Biomedical subjects

S S Oja

Publications and source records attributed to S S Oja.

At least 19 recordsLinked to original sources

PubMed2006

Taurine release in mouse brain stem slices under cell-damaging conditions.

Taurine has been thought to be essential for the development and survival of neural cells and to protect them under cell-damaging conditions. In the brain stem taurine regulates many vital functions, including cardiovascular control and arterial blood pressure. We have recently characterized the release of taurine in the adult and developing brain stem under normal conditions. Now we studied the properties of preloaded [3H]taurine release under various cell-damaging conditions (hypoxia, hypoglycemia, ischemia, the presence of metabolic poisons and free radicals) in slices prepared from the mouse brain stem from developing (7-day-old) and young adult (3-month-old) mice, using a superfusion system. Taurine release was greatly enhanced under these cell-damaging conditions, the only exception being the presence of free radicals in both age groups. The ischemia-induced release was characterized to consist of both Ca2+-dependent and -independent components. Moreover, the release was mediated by Na+-, Cl--dependent transporters operating outwards, particularly in the immature brain stem. Cl- channel antagonists reduced the release at both ages, indicating that a part of the release occurs through ion channels, and protein kinase C appeared to be involved. The release was also modulated by cyclic GMP second messenger systems, since inhibitors of soluble guanylyl cyclase and phosphodiesterases suppressed ischemic taurine release. The inhibition of phospholipases also reduced taurine release at both ages. This ischemia-induced taurine release could constitute an important mechanism against excitotoxicity, protecting the brain stem under cell-damaging conditions.

2,4-Dinitrophenol↗

PubMed2006

Characteristics of taurine release in slices from adult and developing mouse brain stem.

Taurine has been thought to function as a regulator of neuronal activity, neuromodulator and osmoregulator. Moreover, it is essential for the development and survival of neural cells and protects them under cell-damaging conditions. Taurine is also involved in many vital functions regulated by the brain stem, including cardiovascular control and arterial blood pressure. The release of taurine has been studied both in vivo and in vitro in higher brain areas, whereas the mechanisms of release have not been systematically characterized in the brain stem. The properties of release of preloaded [(3)H]taurine were now characterized in slices prepared from the mouse brain stem from developing (7-day-old) and young adult (3-month-old) mice, using a superfusion system. In general, taurine release was found to be similar to that in other brain areas, consisting of both Ca(2+)-dependent and Ca(2+)-independent components. Moreover, the release was mediated by Na(+)-, Cl(-)-dependent transporters operating outwards, as both Na(+)-free and Cl(-) -free conditions greatly enhanced it. Cl(-) channel antagonists and a Cl(-) transport inhibitor reduced the release at both ages, indicating that a part of the release occurs through ion channels. Protein kinases appeared not to be involved in taurine release in the brain stem, since substances affecting the activity of protein kinase C or tyrosine kinase had no significant effects. The release was modulated by cAMP second messenger systems and phospholipases at both ages. Furthermore, the metabotropic glutamate receptor agonists likewise suppressed the K(+)-stimulated release at both ages. In the immature brain stem, the ionotropic glutamate receptor agonists N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) potentiated taurine release in a receptor-mediated manner. This could constitute an important mechanism against excitotoxicity, protecting the brain stem under cell-damaging conditions.

1-Methyl-3-isobutylxanthine↗

PubMed2006

Indoleamine 2,3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality.

Indoleamine 2,3-dioxygenase (IDO), an enzyme degrading tryptophan (trp) to kynurenine (kyn), suppresses T cell activity. Ageing of the immune system, immunosenescence, includes a decline in T cell function. We therefore sought to establish whether IDO activity is involved in immunosenescence and whether it predicts mortality in aged subjects. We measured kyn/trp, reflecting IDO activity, in 284 nonagenarians and 309 blood donor controls. IDO activity was significantly higher in nonagenarians compared with controls and IDO activity at study entry predicted subsequent mortality in nonagenarians. Thus, increased IDO activity might be a mechanism involved in the decline of T cell responses in immunosenescence.

Adult↗

PubMed2006

The activity of the immunoregulatory enzyme indoleamine 2,3-dioxygenase is decreased in smokers.

Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the degradation of the essential amino acid tryptophan (trp) to its main metabolite kynurenine (kyn), suppresses T cell activity. Smoking has marked immunomodulatory effects, above all immunosuppressive, causing a reduction in the levels of immunoglobulins and an increased risk of infections. The immunostimulatory effects of smoking are manifested, for example, in increased autoantibody production. We sought to establish whether IDO activity is involved in the immunomodulatory effects of smoking. To this end we measured the ratio of kyn to trp, reflecting IDO activity, by reverse-phase high-performance liquid chromatography (HPLC) in 784 (464 female, 230 male) subjects of a population-based sample of the adult Finnish population. Serum cotinine concentration as an indicator of active smoking was measured in the patients by radioimmunoassay and detailed data gathered on smoking habits. IDO activity was lower in smokers in this population-based sample compared with non-smokers when active smoking was classified according to serum cotinine concentration or history of smoking habits. Moreover, serum IDO activity correlated inversely with serum cotinine concentration. In conclusion, the activity of the IDO enzyme is decreased in smoking subjects, and the reduction in IDO-dependent immunosuppression could thus be responsible for the known immunostimulatory effects of smoking.

Adult↗

PubMed2005

Mechanisms dependent on tryptophan catabolism regulate immune responses in primary Sjögren's syndrome.

To investigate the possible role of tryptophan metabolism in immune regulation of primary Sjögren's syndrome (pSS) the serum concentrations of tryptophan and its metabolite kynurenine were measured by reverse-phase high-performance liquid chromatography (HPLC) in 103 patients with pSS, 56 patients with sicca symptoms and 309 healthy blood donors. The kynurenine per tryptophan ratio (kyn/trp), which reflects the activity of the indoleamine-pyrrole 2,3-dioxygenase (IDO) enzyme involved in tryptophan catabolism, was calculated. Both female and male patients with pSS had significantly higher serum kynurenine concentrations and kyn/trp than subjects with sicca symptoms or healthy blood donors. The median (quartile range) concentration of kynurenine in female patients with pSS was 2.41 micromol/l (1.86-3.26) compared with 1.85 micromol/l (1.58-2.38, P < 0.0001) in subjects with sicca symptoms and 1.96 micromol/l (1.65-2.27, P < 0.0001) in healthy blood donors. Their kyn/trp x 1000 was 34.0 (25.1-44.3) compared with 25.3 (21.1-31.5, P < 0.0001) in subjects with sicca symptoms and 24.3 (21.0-28.9, P < 0.0001) in healthy blood donors. Female pSS patients with high IDO activity (kyn/trp x 1000 > or = 34.0) had significantly higher ESR, serum C-reactive protein, serum IgA and serum beta-2 microglobulin concentrations as well as higher serum creatinine levels, and they had positive antinuclear antibodies more frequently and presented with more American-European consensus group criteria than those with low IDO activity (kyn/trp x 1000 < 34.0). These data suggest that mechanisms dependent on tryptophan catabolism regulate immune responses in pSS. Tryptophan degradation is enhanced in patients with pSS, and high IDO activity is associated with severity of pSS.

Antibodies, Antinuclear↗

PubMed2005

Association of interferon-gamma +874(T/A) single nucleotide polymorphism with the rate of tryptophan catabolism in healthy individuals.

Abstract Mechanisms induced by tryptophan (trp) catabolism are important in the regulation of both normal and pathogenetic immune responses. The key enzyme is indoleamine-pyrrole 2,3-dioxygenase (EC 1.13.11.42) (IDO) which converts trp to kynurenine (kyn), the main toxic metabolite. It is known that interferon-gamma (IFN-gamma) is able to activate IDO. We wanted to analyse whether the strength of this mechanism would be under genetic control. To this end, we analysed the IFN-gamma+874(T/A) genotypes, which are known to have an effect on IFN-gamma production, of 309 healthy blood donors and correlated these to the levels of trp and kyn in their blood. The data obtained demonstrate that the presence of the high producer T allele was associated with increased IDO activity (i.e. elevated kyn and kyn/trp levels), but this effect was observed only in females. These data show that trp catabolism is genetically controlled by the IFN-gamma gene and may thus be operative in those disease conditions associated with the polymorphisms of the IFN-gamma gene.

Adult↗

PubMed2004

Characteristics of basal taurine release in the rat striatum measured by microdialysis.

