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Changes in plasma concentration of taurine in stroke
Neuroscience Letters 496 (2011) 172–175
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Changes in plasma concentration of taurine in stroke Mohammadreza Ghandforoush-Sattari a,b , Simin O. Mashayekhi c,∗ , Mahboob Nemati d , Hormoz Ayromlou a a
Neurosciences Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran Infectious and Tropical Diseases Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran NPMC, Tabriz University of Medical Sciences, Tabriz, Iran d Applied Drug Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran b c
a r t i c l e
i n f o
Article history: Received 14 January 2011 Received in revised form 10 March 2011 Accepted 6 April 2011 Keywords: Stroke Biomarker Taurine HPLC Amino acid
a b s t r a c t Taurine is critical for proper brain functioning. Increase in plasma taurine concentration has already been shown in many diseases [1,2,5,10,12,14,17,22,25,47]. The plasma concentrations of taurine in 60 patients, suffering from stroke, were compared with that of 54 healthy volunteers. The plasma samples of the patients were obtained three times in the first five days of hospitalization. A Student’s t-test showed a significant difference (P < 0.0001) between the plasma concentrations of taurine of the patients group (136.5 ± 8.2 mmol/L) and the control group (41.9 ± 2.5 mmol/L). In addition, a one-way repeated measures ANOVA test showed that the mean plasma concentration of taurine in the patients during the first five days of hospitalization declined significantly from 136.9 ± 8.2 mmol/L in the first day of hospitalization to 120.1 ± 5.9 mmol/L on the third day and 110.2 ± 7.0 mmol/L by the fifth day (P > 0.05). The plasma concentration of taurine was increased in the patients with stroke probably because of brain tissue damage. Although, according to the result of the study, mean plasma taurine concentration in stroke patients declined during five days of hospitalization. Further studies are needed to introduce taurine as a biomarker of recovery in stroke. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Taurine (2-aminoethanesulfonic acid) is a -amino acid, not incorporated into proteins and is found free in the body. Taurine is also one of the most abundant free amino acids in the mammalian brain and is critical for proper brain functioning [22,21]. Taurine is possibly the only free amino acid, which is found extensively in unicellular bacteria to complex humans and in organs particularly liver, heart, bone and brain [15]. Taurine is widely involved in neurological activities leading to neuroprotection; modulation of neural excitability, maintenance of cerebellar function, motor behaviour modulation through dopaminergic, adrenergic, serotonergic, cholinergic regulation and interaction with glutamate [15]. It has been shown to inhibit seizures in some experimental models [7,44]. Taurine acts as a low affinity agonist for GABA(A) receptors, protects neurons against kainate excitotoxic insults and modulates calcium homeostasis. Therefore, taurine is potentially capable of treating seizure-
∗ Corresponding author at: Dept. Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences. Tel.: +98 411 3341315; fax: +98 411 3344798. E-mail address: [email protected] (S.O. Mashayekhi). 0304-3940/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2011.04.010
associated brain damage [8]. The anticonvulsant effect of taurine might be mediated by 4-aminopyridine–calcium–taurine interactions [33]. Raised taurine concentration in plasma and urine have already been reported after surgical trauma, X-radiation, muscle necrosis, carbon tetrachloride-induced liver damage [47], heroin addiction [12] and paracetamol overdose [10,17]. Changes in taurine concentrations typically occur in stress states, e.g. osmotic changes, anoxia, prolonged illumination of photoreceptors, cell proliferation, brain development [22], pneumococcal meningitis [14], lung cancer [25], myocardial infarction [1], epilepsy [5,13,29,44] and hepatic encephalopathy [2]. Ward et al. showed elevation of plasma taurine concentration