Simo S. Oja

Taurine and neural cell damage.

There is evidence that taurine protects neural cells from excitotoxicity induced by excitatory amino acids8, forestalls harmful metabolic cascades evoked by ischemia or hypoxia40, and attenuates Ca2+ influx during ischemia20. Taurine also ameliorates symptoms in epilepsy29. The mechanism of this neuroprotection is not known, but it may be related, in addition to neuromodulation38, to osmoregulatory, antioxidant and Ca2+ regulatory effects16.

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 α-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).

Taurine and GABA release from mouse cerebral cortex slices: potassium stimulation releases more taurine than GABA from developing brain.

The release of exogenous taurine and gamma-aminobutyric acid (GABA) was studied with slices from the developing mouse cerebral cortex. The spontaneous efflux of GABA increased with the cerebral GABA content during postnatal development, while the spontaneous efflux of taurine was approximately the same in both neonate and adult mice, in spite of a several-fold higher cerebral taurine content in the former. GABA, taurine and their structural analogues caused marked homo- and hetero-trans-stimulation of the release in both adult and developing mice, probably via membrane transport sites. The release was greatly enhanced by both 0.01 mM veratridine and exposure to sodium-free medium, the effects being more pronounced with GABA in the adults and with taurine in the neonates. The excitatory amino acids homocysteate, aspartate and kainate enhanced taurine release particularly from the developing cerebral cortex but were not effective on GABA release in the adults. The potassium stimulation of taurine release had a strikingly slow time course in both adult and developing mice. The responses in GABA release were also fairly slow in the neonates. Potassium stimulation evoked a large release of GABA in adult but not in developing mice. The evoked taurine release was in developing mice several-fold greater than the evoked GABA release, decreasing in magnitude with age. The potassium-stimulated release was only partially calcium dependent, more so with GABA in the adults and with taurine in the neonates, but a high magnesium ion concentration inhibited the release of both amino acids more strongly in the latter age group. Verapamil (0.1 mM) almost abolished the potassium stimulation of GABA release in both adult and neonate mice and was more effective on taurine release in neonate mice. The results suggest that taurine, not GABA, is the major inhibitor of excitability in developing mouse brain.

Taurine as Osmoregulator and Neuromodulator in the Brain

Taurine has been assumed to function as an osmoregulator and neuromodulator in the brain. The pertinent studies are now reviewed in an attempt to formulate a unifying hypothesis as to how taurine could simultaneously act in both roles. Neuromodulatory actions of taurine may also underlie its protective effects against neuronal overexcitation and glutamate agonist-induced neurotoxicity.

Free amino acids in the synaptosome and synaptic vesicle fractions of different bovine brain areas

Free amino acids were quantitatively estimated in intact tissues and isolated synaptosome and synaptic vesicle fractions of the bovine brain regions with the aid of a sensitive amino acid analyzer. The brain areas studied were frontal, parietal and occipital cerebral cortices, cerebellar cortex, caudate and lenticular nuclei, superior colliculi, thalamus, pons and medulla. The most abundant amino acid in tissue samples and synaptosome fractions was glutamic acid, followed by glutamine, aspartic acid, GABA and taurine. The dominatating amino acid in all isolated synaptic vesicle fractions was taurine. The concentrations of glutamic acid, glutamine, GABA and aspartic acid were generally much lower. The 5 transmitter candidates, viz. GABA, glycine, glutamic acid, as particaid and taurine, comprised about one-half of the total amino acids in all samples. Taurine was the only amino acid highly enriched in the vesicle fractions. This enrichment was discernible in all brain areas. It is suggested therefore that taurine is rather a ubiquitous associate of synaptic membrane structures than a specific inhibitory transmitter.

Release of GABA and taurine from brain slices

In brain slices the mechanisms of release of GABA have been extensively studied, but those of taurine markedly less. The knowledge acquired from studies on GABA is, nevertheless, still fragmentary, not to speak of that obtained from the few studies on taurine, and firm conclusions are difficult, even impossible, to draw. This is mainly due to methodological matters, such as the diversity and pitfalls of the techniques applied. Brain slices are relatively easy to prepare and they represent a preparation that may most closely reflect relations prevailing in vivo, since the tissue structure and cellular integrity are largely preserved. In our opinion the most recommendable method at present is to superfuse freely floating agitated slices in continuously oxygenated medium. Taurine is metabolically rather inert in the brain, whereas the metabolism of GABA must be taken into account in all release studies. The use of inhibitors of GABA catabolism is discouraged, however, since a block in GABA metabolism may distort relations between different releasable pools of GABA in tissue. It is not known for sure how well, and homogeneously, incubation of slices with radioactive taurine labels the releasable pools but at least in the case of GABA there may prevail differences in the behavior of labeled and endogenous GABA. It is suggested therefore that the results obtained with radioactive GABA or taurine should be frequently checked and confirmed by analyzing the release of respective endogenous compounds. The spontaneous efflux of both GABA and taurine from brain slices is very slow. The magnitude of stimulation of GABA release by homoexchange is greater than that of taurine under the same experimental conditions. However, the release of both amino acids is generally enhanced by a great number of structural analogs, the most potent being those which are simultaneously the most potent inhibitors of uptake. This may result in part from inhibition of reuptake of amino acid molecules released from slices but the findings may also signify that the efflux of GABA and taurine is at least partially mediated by the membrane carriers operating in an outward direction. It is thus advisable not to interpret that stimulation of release in the presence of uptake inhibitors solely results from the block of reuptake of exocytotically released molecules, since changes in the carrier-mediated transport are also likely to occur upon stimulation. The electrical and K+ stimulation evoke the release of both GABA and taurine. The evoked release of GABA is several-fold greater than that of taurine in slices from the adult brain.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhanced taurine release in cell-damaging conditions in the developing and ageing mouse hippocampus