Taurine is a sulfur-containing amino acid thought to be an osmoregulator, neurotransmitter or neuromodulator in the brain. Our objective was to establish how much taurine is released in the striatum and examine the mechanisms controlling extracellular taurine concentrations under resting conditions. The experiments were made on rats by microdialysis in vivo. Changes in taurine were compared with those in glutamate, glycine and the non-neuroactive amino acid threonine. Using the zero net flux approach we showed the extracellular concentration of taurine to be 25.2 +/- 5.1 muM. Glutamate was increased by tetrodotoxin and decreased by Ca2+ omission, glycine and threonine were not affected and both treatments increased extracellular taurine. The basal taurine release was increased by the taurine transport inhibitor guanidinoethanesulfonate and reduced by the anion channel blocker 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗

PubMed2003

Characteristics of taurine release induced by free radicals in mouse hippocampal slices.

The release of the inhibitory neuromodulator taurine in the hippocampus is markedly enhanced under various neural cell-damaging conditions, including ischemia and exposure to free radicals. The properties and regulation of the release evoked by a medium containing free radicals was investigated in hippocampal slices from adult (3-month-old) and developing (7-day-old) mice, using a superfusion system. The 'free radical damage' was induced by applying 0.01% H(2)O(2). The release of [(3)H]taurine was in both adult and developing hippocampus partly Ca(2+)-independent, mediated by Na(+)-dependent transporters and probably resulting from disruption of cell membranes and subsequent ion imbalance. The release in developing mice appeared to be more susceptible to regulation than that in adults, the stimulation by free radicals being in the latter already maximal. The release was reduced by adenosine A(1) receptor agonist R(-)N(6)-(2-phenylisopropyl)adenosine, which effect was, however, abolished by the antagonist 8-cyclopentyl-1,3-dipropylxanthine only in the immature hippocampus, indicating a receptor-mediated process. Moreover, the evoked taurine release in developing mice was potentiated by the ionotropic glutamate receptor agonists N-methyl-D-aspartate, kainate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate in a receptor-mediated manner, since the effects were abolished by their respective antagonists. The metabotropic glutamate receptors are of only minor significance in the release, the agonists of group I and II receptors slightly reducing the release. Furthermore, NO may also be involved in this release, the NO-generating compounds hydroxylamine and S-nitroso-N-acetylpenicillamine being able to enhance the free-radical-evoked release. It seems that the free-radical-stimulated release, potentiated by ionotropic glutamate receptor activation and NO production, could constitute part of the neuroprotective properties of taurine, being important particularly in the developing hippocampus and hence preventing excitotoxicity.

Animals↗

PubMed2003

Characterization of N-methyl-D-aspartate-evoked taurine release in the developing and adult mouse hippocampus.

Taurine is an inhibitory amino acid acting as an osmoregulator and neuroromodulator in the brain, with neuroprotective properties. The ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) greatly potentiates taurine release from brain preparations in both normal and ischemic conditions, the effect being particularly marked in the developing hippocampus. We now characterized the regulation of NMDA-stimulated taurine release from hippocampal slices from adult (3-month-old) and developing (7-day-old) mouse using a superfusion system. The NMDA-stimulated taurine release was receptor-mediated in both adult and developing mouse hippocampus. In adults, only NO-generating compounds, sodium nitroprusside, S-nitroso-N-acetylpenicillamine and hydroxylamine reduced the release, as did also NO synthase inhibitors, 7-nitroindazole and nitroarginine, indicating that the release is mediated by the NO/cGMP pathway. On the other hand, the regulation of the NMDA-evoked taurine release proved to be somewhat complex in the immature hippocampus. It was not affected by the NOergic compounds, but enhanced by the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate and adenosine receptor A(1) agonists, N(6)-cyclohexyladenosine and R(-)N(6)-(2-phenylisopropyl)adenosine in a receptor-mediated manner. The activation of both ionotropic 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors and metabotropic glutamate group I receptors also enhanced the evoked release. The NMDA-receptor-stimulated taurine release could be a part of the neuroprotective properties of taurine, being important particularly under cell-damaging conditions in the developing hippocampus and hence preventing excitotoxicity.

Animals↗

PubMed2003

Serum amino acid concentrations in aging men and women.