after speedy exercise indicating its possible release from muscle fibers [46]. Taurine is produced by liver, heart, brain, and lung cells in response to a toxic insult and subsequent leakage from damaged cells leads to increased concentrations in the plasma and urine. There are also other factors, which may influence the concentrations of taurine in tissue, blood and urine. Plasma and urinary taurine concentrations may decrease in patients receiving salbutamol and clenbuterol [3] and chemotherapy [6]. Gut flora may also modulate taurine concentrations [42]. Vitamin B6 deficiency [40], also depresses taurine formation with reducing intake of total protein or methionine [9]. Dietary content of methyl donors, may also influence taurine biosynthesis [39]. The range of
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plasma taurine in healthy humans is between 65 and 179 mmol/L (8–22 mg/L) [27]. Taurine has been shown to regulate osmotic pressure in the cell, maintain homeostasis of intracellular ions, inhibit phosphorylation of membrane proteins, and prevent lipid peroxidation. As an osmotic regulator, it has been suggested that taurine, along with glutamic acid, is instrumental in the transport of metabolically generated water from the brain [43]. Other evidences suggest that taurine may function as a potent candidate of inhibitory neurotransmitter or modulator to regulate neuronal activity in many cerebral areas [16,20,22,23]. Previous studies have also demonstrated release of taurine after middle cerebral artery occlusion in rats [28], in human cerebral cortex during membrane depolarization and simulated ischemia [19] and patients with headache during the acute phase of cerebrovascular ischemic disease [4]. It is suggestive that taurine is released from astrocyte cells by a variety of external stimuli including hypoosmotic stress, elevated extracellular potassium, and ammonia [45]. Therefore, we hypothesized that taurine could be suggested as a possible biomarker of stroke. There are several types of cellular release of taurine, of which the basal release described as ‘leaking of taurine’ through membrane is the commonest one. Such leaking depends on the permeability of the membrane to taurine, which in turn depends on lipid composition and several other factors [15]. Fig. 1. Mean of plasma taurine concentration in 60 stroke patients compared with 54 healthy control subjects (P < 0.0001)
2. Materials and methods Sixty patients [48 males and 12 females, aged 58–89 (Median 78)], suffering from stroke, were recruited for the study after giving fully informed written consent. The approval for the study was attained from the ethics committee of Tabriz University of Medical Sciences. The subjects who had Red Bull energy drink or sea food in the last 24 h, were excluded from the study because Red Bull and sea food contain large amount of taurine. Three blood samples (5 mL each) were taken from the brachial vain in the first, third, and fifth days of hospitalization and collected into heparinized tubes. The samples were immediately centrifuged at 4 ◦ C at 2000 rpm. Plasma was removed using a Pasteur pipette and transferred into 5 ml glass tubes and kept frozen at −20 ◦ C until analysis and when thawed, diluted (1:10, v/v) in methanol. On each assay day. 200 L of plasma samples was mixed in 2 mL methanol in glass tubes and centrifuged at 2000 rpm. Supernatants were decanted and stored at −20 ◦ C until required. 250 L of methanolic solution of calibrator or pre-treated samples was treated with 250 L boric acid buffer (618 mg boric acid in 100 mL water, pH 10 with NaOH), 250 L methanol, 250 L OPA (20 mg/mL in methanol), 50 L of a 25 mg/L ␣-amino-butyric acid (internal standard), and 50 L of MPA reagent (in fume hood) and then incubated for 10 min in the dark at −20 ◦ C. 20 L of prepared samples was injected onto the HPLC system which included a Genesis C18 4 15 cm column and disodium hydrogen phosphate 0.0125 M: acetonitrile (94:6) pH 7.2 as mobile phase using fluorescence detection [11]. The data were statistically analysed using Student’s unpaired t-test and one-way repeated measures ANOVA by Graph Pad Prism (ver. 2).
