Simo Oja - Academia.edu (original) (raw)
Papers by Simo Oja
Neurochemical research, Jan 28, 2016
Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profou... more Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profoundly with brain metabolism, astrocyte volume regulation, and in particular mitochondrial functions. Gene expression in the brain and excitatory and inhibitory neurotransmission circuits are also affected. Experiments with a number of pertinent animal models have revealed several potential mechanisms which could underlie the pathological phenomena occurring in hepatic encephalopathy.
Scandinavian Journal of Clinical & Laboratory Investigation, 2008
Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T... more Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T lymphocytes, and its level in blood is increased in several autoimmune and inflammatory diseases. We have previously shown that this activity associates with several signs and risk factors of atherosclerosis in 24 to 39-year-old females. Now we repeat this analysis in an older population (n = 921, age range 46-76 years), i.e. in a population with more advanced atherosclerosis. IDO activity had a significant positive correlation in both sexes with carotid artery intima/media thickness (IMT), an early marker of atherosclerosis. In females, a significant negative correlation with HDL cholesterol and a positive correlation with triglycerides levels was observed. The association with IMT did not remain significant after adjustment with classical risk factors of atherosclerosis. It is thus concluded that IDO is a sensitive marker of atherosclerosis--or the inflammatory response associated wit...
Advances in experimental medicine and biology, 1992
Scandinavian Journal of Clinical & Laboratory Investigation, 2008
Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T... more Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T lymphocytes, and its level in blood is increased in several autoimmune and inflammatory diseases. We have previously shown that this activity associates with several signs and risk factors of atherosclerosis in 24 to 39-year-old females. Now we repeat this analysis in an older population (n = 921, age range 46-76 years), i.e. in a population with more advanced atherosclerosis. IDO activity had a significant positive correlation in both sexes with carotid artery intima/media thickness (IMT), an early marker of atherosclerosis. In females, a significant negative correlation with HDL cholesterol and a positive correlation with triglycerides levels was observed. The association with IMT did not remain significant after adjustment with classical risk factors of atherosclerosis. It is thus concluded that IDO is a sensitive marker of atherosclerosis--or the inflammatory response associated with it--but does not have an independent role in the pathogenesis of this disease.
Amino Acids, 2004
Taurine is a sulfur-containing amino acid thought to be an osmoregulator, neurotransmitter or neu... more 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 AE 5.1 M. Glutamate was increased by tetrodotoxin and decreased by Ca 2þ 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 0-isothiocyanatostilbene-2,2 0-disulfonic acid.
Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the ... more Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the brain. Here we studied the effects of intraperitoneal injections of taurine on the concentrations of glutamate and GABA, and their precursors, glutamine and alanine, in the rat striatum and hippocampus. Injections of 0.25, 0.5 and 1 g/kg taurine led to a gradual increase in taurine tissue
Psychiatry Research, 2005
There are indications that mood disorders may be related to perturbations in the amino acid trans... more There are indications that mood disorders may be related to perturbations in the amino acid transmitters. The amino acids may thus be targets of treatment of depression. The purpose of this pilot study was to measure the acute effects of a single administration of electroconvulsive therapy (ECT) on the plasma levels of amino acids in depressed patients. ECT was administered to 10 patients with major depressive disorder. Altogether 23 plasma amino acids were analyzed before and at 2, 6, 24 and 48 h after ECT. The levels of glutamate and aspartate increased at 6 h after ECT compared with the baseline. Also the levels of total tryptophan increased 2-24 h after ECT. There were also elevations in other amino acids at 6 and 24 h. The levels of gamma-aminobutyric acid (GABA) decreased at 2 h. In this study the acute effects of single ECT were associated with changes in the levels of glutamate, aspartate, GABA, tryptophan and some other amino acids. The preliminary data suggest that the therapeutic effects of ECT in depression may be due to mechanisms involving these amino acid transmitters. D
![Research paper thumbnail of Inhibitory effect of taurine on veratridine-evoked d-[3H]aspartate release from murine corticostriatal slices: Involvement of chloride channels and mitochondria](https://attachments.academia-assets.com/49682374/thumbnails/1.jpg)
](Brain Research, 2007
We have previously shown that the inhibitory neuromodulator taurine attenuates the release of pre... more We have previously shown that the inhibitory neuromodulator taurine attenuates the release of preloaded D-[ 3 H]aspartate from murine corticostriatal slices evoked by ischemic conditions or by application of the sodium channel agonist veratridine. The release of D-[ 3 H] aspartate (a non-metabolized analog of glutamate) was used as an index of glutamate release. The aim of the present study was to reveal the molecular mechanisms responsible for this inhibitory effect of taurine. It was shown that 10 mM taurine suppresses D-[ 3 H] aspartate release evoked by 0.1 mM veratridine, but does not affect the high-K + -(50 mM) or ouabain-(0.1 mM) evoked release. Taurine had no effect in Ca 2+ -free medium when the synaptic exocytosis of D-[ 3 H]aspartate was inhibited. Nor did it suppress the release from slices preloaded with the competitive glutamate uptake blocker DL-threo-βhydroxyaspartate (THBA), which inhibits D-[ 3 H]aspartate release mediated by the reverse action of glutamate transporters. Omission of Cl − from the incubation medium reduced the effect of taurine, signifying the involvement of a Cl − channel. The glycine receptor antagonist strychnine and the GABA A receptor antagonist bicuculline did not block the taurine effect, although picrotoxin, a less specific blocker of agonist-gated chloride channels, completely prevented the effect of taurine on veratridine-induced D-[ 3 H] aspartate release. The respiratory chain blocker rotenone or mitochondrial protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP) in combination with the mitochondrial ATPase inhibitor oligomycin, which inhibits the mitochondrial Ca 2+ uniporter, also reduced the effect of taurine. The results obtained in the present study show that taurine acts specifically on the release of preloaded D-[ 3 H]aspartate evoked by veratridine, but not on that evoked by other depolarizing agents, and affects the release mediated both by synaptic exocytosis and the reverse action of glutamate transporter. Taurine may attenuate D-[ 3 H] aspartate release by regulation of mitochondrial Ca 2+ sequestration and by activation of a chloride channel, but not that governed by GABA A or strychnine-sensitive glycine receptors.
