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S S Oja

Publications and source records attributed to S S Oja.

At least 37 records · Page 2Linked to original sources
PubMed2001

Characteristics of hippocampal glycine release in cell-damaging conditions in the adult and developing mouse.

The release of preloaded [3H]glycine from hippocampal slices from 7-day-old and 3-month-old (adult) mice was studied in different cell-damaging conditions, including hypoxia, hypoglycemia, ischemia, oxidative stress and the presence of free radicals and metabolic poisons, using a superfusion system. Glycine release was greatly enhanced in all the above conditions in both age groups, with the exception of hypoxia in developing mice. This coincides with the increased susceptibility to seizures and excitotoxicity during postnatal development. The ischemia-induced release of glycine was Ca2+-independent at both ages. The release was potentiated by exogenously applied glycine but not in Na+-free conditions, indicating the involvement of Na+-dependent transporters operating outwards. The Cl- channel blockers 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonate and diisothiocyanostilbene-2,2'-disulphonate generally reduced the ischemia-induced release, suggesting that this occurs through anion channels in both developing and adult mice. Furthermore, in the adult hippocampus riluzole and amiloride inhibited the release, indicating that Na+ channels also contribute to the ischemia-evoked release. Since glycine is an essential factor in glutamate-induced Ca2+ channel opening at the N-methyl-D-aspartate receptor, the elevated levels of glycine, together with the increased release of excitatory amino acids, must obviously collaborate in the development of ischemic neuronal damage.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2001

Effects of metabotropic glutamate receptor agonists and antagonists on D-aspartate release from mouse cerebral cortical and striatal slices.

The cytosolic release of L-glutamate has been held to be responsible for the increase in extracellular glutamate to toxic levels in the brain. The mechanism and regulation of this release was now studied in cerebral cortical and striatal slices with D-[3H]aspartate, a non-metabolized analogue of L-glutamate and a poor substrate for vesicular uptake. L-Glutamate and D-aspartate strongly stimulated the release in a concentration-dependent manner. Of the ionotropic glutamate receptor agonists, only kainate enhanced the basal release in the striatum. Of the metabotropic glutamate receptor ligands, the group I agonist (S)-3,5-dihydroxyphenylglycine (S-DHPG) failed to affect the basal release but inhibited the D-aspartate-evoked release in the striatum. The group I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA) had no effect on the basal release in either preparation but enhanced the L-glutamate-evoked release and inhibited the D-aspartate-evoked release in the striatum, not however in the cerebral cortex. The group II agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) and the group II antagonist (2S)-2-ethylglutamate (EGLU) were without effect on the basal, D-aspartate- and L-glutamate-evoked releases of D-[3H]aspartate in either preparation. The group III agonist L-serine-O-phosphate (L-SOP) failed to affect the basal release but reduced the D-aspartate-evoked release in the striatum. The group III antagonist (RS)alpha-methylserine-O-phosphate (MSOP) failed to affect the basal release but increased the glutamate-evoked release and inhibited the D-aspartate-evoked release in the striatum. Both L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC) and (2S,1'S,2'R)-2-carboxycyclopropyl)glycine (L-CCG-III), transportable inhibitors of the high-affinity glutamate uptake, enhanced the basal release, more strongly in the striatum than in the cerebral cortex. L-CCG-III also increased the L-glutamate-evoked release in the striatum. Nontransportable dihydrokainate enhanced the basal release much less and failed to affect the glutamate-evoked release. The results indicate that the release of glutamate from cytosolic pools is carrier-mediated via homoexchange. This process is regulated in the striatum by metabotropic group I and group III receptors in a manner different from the regulation of the vesicular release of glutamate from presynaptic terminals.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2000

Taurine release modified by GABAergic agents in hippocampal slices from adult and developing mice.