and control groups respectively. Plasma taurine concentrations of the first (before treatment) (mean ± SEM: 136.9 ± 8.2 mmol/L), third (120.1 ± 5.9 mmol/L), and fifth day (110.2 ± 7.0 mmol/L) of hospitalization were also compared using a one-way ANOVA test. There was a significant decline (P < 0.05) in the mean plasma taurine during the five day period of hospitalization (Fig. 2). The correlations between plasma taurine with plasma sodium and potassium concentrations which might be involved in osmorgulation were also analysed but there was no significant correlation (P > 0.05) (Figs. 3 and 4). Wong and Read [48] suggested that several aspects of physiology, notably blood pressure, body temperature, blood glucose, and blood oxygen saturation, might be
3. Results Plasma taurine concentrations of 60 patients, suffering from stroke, in the first (before treatment) (mean ± SEM: 136.9 ± 8.2 mmol/L) day of hospitalization were compared with those of 54 healthy control subjects (mean ± SEM: 41.9 ± 2.5 mmol/L) by two-tailed unpaired Student’s t-test. The mean plasma taurine concentration in the stroke group was significantly different from the control group (P < 0.0001) (Fig. 1). Plasma taurine concentrations ranged from 9.9 to 394.9 mmol/L (median 134.5) and 13.8 to 72.8 mmol/L (median 36.8) in the stroke
Fig. 2. Mean of plasma taurine concentration in 60 stroke patients during five days of hospitalization (P < 0.05).
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M. Ghandforoush-Sattari et al. / Neuroscience Letters 496 (2011) 172–175
Fig. 3. Correlation between plasma taurine and sodium concentrations in 60 stroke patients before treatment.
Fig. 4. Correlation between plasma taurine and potassium concentrations in 60 stroke patients before treatment.
altered after an ischemic stroke and intracerebral hemorrhage. Generally, blood pressure and temperature rise acutely after a stroke, before returning to normal. Five of the patients who had high level of plasma taurine, died in a week because of a second stroke, 14 patients had high level of blood sugar, 26 patients had hyperthermia and 12 had hypothermia, 32 patients were hypoxic at the first day of hospitalization. There was only a week significant correlation between plasma taurine and systolic blood pressures of patients at the first day of hospitalization (Fig. 5). There was not any difference between the mean of plasma taurine concentrations in men and women. 4. Discussion There are a number of electrophysiological studies indicating that taurine exerts its actions by interacting with different ion channels [37,38]. The inhibitory amino acid taurine is an osmoregulator and neuromodulator, also exerting neuroprotective actions in neural tissue [36]. Findings have indicated that different transport mechanisms and/or distinct cellular sources mediate hypoosmotic medium induced release of the excitatory amino acids and taurine in vivo [18]. Several neural pathologies, most particularly cerebral ischemia, hyponatremia, hepatic encephalopathy and traumatic brain injury, are associated with pronounced cell
Fig. 5. Correlation between plasma taurine and systolic blood pressures in 60 stroke patients before treatment.
swelling [24,30,41] followed by releasing taurine. Since taurine is a putative inhibitory synaptic transmitter, deficiency of brain taurine may possibly have caused the psychiatric and neurological manifestations of this disorder [35]. Reuptake of taurine to brain cells plays a significant role in determining taurine’s volume in brain tissue and plasma. Oja and Saransaari [31,32] suggested that transport of taurine into cells occurs by Na+ and Cl− -dependent mechanisms and it may be presumed that when external Na+ is reduced from 142 to 122 mmol/L (accompanied by a corresponding reduction in Cl− concentration) the rate of uptake is reduced. The reduction in the net rate of taurine efflux during chronic hyponatraemia may reflect a gradual readjustment of the influx/efflux balance, the effect of which is to maintain the osmotically determined cell water content and hence volume. This contrasts with the acceleration of taurine efflux that is seen in normal cells acutely exposed to hyposmotic media in which efflux occurs in response to sudden swelling following osmotic water entry [26]. We could not found any significant correlation between taurine with sodium and potassium plasma concentrations which might be involved in osmorgulation probably because of low sample size or difference between their plasma half-lives. There was also no correlation between plasma taurine and other biochemical parameters such as Mg, Ca, and phosphate. Pasanet-Morales et al. [34] showed a greater susceptibility to seizures in taurine-deficient rats, as demonstrated by a lowered latency for clonic seizures, an increased incidence of tonic seizures and a higher postseizure mortality. They suggested an involvement of endogenous taurine in nervous excitability. We showed that the plasma concentration of taurine increases in the patients with stroke probably because of brain tissue damage. However, the correlation between plasma taurine and changes in physiological aspects after stroke remains incomplete. Further studies are needed to evaluate plasma and CSF’s taurine concentrations in both ischemic and hemorrhagic strokes on extra patients. Acknowledgments We wish to thank to Dr. Derek Buss (Cardiff University) for his collaboration in writing this paper and the personnel and academic staff of the neurology department of Imam Reza Hospital of Tabriz University of Medical Sciences for their cooperation. References [1] S.K. Bhatnagar, J.D. Welty, A.R. al Yusuf, Significance of blood taurine levels in patients with first time acute ischaemic cardiac pain, Int. J. Cardiol. 27 (1990) 361–366.