Proceedings of the Western Pharmacology Society, 2007
Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the ... more Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the brain. Here we studied the effects of intraperitoneal injections of taurine on the concentrations of glutamate and GABA, and their precursors, glutamine and alanine, in the rat striatum and hippocampus. Injections of 0.25, 0.5 and 1 g/kg taurine led to a gradual increase in taurine tissue concentrations in both hippocampus and striatum. Glutamate and GABA also increased in the hippocampus, but not in the striatum. Glutamine increased and alanine decreased markedly in both brain structures. The results corroborate the neuromodulatory role of taurine in the brain. Taurine administration results in an imbalance in inhibitory and excitatory neurotransmission in the glutamatergic (hippocampus) and GABAergic (striatum) brain structures, affecting more markedly the neurotransmitter precursors.
![Research paper thumbnail of Taurine attenuates d-[3H]aspartate release evoked by depolarization in ischemic corticostriatal slices](https://attachments.academia-assets.com/49682371/thumbnails/1.jpg)
](Brain Research, 2006
Taurine is thought to be protective in ischemia due to its neuroinhibitory effects. The present a... more Taurine is thought to be protective in ischemia due to its neuroinhibitory effects. The present aim was to assess the ability of taurine to attenuate glutamate release evoked by ischemia and to determine which component of this release is affected. The release of preloaded D-[ 3 H]aspartate (a non-metabolized analog of glutamate) from superfused murine corticostriatal slices was used as index of glutamate release. Preincubation of corticostriatal slices with 10 mM taurine reduced the D-[ 3 H]aspartate release evoked by either chemical ischemia (0.5 mM NaCN in glucose-free medium) or oxygen-glucose deprivation. The taurine uptake inhibitor guanidinoethanesulfonate (5 mM), the glycine receptor antagonist strychnine (0.1 mM) and the GABA A receptor antagonist bicuculline (0.1 mM) did not block the taurine effect. To determine which component of ischemia-induced glutamate release is affected by taurine, three pathways of this release were pharmacologically modeled. Unlabeled D-aspartate (0.5 mM) and hypo-osmotic medium (NaCl reduced by 50 mM) evoked D-[ 3 H]aspartate release via homoexchange and hypo-osmotic release pathways, respectively. Taurine did not influence these pathways. However, it suppressed the synaptic release of D-[ 3 H]aspartate evoked by the voltage-gated sodium channel opener veratridine (0.1 mM). Taurine thus reduces glutamate release under ischemic conditions by affecting the depolarization-evoked component.
