments. Riluzole dose-dependently antagonized the MPTP-induced decrease in dopamine, DOPAC and HVA levels in the striatum. MPTP treatment also caused a severe decrease in the amount of nigral tyrosine hydroxylase protein (TH) and microtuble-associated protein 2 (MAP 2) and produced a marked increase in the striatal glial fibrillary acidic protein (GFAP). Our immunohistochemical study with TH and MAP 2 staining showed that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra. Furthermore, riluzole markedly increased the striatal GFAP-positive astrocytes 3 days after MPTP treatments. These results suggest that riluzole is effective against MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway. Our findings also may provide a rationale for the identification of astrocytes as a prominent target for the development of new therapies of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2001

Expression profiling reveals hepsin overexpression in prostate cancer.

Prostate cancer is the most commonly diagnosed noncutaneous cancer in men. Despite this fact, many of the genetic changes that coincide with prostate cancer progression remain enigmatic. We have addressed this problem by characterizing the expression profiles of several benign and malignant human prostate samples, and we have identified several genes that are differentially expressed between benign and malignant glands. One gene that was overexpressed encodes the serine protease hepsin. We used an independent sample set to confirm that hepsin is overexpressed in prostate tumors, and in situ hybridization demonstrates that hepsin is specifically overexpressed in the carcinoma cells themselves. These facts, together with the molecular properties of hepsin, make it an ideal target for prostate cancer therapy.

Gene Expression Profiling↗

PubMed2001

Identification of genes induced in peripheral nerve after injury. Expression profiling and novel gene discovery.

Peripheral nerve injury results in axonal degeneration and in phenotypic changes of the surrounding Schwann cells, whose presence is critical for nerve regeneration. To identify genes induced after nerve injury in Schwann cells, we developed a strategy that included differential screening of a subtractive library enriched for cDNAs expressed in injured nerve, sequence analysis, and expression profiling. By using real time quantitative reverse transcriptase-polymerase chain reaction, we found that injury-induced genes could be categorized into four temporal expression patterns. Among the clones we identified were a number that were homologous only to expressed sequence tags in the data base. These were stratified based on their expression profile, presence of identifiable sequence motifs, homologies to other proteins, and evolutionary conservation. We chose one representative gene, nin283, to analyze in detail. The nin283 gene encodes a 227-residue protein containing both a zinc finger and a RING finger motif. nin283 is highly expressed in the central nervous system, particularly in the developing cortical plate in embryos. It is also expressed in peripheral ganglia and is induced by nerve growth factor in PC12 cells. Subcellular localization analysis demonstrated that Nin283 is located in the endosome/lysosome compartment, suggesting that it may participate in ubiquitin-mediated protein modification.

Amino Acid Motifs↗