M. Ghandforoush-Sattari et al. / Neuroscience Letters 496 (2011) 172–175 [2] R.F. Butterworth, Taurine in hepatic encephalopathy, Adv. Exp. Med. Biol. 403 (1996) 601–606. [3] F. Carvalho, C. Waterfield, M. Ferreira, M.d.L. Bastos, J. Timbrell, Effect of repeated exposure to salbutamol on urinary and liver taurine levels in rats, Hum. Exp. Toxicol. 13 (1994) 291. [4] J. Castillo, F. Martinez, E. Corredera, J.M. Aldrey, M. Noya, Amino acid transmitters in patients with headache during the acute phase of cerebrovascular ischemic disease, Stroke 26 (1995) 2035–2039. [5] B.W. Collins, H.O. Goodman, C.H. Swanton, C.N. Remy, Plasma and urinary taurine in epilepsy, Clin. Chem. 34 (1988) 671–675. [6] T.K. Desai, J. Maliakkal, J.L. Kinzie, M.N. Ehrinpreis, G.D. Luk, J. Cejka, Taurine deficiency after intensive chemotherapy and/or radiation, Am. J. Clin. Nutr. 55 (1992) 708–711. [7] L. Durelli, G. Quattrocolo, C. Buffa, C. Valentini, R. Mutani, Antagonism between focal epilepsy and taurine administered by cortical perfusion, Riv. Neurol. 46 (1976) 254–261. [8] A. El Idrissi, J. Messing, J. Scalia, E. Trenkner, Prevention of epileptic seizures by taurine, Adv. Exp. Med. Biol. 526 (2003) 515–525. [9] A.L. Friedman, P.W. Albright, N. Gusowski, M. Padilla, R.W. Chesney, Renal adaptation to alteration in dietary amino acid intake, Am. J. Physiol. 245 (1983) F159–166. [10] M. Ghandforoush-Sattari, S. Mashayekhi, Evaluation of taurine as a biomarker of liver damage in paracetamol poisoning, Eur. J. Pharmacol. 581 (2008) 171–176. [11] M. Ghandforoush-Sattari, S. Mashayekhi, M. Nemati, P.A. Routledge, A rapid determination of taurine in human plasma by LC, Chromatographia 69 (2009) 1427–1430. [12] M. Ghandforoush-Sattari, S. Mashayekhi, M. Nemati, A. Seydi, H. Azadi, Changes in plasma taurine concentration during a period of heroin detoxification, Toxicol. Environ. Chem. 92 (2010) 1505–1512. [13] H.O. Goodman, B.M. Connolly, W. McLean, M. Resnick, Taurine transport in epilepsy, Clin. Chem. 26 (1980) 414–419. [14] L. Guerra-Romero, J.H. Tureen, M.A. Fournier, V. Makrides, M.G. Tauber, Amino acids in cerebrospinal and brain interstitial fluid in experimental pneumococcal meningitis, Pediatr. Res. 33 (1993) 510–513. [15] R.C. Gupta, T. Win, S. Bittner, Taurine analogues; a new class of therapeutics: retrospect and prospects, Curr. Med. Chem. 12 (2005) 2021–2039. [16] H.L. Haas, L. Hosli, The depression of brain stem neurones by taurine and its interaction with strychnine and bicuculline, Brain Res. 52 (1973) 399–402. [17] F. Harry, A. Hale, D. Buss, A. Hutchings, P. Routledge, Serum taurine levels in healthy subjects and in paracetamol poisoned patients, Hum. Exp. Toxicol. 