In order to characterize the possible regulation of taurine release by GABAergic terminals, the effects of several agonists and antagonists of GABA receptors on the basal and K+-stimulated release of [3H]taurine were investigated in hippocampal slices from adult (3-month-old) and developing (7-day-old) mice using a superfusion system. Taurine release was concentration-dependently potentiated by GABA, which effect was reduced by phaclofen, saclofen and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at both ages, suggesting regulation by both GABA(B) and GABA(C) receptors. The involvement of GABA(A) receptors could not be excluded since the antagonist bicuculline was able to affect both basal and K+-evoked taurine release. Furthermore, several GABA(B) receptor effectors were able to inhibit K+-stimulated taurine release in the adults, while the GABA(C) receptor agonists trans-4-aminocrotonic acid (TACA) and cis-4-aminocrotonic acid (CACA) potentiated this release. The potentiation of taurine release by agents acting on the three types of GABA receptors in both adult and developing hippocampus further indicates the involvement of transporters operating in an outward direction. This inference is corroborated by the moderate but significant inhibition of taurine uptake by the same compounds.

Age Factors↗
PubMed2000

Taurine and neural cell damage.

The inhibitory amino acid taurine is an osmoregulator and neuromodulator, also exerting neuroprotective actions in neural tissue. We review now the involvement of taurine in neuron-damaging conditions, including hypoxia, hypoglycemia, ischemia, oxidative stress, and the presence of free radicals, metabolic poisons and an excess of ammonia. The brain concentration of taurine is increased in several models of ischemic injury in vivo. Cell-damaging conditions which perturb the oxidative metabolism needed for active transport across cell membranes generally reduce taurine uptake in vitro, immature brain tissue being more tolerant to the lack of oxygen. In ischemia nonsaturable diffusion increases considerably. Both basal and K+-stimulated release of taurine in the hippocampus in vitro is markedly enhanced under cell-damaging conditions, ischemia, free radicals and metabolic poisons being the most potent. Hypoxia, hypoglycemia, ischemia, free radicals and oxidative stress also increase the initial basal release of taurine in cerebellar granule neurons, while the release is only moderately enhanced in hypoxia and ischemia in cerebral cortical astrocytes. The taurine release induced by ischemia is for the most part Ca2+-independent, a Ca2+-dependent mechanism being discernible only in hippocampal slices from developing mice. Moreover, a considerable portion of hippocampal taurine release in ischemia is mediated by the reversal of Na+-dependent transporters. The enhanced release in adults may comprise a swelling-induced component through Cl- channels, which is not discernible in developing mice. Excitotoxic concentrations of glutamate also potentiate taurine release in mouse hippocampal slices. The ability of ionotropic glutamate receptor agonists to evoke taurine release varies under different cell-damaging conditions, the N-methyl-D-aspartate-evoked release being clearly receptor-mediated in ischemia. Neurotoxic ammonia has been shown to provoke taurine release from different brain preparations, indicating that the ammonia-induced release may modify neuronal excitability in hyperammonic conditions. Taurine released simultane ously with an excess of excitatory amino acids in the hippocampus under ischemic and other neuron-damaging conditions may constitute an important protective mechanism against excitotoxicity, counteracting the harmful effects which lead to neuronal death. The release of taurine may prevent excitation from reaching neurotoxic levels.

Animals↗
PubMed2000

Modulation of taurine release by glutamate receptors and nitric oxide.

Taurine is held to function as a modulator and osmoregulator in the central nervous system, being of particular importance in the immature brain. In view of the possible involvement of excitatory pathways in the regulation of taurine function in the brain, the interference of glutamate receptors with taurine release from different tissue preparations in vitro and from the brain in vivo is of special interest. The release of taurine from the brain is enhanced by glutamate receptor agonists. This enhancement is inhibited by the respective receptor antagonists both in vitro and in vivo. The ionotropic N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor agonists appear to be the most effective in enhancing taurine release, their effects being receptor-mediated. Kainate is less effective, particularly in adults. Of the glutamate receptors, the NMDA class seems to be the most susceptible to modulation by nitric oxide. Nitric oxide also modulates taurine release, enhancing the basal release in both immature and mature hippocampus, whereas the K(+)-stimulated release is generally inhibited. Metabotropic glutamate receptors also participate in the regulation of taurine release, group I metabotropic glutamate receptors potentiating the release in the developing hippocampus, while group III receptors may be involved in the adult. Under various cell-damaging conditions, including ischemia, hypoxia and hypoglycemia, taurine release is enhanced, together with an enhanced release of excitatory amino acids. The increase in extracellular taurine upon excessive stimulation of glutamate receptors and under cell-damaging conditions may serve as an important protective mechanism against excitotoxicity, being particularly effective in the immature brain.