The sulfur-containing amino acid taurine is an inhibitory neuromodulator in the brain of mammals,... more The sulfur-containing amino acid taurine is an inhibitory neuromodulator in the brain of mammals, as well as a key substance in the regulation of cell volumes. The effect of Ca 2+ on extracellular taurine concentrations is of special interest in the context of the regulatory mechanisms of taurine release. The aim of this study was to characterize the basal release of taurine in Ca 2+ -free medium using in vivo microdialysis of the striatum of anesthetized rats. Perfusion of Ca 2+ -free medium via a microdialysis probe evoked a sustained release of taurine (up to 180 % compared to the basal levels). The Ca 2+ chelator EGTA (1 mM) potentiated Ca 2+ depletion-evoked taurine release. The substitution of CaCl 2 by choline chloride did not alter the observed effect. Ca 2+ -free solution did not significantly evoke release of taurine from tissue loaded with the competitive inhibitor of taurine transporter guanidinoethanesulfonate (1 mM), suggesting that in Ca 2+ depletion taurine is released by the transporter operating in the outward direction. The volume-sensitive chloride channel blocker diisothiocyanostilbene-2,2 0 -disulfonate (1 mM) did not attenuate the taurine release evoked by Ca 2+ depletion. The non-specific blocker of voltage-sensitive Ca 2+ channels NiCl 2 (0.65 mM) enhanced taurine release in the presence of Ca 2+ . CdCl 2 (0.25 mM) had no effect under these conditions. However, both CdCl 2 and NiCl 2 attenuated the effect of Ca 2+ -free medium on the release of taurine. The data obtained imply the involvement of both decreased influx of Ca 2+ and increased non-specific influx of Na + through voltage-sensitive calcium channels in the regulation of transporter-mediated taurine release in Ca 2+ depletion. #
Advances in Experimental Medicine and Biology, Feb 1, 1981
Neurochemical Research, 2009
In the brain stem glycine is associated with multiple sensory and visceral regulations, being inv... more In the brain stem glycine is associated with multiple sensory and visceral regulations, being involved in, for instance, cardiovascular, respiratory and auditory functions. We here studied the mechanisms of the release of preloaded [ 3 H]glycine from mouse brain stem slices in a superfusion system. A depolarizing concentration of K + ions (50 mM) evoked glycine release, but in the absence of Ca 2+ the effect was attenuated, indicating that a part of the evoked release represents Ca 2+ -dependent exocytosis. The Ca 2+independent release was enhanced by omission of Na + and Cl -. The stimulatory effect of extracellular glycine confirmed the involvement of transporters functioning in a reverse direction. A part of the release is mediated by Na + and Clchannels, since it was inhibited by the inhibitors of these, riluzole and 4-acetamido-4 0 -isothiocyanostilbene-2,2 0 -disulphonate, respectively. Glycine release was potentiated by the activation of protein kinase C and diminished by increasing cyclic guanosine monophosphate levels with a phosphodiesterase inhibitor, zaprinast. The release was also modulated by the phospholipase inhibitor quinacrine and the tyrosine kinase inhibitor genistein. Adenosine A 1 receptors likewise regulate glycine release, since it was enhanced by their agonist R(-)N 6 -(2-phenylisopropyl)adenosine, which effect was blocked by the antagonist 8-cyclopentyl-1,3-dipropylxanthine. The ionotropic glutamate receptor agonists N-methyl-D-aspartate, kainate and 2-amino-3-hydroxy-5methyl-4-isoxazolepropionate failed to have any effects contrary to their effects in higher brain regions, e.g., in the hippocampus. The group I and III metabotropic glutamate receptor agonists (S)-3,5-dihydroxyphenylglycine and O-phospho-L-serine, respectively, increased the release in a receptor-mediated manner. Glycine release in the brain stem was also markedly enhanced by cell-damaging conditions, including hypoxia, hypoglycemia and ischemia.
Amino Acids, 2010
The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions i... more The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions in both adult and developing brain stem, together with a pronounced increase in the release of the neuromodulator adenosine. We now studied the effects of adenosine receptor agonists and antagonists on [(3)H]taurine release in the brain stem in normoxia and ischemia, using a superfusion system. Under standard conditions, the adenosine A(1) receptor agonist N(6)-cyclohexyladenosine (CHA) potentiated basal taurine release in adult mice, which response was blocked by the antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). CHA and the A(2a) receptor agonist 2-p-(2-carboxyethyl)phenylamino-5'-N-ethylcarboxaminoadenosinehydrochloride (CGS 21680) had no effect on the release in developing mice. In ischemia, CHA depressed both basal and K(+)-stimulated taurine release in developing mice in a receptor-mediated manner, blocked by DPCPX. The A(2a) receptor agonist CGS 21680 was also inhibitory. Taurine and adenosine may thus not cooperate in developing mice to prevent ischemic neuronal damage. On the other hand, CGS 21680 enhanced taurine release in the adult brain stem in ischemia, both basal and K(+)-stimulated release being affected. These effects were abolished by the antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), indicating a receptor-mediated process. In this case elevated levels of taurine could be beneficial, protecting against hyperexcitation and excitotoxicity.
Molecular Immunology, Mar 31, 2006
Tryptophan catabolism activated by the indoleamine 2,3-dioxygenase (EC 1.13.11.42) (IDO) enzyme i... more Tryptophan catabolism activated by the indoleamine 2,3-dioxygenase (EC 1.13.11.42) (IDO) enzyme in antigen presenting cells has a central role in induction of mechanisms suppressing T cell activation or clonal expansion. There is evidence suggesting that IDO activity is mainly upregulated by typical Th1-differentiating signals such as interferon-␥ and bacterial lipopolysaccharide (LPS). Therefore, we hypothesized that IDO activity would be lower in a Th2-associated disease such as atopy and that it would be higher in the presence of environmental factors known to favor Th1 differentiation. Here we show that this was the case. Concentrations of tryptophan (trp) and kynurenine (kyn), the main metabolite, were determined by reverse phase liquid chromatography from serum samples of a cohort of 392 non-asthmatic individual of whom 149 were atopics (one or more positive skin test when tested with a panel of 22 allergens). Kyn/trp ratio, as an indicator of IDO activity, was significantly lower in atopic than in non-atopic individuals. The cohort was stratified according to two known atopy-protecting factors, presence of antibodies against Helicobacter pylori or anamnestic information about childhood on a farm environment. As expected, IDO activity was significantly higher in their presence than absence.