The age and gender related differences in serum amino acid concentrations have been assessed in 72 (23-92 years) medically screened healthy men and women who were divided into three male and three female groups according to age. Free-time physical activity and food intake were analysed from the 5-day diaries. The subjects were instructed to eat according to their normal dietary habits and to avoid any clinical complementary nutritional products or other products that could increase protein or energy intake. The blood samples (5 ml) taken from the antecubital vein after an over-night fast were analysed for their amino acid contents by chromatography. In total nutrient intake of energy (P < 0.001), protein (P < 0.001), alcohol (P < 0.05), water (P < 0.01), sodium (P < 0.001) and fiber P < 0.001) decreased significantly with age. The concentration of total amino acids (P < 0.01), essential amino acids (P < 0.001), non-essential amino acids (P < 0.05) and branched-chain amino acids (P < 0.05) decreased, whereas citrulline (P < 0.001) and cysteine (P < 0.001) were the only amino acids, which increased with aging. In addition, men had significantly higher concentrations than women of essential amino acids (P < 0.001), branched-chain amino acids (P < 0.001), and 10 of the 22 individual amino acids assayed (P < 0.01). Women had significantly higher concentrations of aspartate (P < 0.05), glycine (P < 0.01), serine (P < 0.001) and taurine (P < 0.01) than men. It is concluded that the decrease in serum total amino acid concentration is associated with decreased energy and protein intake with aging and men have higher essential amino acid concentration in serum than women.

Adult↗

PubMed2003

Leucine supplementation does not enhance acute strength or running performance but affects serum amino acid concentration.

This study described the effect of leucine supplementation on serum amino acid concentration during two different exercise sessions in competitive male power athletes. The subjects performed a strength exercise session (SES; n = 16; 26 +/- 4 years) or a maximal anaerobic running exercise session (MARE; n = 12; 27 +/- 5 years) until exhaustion twice at a 7-day interval. The randomized subjects consumed drinks containing leucine (100 mg x kg/body weight before and during SES or 200 mg x kg/body weight before MARE) or placebo. Blood specimens taken 10 min before (B) and after (A) the sessions were analyzed for serum amino acids. In SES the concentration of leucine was distinctly higher in the leucine supplemented group than in the placebo group in both B (p < 0.001) and A (p < 0.001) samples. The leucine concentration decreased in placebo but not in the leucine supplemented group following the exercise session. Isoleucine (p = 0.017) and valine (p = 0.006) concentration decreased more in the leucine supplemented group than in placebo in A samples. In MARE the concentration of leucine was higher in the leucine supplemented group than in placebo in both B (p < 0.001) and A (p < 0.001) samples and increased (p < 0.001) in the supplemented group following the session. Isoleucine (p = 0.020) and valine (p = 0.006) concentration decreased in the supplemented group in A samples. There were no differences in a counter movement jump after SES or in the running performance in MARE between the leucine supplemented group and placebo. These findings indicate that consuming leucine before or before and during exercise sessions results in changes in blood amino acid concentration. However, the supplementation does not affect an acute physical performance.

Adult↗

PubMed2002

Ammonia-induced extracellular accumulation of taurine in the rat striatum in vivo: role of ionotropic glutamate receptors.

Accumulation of taurine (Tau), glutamate (Glu) and glutamine (Gln) was measured in vivo in microdialysates of the rat striatum following a direct application to the microdialysis tube of 60 mM ammonium chloride which renders the final ammonia concentration in the extracellular space to approximately 5 mM. The following compounds were coadministered with ammonia to distinguish between the different mechanisms that may underlie the accumulation of amino acids: ion transport inhibitors, diisothiocyanostilbene-2,2'-disulfonate (DIDS) and furosemide, a Glu transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (PDC), an NMDA receptor antagonist dizocilpine (MK-801) and an 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate (KA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). Ammonia stimulated Tau accumulation in the microdialysates to approximately 250% of the basal value. Furosemide did not significantly affect the stimulation by ammonia and DIDS only moderately depressed the effect. The ammonia-dependent Tau accumulation was increased by approximately 50% in the presence of PDC and reduced by approximately 35% in the presence dizocilpine and DNQX. In the microdialysates ammonia stimulated Glu and Gln accumulation somewhat less than Tau accumulation. Except for stimulation of Gln accumulation by DNQX, the effects were not modified by any of the cotreatments. The results are consistent with the assumption that ammonia stimulates Tau efflux mainly via activation of ionotropic Glu receptors.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2002

Effects of acute toxic doses of psychostimulants on extracellular levels of excitatory amino acids and taurine in rats: comparison of d-amphetamine and sydnocarb.