Animals↗
PubMed2000

Modulation of the ischemia-induced taurine release by adenosine receptors in the developing and adult mouse hippocampus.

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 [(3)H]taurine release in normoxia and ischemia, using a superfusion system. Under standard conditions the adenosine A(1) receptor agonists N(6)-cyclohexyladenosine and R(-)N(6)-(2-phenylisopropyl)adenosine potentiated basal taurine release in developing mice and depressed the release in adults in a receptor-mediated manner. Adenosine A(2) 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 A(1) 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 A(1) 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.

Age Factors↗
PubMed2000

Specific glutathione binding sites in pig cerebral cortical synaptic membranes.

Glutathione (gamma-glutamylcysteinylglycine) is a neuromodulator at glutamate receptors, but may also act as a neurotransmitter at sites of its own. The Na+-independent binding of [3H]glutathione to pig cortical synaptic membranes was characterized here using glycine, cysteine analogs, dipeptides and glutathione derivatives, and ligands selective for known glutamate receptors. L-Glutamate, pyroglutamate, quinolinate, (S)-5-fluorowillardiine and 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione were weak inhibitors at concentrations of 0.5 or 1 mM. D-Glutamate, L- and D-aspartate, glutamine, quisqualate, kynurenate, other N-methyl-D-aspartate receptor ligands and non-N-methyl-D-aspartate receptor ligands failed to displace [3H]glutathione. Except for weak inhibition by D-serine (0.5 mM), glycine and other ligands of the glycine co-activatory site in the N-methyl-D-aspartate receptors had no displacing effect. Similarly, metabotropic glutamate group I, II and III receptor agonists and antagonists and compounds acting at the glutamate uptake sites were generally inactive. Glutathione, oxidized glutathione, S-nitrosoglutathione, gamma-L-glutamylcysteine, cysteinylglycine, cysteine, cysteamine and cystamine were the most potent displacers (IC50 values in the micromolar range), followed by dithiothreitol, glutathione sulfonate and the S-alkyl derivatives of glutathione (S-methyl-, -ethyl-, -propyl-, -butyl- and -pentylglutathione). L-Homocysteinate and aminomethanesulfonate exhibited a moderate efficacy. Thiokynurenate, a cysteine analog and an antagonist at the N-methyl-D-aspartate receptor glycine co-activatory site, was a potent activator of glutathione binding. At 1 mM, some dipeptides also slightly activated the binding, gamma-L-glutamylleucine and gamma-L-glutamyl-GABA being the most effective. The specific binding sites for glutathione in brain synaptic membranes are not identical to any known excitatory amino acid receptor. The cysteinyl moiety is crucial in the binding of glutathione. The oxidation or alkylation of the cysteine thiol group reduces the binding affinity. The strong activation by thiokynurenate may indicate that the glutathione receptor protein contains a modulatory site to which co-agonists may bind and allosterically activate glutathione binding. The novel population of specific binding sites of glutathione gives rise to the possibility that they may have profound effects on synaptic functions in the mammalian central nervous system. The glutathione binding sites may be an important, and for the most part unrecognized, component in signal transduction in the brain.

Animals↗
PubMed2000

Mechanisms of L-cysteine neurotoxicity.