Amino Acids, 2008
Glutathione (reduced form GSH and oxidized form GSSG) constitutes an important defense against ox... more Glutathione (reduced form GSH and oxidized form GSSG) constitutes an important defense against oxidative stress in the brain, and taurine is an inhibitory neuromodulator particularly in the developing brain. The effects of GSH and GSSG and glycylglycine, γ-glutamylcysteine, cysteinylglycine, glycine and cysteine on the release of [ 3 H]taurine evoked by K + -depolarization or the ionotropic glutamate receptor agonists glutamate, kainate, 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) were now studied in slices from the hippocampi from 7-day-old mouse pups in a perfusion system. All stimulatory agents (50 mM K + , 1 mM glutamate, 0.1 mM kainate, 0.1 mM AMPA and 0.1 mM NMDA) evoked taurine release in a receptor-mediated manner. Both GSH and GSSG significantly inhibited the release evoked by 50 mM K + . The release induced by AMPA and glutamate was also inhibited, while the kainate-evoked release was significantly activated by both GSH and GSSG. The NMDA-evoked release proved the most sensitive to modulation: L-Cysteine and glycine enhanced the release in a concentration-dependent manner, whereas GSH and GSSG were inhibitory at low (0.1 mM) but not at higher (1 or 10 mM) concentrations. The release evoked by 0.1 mM AMPA was inhibited by γ-glutamylcysteine and cysteinylglycine, whereas glycylglycine had no effect. The 0.1 mM NMDA-evoked release was inhibited by glycylglycine and γ-glutamylcysteine. In turn, cysteinylglycine inhibited the NMDAevoked release at 0.1 mM, but was inactive at 1 mM. Glutathione exhibited both enhancing and attenuating effects on taurine release, depending on the glutathione concentration and on the agonist used. Both glutathione and taurine act as endogenous neuroprotective effectors during early postnatal life.
Brain Res, 1973
Electrical stimulation of brain slices of newborn and adult rats enhanced the decarboxylation of ... more Electrical stimulation of brain slices of newborn and adult rats enhanced the decarboxylation of glutamate and cysteine sulphinate. The activity of both decarboxylases increased with age, that of glutamate decarboxylase more sharply. The rate of oxidation of hypotaurine to taurine was highest in the brain, liver and kidney of 10day-old rats. No measurable conversion of hypotaurine to taurine occurred in preparations from the brain of adults, neither did electrical stimulation induce the oxidation of hypotaurine in these preparations.
Med Sci Sport Exercise, 1996
International Journal of Developmental Neuroscience, Aug 31, 1994
The sodium-independent binding of [3-alanine to cerebral cortical membranes from adult (3-and 12-... more The sodium-independent binding of [3-alanine to cerebral cortical membranes from adult (3-and 12-month-old) and developing (7-day-old) mice was characterized for the first time. The binding was saturable in each age group, consisting of only one component. The affinity for [3-alanine was highest and the number of available binding sites greatest in young animals. The binding was not affected by strychnine, but inhibited by [3-alanine itself, glycine, L-alanine and L-serine, the lCs0 values being lower in immature mice. Glycine was shown to be a competitive inhibitor. The binding was also inhibited, albeit only in adults, by N-methyl-D-aspartate receptor antagonists acting at the glycine modulatory site and by some GABAergic substances. It is concluded that even though [3-alanine may possess binding sites of its own, particularly in the immature cerebral cortex, [3-alanine could at least partly bind to strychnine-insensitive glycine sites in the N-methyl-D-aspartate receptor complex.
Neuroscience, Feb 1, 2000
The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions i... more The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions in both adult and developing hippocampus, together with a pronounced increase in the release of excitatory amino acids and the neuromodulator adenosine. We studied the effects of adenosine receptor agonists and antagonists as well as adenosine transport inhibitors on hippocampal [3H]taurine release in normoxia and ischemia, using a superfusion system. Under standard conditions the adenosine A1 receptor agonists N6-cyclohexyladenosine and R(−)N6-(2-phenylisopropyl)adenosine potentiated basal taurine release in developing mice and depressed the release in adults in a receptor-mediated manner. Adenosine A2 receptor compounds had only minor effects on the basal release and the K+-stimulated release was not affected by these drugs. The adenosine uptake inhibitor dipyridamole enhanced basal taurine release in the developing hippocampus and reduced it in the adult. In ischemia the adenosine compounds had no marked effects on taurine release in immature animals, whereas A1 receptor activation was still able to evoke taurine release in adults by a receptor-mediated mechanism. The results show that the basal release of taurine is modulated by A1 receptors in both mature and immature hippocampus, whereas in ischemia these receptors potentiate taurine release only in adults.The elevated taurine levels together with the depression of excitatory amino acid release by adenosine receptor activation could be beneficial under ischemic conditions, protecting neural cells against excitotoxicity and hyperexcitation.