We used microdialysis to study how acute toxic doses of d-amphetamine and sydnocarb [3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine], an original Russian psychostimulant, affect extracellular levels of glutamate, aspartate, and taurine in the neostriatum of halothane-anesthetized male Sprague-Dawley rats. The administration of d-amphetamine (5.0 mg/kg x 4 i.p.) caused gradual fivefold increases in the extracellular glutamate and taurine levels and moderate increases in the extracellular aspartate level. Sydnocarb administration (23.8 mg/kg x 4 i.p., a dose equimolar to 5.0 mg/kg d-amphetamine) elicited a marked increase in the extracellular aspartate level and a small increase in the extracellular level of glutamate. The extracellular taurine level increased only after the last (fourth) injection. We conclude that a massive increase in extracellular taurine reflects hyperactivation of glutamatergic neurotransmission elicited by acute toxic dose of d-amphetamine. Sydnocarb seems to be less neurotoxic than d-amphetamine, because it elicits lesser changes in the extracellular levels of glutamate and taurine.

Animals↗

PubMed2002

Methylenetetrahydrofolate reductase gene polymorphism, hyperhomocysteinemia and occlusive retinal vascular disease in type 2 diabetic and non-diabetic subjects.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism may cause hyperhomocysteinemia, which affects the vascular endothelium and may induce occlusive vascular disease (OVD). Hypertension thickens small-sized arterial walls and attenuates intramural blood flow. Such OVD can be studied in retinal angiograms as a decrease in the arterio-venous ratio (AVR). Diabetes, by altering microvascular structure and function, in many ways modifies this AVR. OBJECTIVE: To assess whether MTHFR gene polymorphism (C677T) by causing hyperhomocysteinemia affects the retinal AVR in type 2 diabetic and non-diabetic subjects. METHODS: Eighty-four recently diagnosed (< 1 year) type 2 diabetic and 115 non-diabetic subjects were included in the study. Retinal fluoresceine angiograms were recorded and the mean AVR was calculated by measuring transverse vessel diameters at 6 locations. The mean AVR was used as a marker of OVD. The MTHFR VV, VA and AA genotypes were determined by PCR and plasma homocysteine by high-pressure liquid chromatography. RESULTS: In the diabetic subjects with the VV, VA and AA genotypes, the plasma homocysteine levels were 16.5 +/- 7, 12.5 +/- 4.6 and 11.3 +/- 4.9 microM, respectively (p = 0.008, ANCOVA). The corresponding values in controls were 14.6 +/- 3.8, 13.7 +/- 5.7 and 11.6 +/- 4.4 (p = 0.08). Correspondingly, in the diabetic subjects, the AVR values were 0.71 +/- 0.07, 0.75 +/- 0.07 and 0.73 +/- 0.1 (p = NS, ANOVA) and in the control subjects they were 0.8 +/- 0.14, 0.81 +/- 0.12 and 0.76 +/- 0.09 (p = NS, ANOVA). Multiple linear regression analysis (best model chi2 = 18.2, R2 = 0.10, p < 0.001) showed that AVR was related to diastolic blood pressure (t = -3.7, p < 0.001) and GFR (t = -2.2, p = 0.03). There was no relation between the AVR and plasma homocysteine levels. CONCLUSION: In the present study of recently diagnosed type 2 diabetic and non-diabetic subjects, MTHFR gene polymorphism (C677T mutation) slightly affected the plasma homocysteine level but did not alter the arterio-venous ratio.

Adult↗

PubMed2002

Serum amino acid responses to three different exercise sessions in male power athletes.

BACKGROUND: The purpose of this study was to investigate serum amino acid responses to 3 different exercise sessions in male power athletes (sprinters and jumpers; n=11). METHODS: All subjects performed 2 running exercise sessions: a short run session (SRS) of 3 x 4 x 60 m with recoveries of 120 and 360 sec, and a long run session (LRS) of 20 sec runs with recoveries of 100 sec until exhaustion. Ten subjects performed a strength exercise session (SES) of 90 min. Serum amino acids (n=21) were assayed 10 min before and 10 min after the sessions. Peak blood lactate was analyzed from fingertip blood samples taken 1 and 5 min after the sessions. RESULTS: The before-after comparisons showed that the essential amino acids (EAAs) decreased by 8.7% (p<0.01) and alanine increased by 26.7% (p<0.001) after SRS. Following LRS the EAAs decreased also by 8.7% (p<0.01) and alanine increased by 25.3% (p<0.001). In the sum of all amino acids there were no changes after SRS and LRS but a significant decrease (14.8%; p<0.01) was observed after SES. Also the EAAs decreased (20.6%; p<0.001) but alanine, taurine and citrulline were the only single amino acids with no changes after SES. The peak blood lactate concentrations after SRS, LRS and SES were 13.8+/-1.9, 16.4+/-1.3 and 2.5+/-0.4 mmol/L, respectively. The lactate value after SES differed (p<0.001) from the values observed after SRS and LRS. The comparison of the changes in the serum amino acid concentrations following the 3 exercise sessions revealed that SRS and LRS were very similar but SES differed from SRS and LRS strongly (p<0.01) in the sum of all amino acids. CONCLUSIONS: The current data indicate that the sum concentrations of all amino acids in serum decrease after the strength exercise session but not after the lactic anaerobic running exercises.