We review here the possible mechanisms of neuronal degeneration caused by L-cysteine, an odd excitotoxin. L-Cysteine lacks the omega carboxyl group required for excitotoxic actions via excitatory amino acid receptors, yet it evokes N-methyl-D-aspartate (NMDA) -like excitotoxic neuronal death and potentiates the Ca2+ influx evoked by NMDA. Both actions are prevented by NMDA antagonists. One target for cysteine effects is thus the NMDA receptor. The following mechanisms are discussed now: (1) possible increase in extracellular glutamate via release or inhibition of uptake/degradation, (2) generation of cysteine alpha-carbamate, a toxic analog of NMDA, (3) generation of toxic oxidized cysteine derivatives, (4) chelation of Zn2+ which blocks the NMDA receptor-ionophore, (5) direct interaction with the NMDA receptor redox site(s), (6) generation of free radicals, and (7) formation of S-nitrosocysteine. In addition to these, we describe another new alternative for cytotoxicity: (8) generation of the neurotoxic catecholamine derivative, 5-S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac).

Animals↗
PubMed2000

Interference of S-nitrosoglutathione with the binding of ligands to ionotropic glutamate receptors in pig cerebral cortical synaptic membranes.

The interactions of S-nitrosoglutathione (GSNO) with the ionotropic glutamate receptors were studied on synaptic membranes isolated from the pig cerebral cortex. GSNO displaced the binding of [3H]glutamate, 3-[(R)-2-carboxypiperazin-4-yl] [3H]propyl-1-phosphonate ([3H]CPP), a competitive N-methyl-D-aspartate (NMDA) antagonist, and [3H]kainate, with IC50 values in the low micromolar range. It failed to displace (S)-5-fluoro-[3H]willardiine, a selective agonist of 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Reduced and oxidized glutathione were almost as effective as GSNO in glutamate and CPP binding. Of the three, GSNO was the most potent in kainate binding. They all stimulated [3H]dizocilpine binding in a concentration-dependent manner. This effect was additive to that of glycine and not mimicked by NO donors such as S-nitroso-N-acetylpenicillamine, 5-amino-3-morpholinyl-1,2,3-oxadiazolium chloride (SIN-1) and nitroglycerin. We assume that GSNO may act as an endogenous ligand at the NMDA and non-NMDA classes of glutamate receptors. In this manner it may facilitate NO transfer and target its delivery to specific sites in these receptors.

Alanine↗
PubMed2000

Involvement of metabotropic glutamate receptors in ischemia-induced taurine release in the developing and adult hippocampus.

Metabotropic glutamate receptors have recently been envisaged as involved in both potentiation and prevention of ischemic and excitotoxic neuronal damage. The release of the inhibitory amino acid taurine is markedly enhanced in ischemia in both the immature and mature mouse hippocampus. The modulation of [3H]taurine release by metabotropic receptor agonists and antagonists was studied in hippocampal slices from developing (7-day-old) and adult (3-month-old) mice using a superfusion system. Agonists of group I, II and III metabotropic glutamate receptors generally reduced the ischemia-induced release in adult animals. In the immature hippocampus the group I agonists (S)-3,5-dihydroxyphenylglycine and (1+/-)-1-aminocyclopentane-trans-1,3-dicarboxylate, which mainly enhance neuronal excitation, potentiated initial taurine release in ischemia. Ionotropic glutamate receptor agonists also enhance the ischemia-induced taurine release in developing mice. This glutamate-activated taurine release may thus constitute an important protective mechanism against excitotoxicity in the immature hippocampus.

Aging↗
PubMed2000

Effect of acute hepatic encephalopathy on [3H]dopamine release from rat cerebral cortex and striatum in vitro: role of Ca2+.