Neurochemical research, Jan 28, 2016
Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profou... more Abnormal liver function has dramatic effects on brain functions. Hyperammonemia interferes profoundly with brain metabolism, astrocyte volume regulation, and in particular mitochondrial functions. Gene expression in the brain and excitatory and inhibitory neurotransmission circuits are also affected. Experiments with a number of pertinent animal models have revealed several potential mechanisms which could underlie the pathological phenomena occurring in hepatic encephalopathy.
Scandinavian Journal of Clinical & Laboratory Investigation, 2008
Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T... more Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T lymphocytes, and its level in blood is increased in several autoimmune and inflammatory diseases. We have previously shown that this activity associates with several signs and risk factors of atherosclerosis in 24 to 39-year-old females. Now we repeat this analysis in an older population (n = 921, age range 46-76 years), i.e. in a population with more advanced atherosclerosis. IDO activity had a significant positive correlation in both sexes with carotid artery intima/media thickness (IMT), an early marker of atherosclerosis. In females, a significant negative correlation with HDL cholesterol and a positive correlation with triglycerides levels was observed. The association with IMT did not remain significant after adjustment with classical risk factors of atherosclerosis. It is thus concluded that IDO is a sensitive marker of atherosclerosis--or the inflammatory response associated wit...
Advances in experimental medicine and biology, 1992
Scandinavian Journal of Clinical & Laboratory Investigation, 2008
Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T... more Indoleamine 2,3-dioxygenase (IDO) is an important immunomodulator suppressing the activation of T lymphocytes, and its level in blood is increased in several autoimmune and inflammatory diseases. We have previously shown that this activity associates with several signs and risk factors of atherosclerosis in 24 to 39-year-old females. Now we repeat this analysis in an older population (n = 921, age range 46-76 years), i.e. in a population with more advanced atherosclerosis. IDO activity had a significant positive correlation in both sexes with carotid artery intima/media thickness (IMT), an early marker of atherosclerosis. In females, a significant negative correlation with HDL cholesterol and a positive correlation with triglycerides levels was observed. The association with IMT did not remain significant after adjustment with classical risk factors of atherosclerosis. It is thus concluded that IDO is a sensitive marker of atherosclerosis--or the inflammatory response associated with it--but does not have an independent role in the pathogenesis of this disease.
Amino Acids, 2004
Taurine is a sulfur-containing amino acid thought to be an osmoregulator, neurotransmitter or neu... more 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 AE 5.1 M. Glutamate was increased by tetrodotoxin and decreased by Ca 2þ 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 0-isothiocyanatostilbene-2,2 0-disulfonic acid.
Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the ... more Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the brain. Here we studied the effects of intraperitoneal injections of taurine on the concentrations of glutamate and GABA, and their precursors, glutamine and alanine, in the rat striatum and hippocampus. Injections of 0.25, 0.5 and 1 g/kg taurine led to a gradual increase in taurine tissue
Psychiatry Research, 2005
There are indications that mood disorders may be related to perturbations in the amino acid trans... more There are indications that mood disorders may be related to perturbations in the amino acid transmitters. The amino acids may thus be targets of treatment of depression. The purpose of this pilot study was to measure the acute effects of a single administration of electroconvulsive therapy (ECT) on the plasma levels of amino acids in depressed patients. ECT was administered to 10 patients with major depressive disorder. Altogether 23 plasma amino acids were analyzed before and at 2, 6, 24 and 48 h after ECT. The levels of glutamate and aspartate increased at 6 h after ECT compared with the baseline. Also the levels of total tryptophan increased 2-24 h after ECT. There were also elevations in other amino acids at 6 and 24 h. The levels of gamma-aminobutyric acid (GABA) decreased at 2 h. In this study the acute effects of single ECT were associated with changes in the levels of glutamate, aspartate, GABA, tryptophan and some other amino acids. The preliminary data suggest that the therapeutic effects of ECT in depression may be due to mechanisms involving these amino acid transmitters. D
Brain Research, 2007
We have previously shown that the inhibitory neuromodulator taurine attenuates the release of pre... more We have previously shown that the inhibitory neuromodulator taurine attenuates the release of preloaded D-[ 3 H]aspartate from murine corticostriatal slices evoked by ischemic conditions or by application of the sodium channel agonist veratridine. The release of D-[ 3 H] aspartate (a non-metabolized analog of glutamate) was used as an index of glutamate release. The aim of the present study was to reveal the molecular mechanisms responsible for this inhibitory effect of taurine. It was shown that 10 mM taurine suppresses D-[ 3 H] aspartate release evoked by 0.1 mM veratridine, but does not affect the high-K + -(50 mM) or ouabain-(0.1 mM) evoked release. Taurine had no effect in Ca 2+ -free medium when the synaptic exocytosis of D-[ 3 H]aspartate was inhibited. Nor did it suppress the release from slices preloaded with the competitive glutamate uptake blocker DL-threo-βhydroxyaspartate (THBA), which inhibits D-[ 3 H]aspartate release mediated by the reverse action of glutamate transporters. Omission of Cl − from the incubation medium reduced the effect of taurine, signifying the involvement of a Cl − channel. The glycine receptor antagonist strychnine and the GABA A receptor antagonist bicuculline did not block the taurine effect, although picrotoxin, a less specific blocker of agonist-gated chloride channels, completely prevented the effect of taurine on veratridine-induced D-[ 3 H] aspartate release. The respiratory chain blocker rotenone or mitochondrial protonophore carbonyl cyanide 3-chlorophenylhydrazone (CCCP) in combination with the mitochondrial ATPase inhibitor oligomycin, which inhibits the mitochondrial Ca 2+ uniporter, also reduced the effect of taurine. The results obtained in the present study show that taurine acts specifically on the release of preloaded D-[ 3 H]aspartate evoked by veratridine, but not on that evoked by other depolarizing agents, and affects the release mediated both by synaptic exocytosis and the reverse action of glutamate transporter. Taurine may attenuate D-[ 3 H] aspartate release by regulation of mitochondrial Ca 2+ sequestration and by activation of a chloride channel, but not that governed by GABA A or strychnine-sensitive glycine receptors.