Adult↗

PubMed2001

Effects of sydnocarb and D-amphetamine on the extracellular levels of amino acids in the rat caudate-putamen.

The neurotoxic effects of psychostimulants at high dosages limit their clinical applicability but the mechanism of neurotoxicity is still unsettled. We now studied by microdialysis how acute and subchronic (four times at 2-h intervals) administrations of D-amphetamine and sydnocarb [3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine], an original novel Russian psychostimulant, affected the extracellular levels of amino acids in the caudate-putamen of halothane-anesthetized male Sprague-Dawley rats. Acute D-amphetamine administration (5.0 mg/kg, i.p.) produced a moderate accumulation of extracellular glutamate and aspartate. Sydnocarb (23.8 mg/kg, i.p., a dose equimolar to 5.0 mg/kg D-amphetamine) also increased extracellular glutamate and alanine. Subchronic D-amphetamine administration (5.0 mg/kg x 4, i.p.) caused gradual fivefold increases in the glutamate and taurine levels and moderate increases in the aspartate and alanine levels. Subchronic sydnocarb administration (23.8 mg/kg x 4, i.p.) elicited a marked increase in the aspartate level and a small increase in the level of glutamate. The alanine level increased temporarily after each administration of sydnocarb, while the taurine level increased only after the last injection. We conclude that the mode of action of sydnocarb differs from that of D-amphetamine. Sydnocarb also seems to be less neurotoxic than D-amphetamine, since it elicits lesser changes in the extracellular level of glutamate.

Amino Acids↗

PubMed2001

Lubeluzole attenuates K(+)-evoked extracellular accumulation of taurine in the striatum of healthy rats and rats with hepatic failure.

Lubeluzole is a newly designed neuroprotectant which has proved effective in the treatment of experimental stroke in rats, mainly by inhibition of the glutamate-activated NO pathway, but also by counteracting osmotic stress by a mechanism associated with the release of the osmotically active amino acid taurine (Tau). Here we show that lubeluzole administered i.p. decreases by 25% the high (50 mM) K+-evoked accumulation of Tau in striatal microdialysates of healthy rats and by 34% in rats with thioacetamide-induced hepatic failure, where the increased extracellular accumulation of Tau signifies ongoing hepatic encephalopathy. Lubeluzole does not affect the nonstimulated accumulation of Tau in either group of rats. The results indicate that lubeluzole may be effective in ameliorating ionic or osmotic stress in a range of pathological conditions involving the rise of extracellular K+, and also in decreasing the vulnerability to stress in rats with hepatic failure.

Animals↗

PubMed2001

Metabotropic glutamate receptors modulate GABA release from mouse hippocampal slices.

The effects of metabotropic glutamate receptor agonists on the basal and potassium (50 mM K+)-stimulated release of [3H]GABA from mouse hippocampal slices were investigated using a superfusion system. The group I agonist (1+/-)-1-aminocyclopentane-trans-1,3-dicarboxylate enhanced the basal GABA release and reduced the K+-evoked release by a mechanism antagonized by (RS)-1-aminoindan-1,5-dicarboxylate in both cases. The group II agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine failed to have any effect on the basal release, but inhibited the stimulated release. This inhibition was not affected by the antagonist (2S)-2-ethylglutamate. The group III agonists L(+)-amino-4-phosphonobutyrate and O-phospho-L-serine inhibited the basal GABA release, which effects were blocked by the antagonist (RS)-2-cyclopropyl-4-phosphonophenylglycine. Moreover, the suppression of the K+-evoked release by L(+)2-amino-4-phosphonobutyrate was apparently receptor-mediated, being blocked by (RS)-2-cyclopropyl-4-phosphonophenylglycine. The results show that activation of metabotropic glutamate receptors of group I is able to potentiate the basal release of GABA, whereas activation of groups I and III receptors reduce K+-stimulated release in mouse hippocampal slices.

Animals↗