Hepatic encephalopathy (HE) is characterized by motor symptoms associated with disturbed functions of the dopaminergic systems, but the underlying mechanisms are not clear. A previous study from our laboratories revealed that HE, induced in rats by repeated treatment with thioacetamide, enhanced the 50 mM potassium (KCl)-stimulated release of newly loaded [3H]dopamine in both striatal and frontal cerebral cortical slices in the presence of Ca2+. In the present study we compared the effects of HE on dopamine release in striatal and frontal cerebral cortical slices and synaptosomes in the presence and absence of Ca2+. HE enhanced the KCl-stimulated [3H]dopamine release from striatal and frontal cortical synaptosomes in the presence of Ca2+ to the same extent as in slices prepared from the respective brain regions. In the absence of Ca2+ a slight reduction in dopamine release was observed in frontal cortical synaptosomes from HE rats when compared to control rats, while no effect of HE on the release was discernible in frontal cortical and striatal slices and striatal synaptosomes. We conclude that in both brain regions studied HE stimulates dopamine exocytosis triggered by Ca2+ influx without affecting the release mediated by means of plasma membrane transporters or exocytosis involving intraterminal Ca2+.

Acute Disease↗
PubMed1999

N-methyl-D-aspartate-evoked changes in the striatal extracellular levels of dopamine and its metabolites in vivo in rats with acute hepatic encephalopathy.

Acute hepatic encephalopathy (HE) is associated with disturbances in motor functions, but the underlying mechanisms remain obscure. Considerable experimental evidence suggests that motor activity is modulated by striatal dopamine neurons whose discharge is under glutamatergic control, mostly through activation of N-methyl-D-aspartate (NMDA) receptors. In this study we used intrastriatal microdialysis to compare the effects of infusion of 10 mM NMDA or 50 mM KCl as a general release stimulus, on the extracellular levels of endogenous dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in control rats and in rats with acute HE induced by repeated administration of thioacetamide. The basal levels of DA and DOPAC were not significantly altered by HE, while the HVA level was reduced. HE did not significantly affect the NMDA- or KCl-evoked increase in extracellular DA. Infusion of NMDA or KCl led to a decrease in extracellular DOPAC, and HE did not modulate these effects. However, HE attenuated the NMDA- but not the KCl-induced reduction in extracellular HVA. The results point to the impairment of modulation of striatal DA discharge and metabolism by glutamate acting at NMDA receptors, contributing to the motor disturbances in HE.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Changes in the extracellular profiles of neuroactive amino acids in the rat striatum at the asymptomatic stage of hepatic failure.

Rats were treated with a hepatotoxin thioacetamide (TAA) and examined 21 days later, when they showed moderate fatty metamorphosis of the liver and morphological changes in brain indicative of excitotoxic neuronal damage, but no evident biochemical or neurophysiological symptoms of hepatic encephalopathy (HE). High-performance liquid chromatography (HPLC) analysis of extracellular amino acids in striatal microdialysates of TAA-treated rats revealed a significant increase in the excitatory amino acids glutamate (Glu) and aspartate (Asp) and their amino acid metabolites glutamine (Gln) and alanine (Ala). Microdialysis in the presence of 50 mM K+ triggered in TAA-treated rats an accumulation of Asp and Glu, and diminished the accumulation of Gln. These effects were virtually absent in control rats. None of the treatments affected the accumulation of the nontransmitter amino acid leucine (Leu). The above changes mirror those previously described in symptomatic HE and are likely to contribute to excitotoxic damage. The basal microdialysate content of taurine (Tau), an amino acid with antioxidant and volume regulatory properties, was 60% lower in TAA-treated rats than in control rats despite its increased blood-to-brain transport. The decrease in extracellular Tau may thus reflect Tau redistribution to adjacent central nervous system (CNS) cells manifesting a cell-protective response. Stimulation with 50 mM K+ increased extracellular Tau in control rats by 182% and in TAA-treated rats by 322%. Stimulation with 100 microM N-methyl-D-aspartate (NMDA) increased extracellular Tau in control rats by 27 % and in TAA-treated rats by as much as 250%. The increase of K+- or NMDA-dependent Tau release may reflect improved cell volume regulation and neuroprotection and contribute to attenuation of neurologic symptoms in rats with liver failure.

Alanine↗