Proceedings of the Western Pharmacology Society, 2007
Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the ... more Taurine, a non-protein amino acid, acts as an osmoregulator and inhibitory neuromodulator in the brain. Here we studied the effects of intraperitoneal injections of taurine on the concentrations of glutamate and GABA, and their precursors, glutamine and alanine, in the rat striatum and hippocampus. Injections of 0.25, 0.5 and 1 g/kg taurine led to a gradual increase in taurine tissue concentrations in both hippocampus and striatum. Glutamate and GABA also increased in the hippocampus, but not in the striatum. Glutamine increased and alanine decreased markedly in both brain structures. The results corroborate the neuromodulatory role of taurine in the brain. Taurine administration results in an imbalance in inhibitory and excitatory neurotransmission in the glutamatergic (hippocampus) and GABAergic (striatum) brain structures, affecting more markedly the neurotransmitter precursors.
Brain Research, 2006
Taurine is thought to be protective in ischemia due to its neuroinhibitory effects. The present a... more Taurine is thought to be protective in ischemia due to its neuroinhibitory effects. The present aim was to assess the ability of taurine to attenuate glutamate release evoked by ischemia and to determine which component of this release is affected. The release of preloaded D-[ 3 H]aspartate (a non-metabolized analog of glutamate) from superfused murine corticostriatal slices was used as index of glutamate release. Preincubation of corticostriatal slices with 10 mM taurine reduced the D-[ 3 H]aspartate release evoked by either chemical ischemia (0.5 mM NaCN in glucose-free medium) or oxygen-glucose deprivation. The taurine uptake inhibitor guanidinoethanesulfonate (5 mM), the glycine receptor antagonist strychnine (0.1 mM) and the GABA A receptor antagonist bicuculline (0.1 mM) did not block the taurine effect. To determine which component of ischemia-induced glutamate release is affected by taurine, three pathways of this release were pharmacologically modeled. Unlabeled D-aspartate (0.5 mM) and hypo-osmotic medium (NaCl reduced by 50 mM) evoked D-[ 3 H]aspartate release via homoexchange and hypo-osmotic release pathways, respectively. Taurine did not influence these pathways. However, it suppressed the synaptic release of D-[ 3 H]aspartate evoked by the voltage-gated sodium channel opener veratridine (0.1 mM). Taurine thus reduces glutamate release under ischemic conditions by affecting the depolarization-evoked component.