Taurine has been shown to be essential for neuronal development and survival in the central nervous system. The release of preloaded [3H]taurine was studied in hippocampal slices from seven-day-, three-month- and 18-22-month-old mice in cell-damaging conditions. The slices were superfused in hypoxic, hypoglycemic and ischemic conditions and exposed to free radicals and oxidative stress. The release of taurine was greatly enhanced in the above conditions in all age groups, except in oxidative stress. The release was large in ischemia, particularly in the hippocampus of aged mice. Potassium stimulation was still able to release taurine in cell-damaging conditions in immature mice, whereas in adult and aged animals the release was so substantial that this additional stimulus failed to work. Taurine release was partially Ca2+-dependent in all cases. The massive release of the inhibitory amino acid taurine in ischemic conditions could act neuroprotectively, counteracting in several ways the effects of simultaneous release of excitatory amino acids. This protection could be of great importance in developing brain tissue, while also having an effect in aged brains.

Indoleamine 2,3-dioxygenase enzyme activity correlates with risk factors for atherosclerosis: the Cardiovascular Risk in Young Finns Study.

Indoleamine 2,3 dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, suppresses T cell activity and is up‐regulated by various inflammatory stimuli. The ratio of kynurenine, the main metabolite of tryptophan, to tryptophan (kyn/trp) reflects IDO activity. We calculated IDO activity and measured carotid intima‐media thickness (IMT), a presymptomatic predictor of atherosclerosis, in 986 young adults (544 female, 442 male) for whom data on levels of high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), triglyceride, high sensitive C‐reactive protein (CRP), body mass index (BMI), waist circumference, waist‐to‐hip ratio, systolic and diastolic blood pressure and smoking habits were available. IDO activity correlated significantly with IMT in female subjects, but not in males. In a multivariate linear regression model, IDO did not correlate independently with IMT in female subjects. However, IDO activity correlated significantly with several risk factors for atherosclerosis in females, i.e. with age, LDL‐C, BMI, weakly with CRP and inversely with HDL‐C and triglyceride. In males IDO activity correlated significantly with CRP and inversely with HDL‐C. In conclusion, our results suggest that the IDO enzyme is involved in the immune regulation of early atherosclerosis, particularly in young female adults, and could constitute a novel marker of immune activation in early atherosclerosis in females.

Modulation of glutamate receptor functions by glutathione.

In addition to its well-known antioxidant effects, glutathione apparently has an additional double role in the central nervous system as a neurotransmitter and neuromodulator. A number of recent neurochemical, neuropharmacological and electrophysiological studies have yielded evidence on both functions. As an excitatory neurotransmitter, glutathione depolarizes neurons by acting as ionotropic receptors of its own which are different from any other excitatory amino acid receptors. As a neuromodulator, it displaces ionotropic glutamate receptor ligands from their binding sites and regulates calcium influx through N-methyl-D-aspartate receptor-governed ionophores. In brain slices glutathione has been shown to regulate the release of other transmitters, e.g., gamma-aminobutyrate and dopamine, mediated by N-methyl-D-aspartate receptors. In the present article, we review recent findings on the neuromodulatory actions of glutathione and discuss possible physiological and pathophysiological consequences.

Release of Endogenous Glutamate, Aspartate, GABA, and Taurine from Hippocampal Slices from Adult and Developing Mice under Cell-Damaging Conditions

The releases of endogenous glutamate, aspartate, GABA and taurine from hippocampal slices from 7-day-, 3-, 12-, and 18-month-old mice were investigated under cell-damaging conditions using a superfusion system. The slices were superfused under hypoxic conditions in the presence and absence of glucose and exposed to hydrogen peroxide. In the adult hippocampus under normal conditions the basal release of taurine was highest, with a response only about 2-fold to potassium stimulation (50 mM). The low basal releases of glutamate, aspartate, and GABA were markedly potentiated by K+ ions. In general, the release of the four amino acids was enhanced under all above cell-damaging conditions. In hypoxia and ischemia (i.e., hypoxia in the absence of glucose) the release of glutamate, aspartate and GABA increased relatively more than that of taurine, and membrane depolarization by K+ markedly potentiated the release processes. Taurine release was doubled in hypoxia and tripled in ischemia but K+ stimulation was abolished. In both the mature and immature hippocampus the release of glutamate and aspartate was greatly enhanced in the presence of H2O2, that of aspartate particularly in developing mice. In the immature hippocampus the increase in taurine release was 10-fold in hypoxia and 30-fold in ischemia, and potassium stimulation was partly preserved. The release processes of the four amino acids in ischemia were all partially Ca2+-dependent. High concentrations of excitatory amino acids released under cell-damaging conditions are neurotoxic and contribute to neuronal death during ischemia. The substantial amounts of the inhibitory amino acids GABA and taurine released simultaneously may constitute an important protective mechanism against excitatory amino acids in excess, counteracting their harmful effects. In the immature hippocampus in particular, the massive release of taurine under cell-damaging conditions may have a significant function in protecting neural cells and aiding in preserving their viability.