The sulfur-containing amino acid taurine is an inhibitory neuromodulator in the brain of mammals,... more The sulfur-containing amino acid taurine is an inhibitory neuromodulator in the brain of mammals, as well as a key substance in the regulation of cell volumes. The effect of Ca 2+ on extracellular taurine concentrations is of special interest in the context of the regulatory mechanisms of taurine release. The aim of this study was to characterize the basal release of taurine in Ca 2+ -free medium using in vivo microdialysis of the striatum of anesthetized rats. Perfusion of Ca 2+ -free medium via a microdialysis probe evoked a sustained release of taurine (up to 180 % compared to the basal levels). The Ca 2+ chelator EGTA (1 mM) potentiated Ca 2+ depletion-evoked taurine release. The substitution of CaCl 2 by choline chloride did not alter the observed effect. Ca 2+ -free solution did not significantly evoke release of taurine from tissue loaded with the competitive inhibitor of taurine transporter guanidinoethanesulfonate (1 mM), suggesting that in Ca 2+ depletion taurine is released by the transporter operating in the outward direction. The volume-sensitive chloride channel blocker diisothiocyanostilbene-2,2 0 -disulfonate (1 mM) did not attenuate the taurine release evoked by Ca 2+ depletion. The non-specific blocker of voltage-sensitive Ca 2+ channels NiCl 2 (0.65 mM) enhanced taurine release in the presence of Ca 2+ . CdCl 2 (0.25 mM) had no effect under these conditions. However, both CdCl 2 and NiCl 2 attenuated the effect of Ca 2+ -free medium on the release of taurine. The data obtained imply the involvement of both decreased influx of Ca 2+ and increased non-specific influx of Na + through voltage-sensitive calcium channels in the regulation of transporter-mediated taurine release in Ca 2+ depletion. #
Advances in Experimental Medicine and Biology, Feb 1, 1981
Neurochemical Research, 2009
In the brain stem glycine is associated with multiple sensory and visceral regulations, being inv... more In the brain stem glycine is associated with multiple sensory and visceral regulations, being involved in, for instance, cardiovascular, respiratory and auditory functions. We here studied the mechanisms of the release of preloaded [ 3 H]glycine from mouse brain stem slices in a superfusion system. A depolarizing concentration of K + ions (50 mM) evoked glycine release, but in the absence of Ca 2+ the effect was attenuated, indicating that a part of the evoked release represents Ca 2+ -dependent exocytosis. The Ca 2+independent release was enhanced by omission of Na + and Cl -. The stimulatory effect of extracellular glycine confirmed the involvement of transporters functioning in a reverse direction. A part of the release is mediated by Na + and Clchannels, since it was inhibited by the inhibitors of these, riluzole and 4-acetamido-4 0 -isothiocyanostilbene-2,2 0 -disulphonate, respectively. Glycine release was potentiated by the activation of protein kinase C and diminished by increasing cyclic guanosine monophosphate levels with a phosphodiesterase inhibitor, zaprinast. The release was also modulated by the phospholipase inhibitor quinacrine and the tyrosine kinase inhibitor genistein. Adenosine A 1 receptors likewise regulate glycine release, since it was enhanced by their agonist R(-)N 6 -(2-phenylisopropyl)adenosine, which effect was blocked by the antagonist 8-cyclopentyl-1,3-dipropylxanthine. The ionotropic glutamate receptor agonists N-methyl-D-aspartate, kainate and 2-amino-3-hydroxy-5methyl-4-isoxazolepropionate failed to have any effects contrary to their effects in higher brain regions, e.g., in the hippocampus. The group I and III metabotropic glutamate receptor agonists (S)-3,5-dihydroxyphenylglycine and O-phospho-L-serine, respectively, increased the release in a receptor-mediated manner. Glycine release in the brain stem was also markedly enhanced by cell-damaging conditions, including hypoxia, hypoglycemia and ischemia.
Amino Acids, 2010
The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions i... more The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions in both adult and developing brain stem, together with a pronounced increase in the release of the neuromodulator adenosine. We now studied the effects of adenosine receptor agonists and antagonists on [(3)H]taurine release in the brain stem in normoxia and ischemia, using a superfusion system. Under standard conditions, the adenosine A(1) receptor agonist N(6)-cyclohexyladenosine (CHA) potentiated basal taurine release in adult mice, which response was blocked by the antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). CHA and the A(2a) receptor agonist 2-p-(2-carboxyethyl)phenylamino-5'-N-ethylcarboxaminoadenosinehydrochloride (CGS 21680) had no effect on the release in developing mice. In ischemia, CHA depressed both basal and K(+)-stimulated taurine release in developing mice in a receptor-mediated manner, blocked by DPCPX. The A(2a) receptor agonist CGS 21680 was also inhibitory. Taurine and adenosine may thus not cooperate in developing mice to prevent ischemic neuronal damage. On the other hand, CGS 21680 enhanced taurine release in the adult brain stem in ischemia, both basal and K(+)-stimulated release being affected. These effects were abolished by the antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), indicating a receptor-mediated process. In this case elevated levels of taurine could be beneficial, protecting against hyperexcitation and excitotoxicity.
Molecular Immunology, Mar 31, 2006
Tryptophan catabolism activated by the indoleamine 2,3-dioxygenase (EC 1.13.11.42) (IDO) enzyme i... more Tryptophan catabolism activated by the indoleamine 2,3-dioxygenase (EC 1.13.11.42) (IDO) enzyme in antigen presenting cells has a central role in induction of mechanisms suppressing T cell activation or clonal expansion. There is evidence suggesting that IDO activity is mainly upregulated by typical Th1-differentiating signals such as interferon-␥ and bacterial lipopolysaccharide (LPS). Therefore, we hypothesized that IDO activity would be lower in a Th2-associated disease such as atopy and that it would be higher in the presence of environmental factors known to favor Th1 differentiation. Here we show that this was the case. Concentrations of tryptophan (trp) and kynurenine (kyn), the main metabolite, were determined by reverse phase liquid chromatography from serum samples of a cohort of 392 non-asthmatic individual of whom 149 were atopics (one or more positive skin test when tested with a panel of 22 allergens). Kyn/trp ratio, as an indicator of IDO activity, was significantly lower in atopic than in non-atopic individuals. The cohort was stratified according to two known atopy-protecting factors, presence of antibodies against Helicobacter pylori or anamnestic information about childhood on a farm environment. As expected, IDO activity was significantly higher in their presence than absence.
Amino Acids, 2008
Glutathione (reduced form GSH and oxidized form GSSG) constitutes an important defense against ox... more Glutathione (reduced form GSH and oxidized form GSSG) constitutes an important defense against oxidative stress in the brain, and taurine is an inhibitory neuromodulator particularly in the developing brain. The effects of GSH and GSSG and glycylglycine, γ-glutamylcysteine, cysteinylglycine, glycine and cysteine on the release of [ 3 H]taurine evoked by K + -depolarization or the ionotropic glutamate receptor agonists glutamate, kainate, 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) were now studied in slices from the hippocampi from 7-day-old mouse pups in a perfusion system. All stimulatory agents (50 mM K + , 1 mM glutamate, 0.1 mM kainate, 0.1 mM AMPA and 0.1 mM NMDA) evoked taurine release in a receptor-mediated manner. Both GSH and GSSG significantly inhibited the release evoked by 50 mM K + . The release induced by AMPA and glutamate was also inhibited, while the kainate-evoked release was significantly activated by both GSH and GSSG. The NMDA-evoked release proved the most sensitive to modulation: L-Cysteine and glycine enhanced the release in a concentration-dependent manner, whereas GSH and GSSG were inhibitory at low (0.1 mM) but not at higher (1 or 10 mM) concentrations. The release evoked by 0.1 mM AMPA was inhibited by γ-glutamylcysteine and cysteinylglycine, whereas glycylglycine had no effect. The 0.1 mM NMDA-evoked release was inhibited by glycylglycine and γ-glutamylcysteine. In turn, cysteinylglycine inhibited the NMDAevoked release at 0.1 mM, but was inactive at 1 mM. Glutathione exhibited both enhancing and attenuating effects on taurine release, depending on the glutathione concentration and on the agonist used. Both glutathione and taurine act as endogenous neuroprotective effectors during early postnatal life.
Brain Res, 1973
Electrical stimulation of brain slices of newborn and adult rats enhanced the decarboxylation of ... more Electrical stimulation of brain slices of newborn and adult rats enhanced the decarboxylation of glutamate and cysteine sulphinate. The activity of both decarboxylases increased with age, that of glutamate decarboxylase more sharply. The rate of oxidation of hypotaurine to taurine was highest in the brain, liver and kidney of 10day-old rats. No measurable conversion of hypotaurine to taurine occurred in preparations from the brain of adults, neither did electrical stimulation induce the oxidation of hypotaurine in these preparations.
Med Sci Sport Exercise, 1996
International Journal of Developmental Neuroscience, Aug 31, 1994
The sodium-independent binding of [3-alanine to cerebral cortical membranes from adult (3-and 12-... more The sodium-independent binding of [3-alanine to cerebral cortical membranes from adult (3-and 12-month-old) and developing (7-day-old) mice was characterized for the first time. The binding was saturable in each age group, consisting of only one component. The affinity for [3-alanine was highest and the number of available binding sites greatest in young animals. The binding was not affected by strychnine, but inhibited by [3-alanine itself, glycine, L-alanine and L-serine, the lCs0 values being lower in immature mice. Glycine was shown to be a competitive inhibitor. The binding was also inhibited, albeit only in adults, by N-methyl-D-aspartate receptor antagonists acting at the glycine modulatory site and by some GABAergic substances. It is concluded that even though [3-alanine may possess binding sites of its own, particularly in the immature cerebral cortex, [3-alanine could at least partly bind to strychnine-insensitive glycine sites in the N-methyl-D-aspartate receptor complex.
Neuroscience, Feb 1, 2000
The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions i... more The release of the inhibitory amino acid taurine is markedly enhanced under ischemic conditions in both adult and developing hippocampus, together with a pronounced increase in the release of excitatory amino acids and the neuromodulator adenosine. We studied the effects of adenosine receptor agonists and antagonists as well as adenosine transport inhibitors on hippocampal [3H]taurine release in normoxia and ischemia, using a superfusion system. Under standard conditions the adenosine A1 receptor agonists N6-cyclohexyladenosine and R(−)N6-(2-phenylisopropyl)adenosine potentiated basal taurine release in developing mice and depressed the release in adults in a receptor-mediated manner. Adenosine A2 receptor compounds had only minor effects on the basal release and the K+-stimulated release was not affected by these drugs. The adenosine uptake inhibitor dipyridamole enhanced basal taurine release in the developing hippocampus and reduced it in the adult. In ischemia the adenosine compounds had no marked effects on taurine release in immature animals, whereas A1 receptor activation was still able to evoke taurine release in adults by a receptor-mediated mechanism. The results show that the basal release of taurine is modulated by A1 receptors in both mature and immature hippocampus, whereas in ischemia these receptors potentiate taurine release only in adults.The elevated taurine levels together with the depression of excitatory amino acid release by adenosine receptor activation could be beneficial under ischemic conditions, protecting neural cells against excitotoxicity and hyperexcitation.