18 (1999) 531. [18] R.E. Haskew-Layton, A. Rudkouskaya, Y. Jin, P.J. Feustel, H.K. Kimelberg, A.A. Mongin, Two distinct modes of hypoosmotic medium-induced release of excitatory amino acids and taurine in the rat brain in vivo, PLoS One 3 (2008) e3543. [19] E. Hegstad, J. Berg-Johnsen, T.S. Haugstad, E. Hauglie-Hanssen, I.A. Langmoen, Amino-acid release from human cerebral cortex during simulated ischaemia in vitro, Acta Neurochir. (Wien) 138 (1996) 234–241. [20] N. Hussy, C. Deleuze, A. Pantaloni, M.G. Desarmenien, F. Moos, Agonist action of taurine on glycine receptors in rat supraoptic magnocellular neurones: possible role in osmoregulation, J. Physiol. 502 (Pt 3) (1997) 609–621. [21] R.J. Huxtable, Taurine in the central nervous system and the mammalian actions of taurine, Prog. Neurobiol. 32 (1989) 471–533. [22] R.J. Huxtable, Physiological actions of taurine, Physiol. Rev. 72 (1992) 101–163. [23] Z. Jiang, K. Krnjevic, F. Wang, J.H. Ye, Taurine activates strychnine-sensitive glycine receptors in neurons freshly isolated from nucleus accumbens of young rats, J. Neurophysiol. 91 (2004) 248–257. [24] H.K. Kimelberg, Current concepts of brain edema. Review of laboratory investigations, J. Neurosurg. 83 (1995) 1051–1059. [25] K. Kirk, J. Kirk, Volume-regulatory taurine release from a human lung cancer cell line. Evidence for amino acid transport via a volume-activated chloride channel, FEBS Lett. 336 (1993) 153–158.
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[26] R.O. Law, The role of taurine in the regulation of brain cell volume in chronically hyponatraemic rats, Neurochem. Int. 33 (1998) 467–472. [27] P. Lee, D. Brenton, Inborn errors of amino acid and organic acid metabolism, in: D. Warrell, T. Cox, J. Firth (Eds.), Oxford Textbook of Medicine, Oxford University Press, 2003, p. 9. [28] A. Melani, L. Pantoni, C. Corsi, L. Bianchi, A. Monopoli, R. Bertorelli, G. Pepeu, F. Pedata, Striatal outflow of adenosine, excitatory amino acids, gamma-aminobutyric acid, and taurine in awake freely moving rats after middle cerebral artery occlusion: correlations with neurological deficit and histopathological damage, Stroke 30 (1999) 2448–2454 (discussion 2455). [29] F. Monaco, R. Mutani, L. Durelli, M. Delsedime, Free amino acids in serum of patients with epilepsy: significant increase in taurine, Epilepsia 16 (1975) 245–249. [30] A. Mongin, H. Kimelberg, Astrocytic swelling in neuropathology, in: H. Kettenmann, B. Ransom (Eds.), Neuroglia, Oxford University Press, Oxford-New York, 2005, pp. 550–562. [31] S.S. Oja, P. Saransaari, Kinetic analysis of taurine influx into cerebral cortical slices from adult and developing mice in different incubation conditions, Neurochem. Res. 21 (1996) 161–166. [32] S.S. Oja, P. Saransaari, Taurine as osmoregulator and neuromodulator in the brain, Metab. Brain Dis. 11 (1996) 153–164. [33] H. Pasantes-Morales, M.E. Arzate, Effect of taurine on seizures induced by 4aminopyridine, J. Neurosci. Res. 6 (1981) 465–474. [34] H. Pasantes-Morales, M.E. Arzate, O. Quesada, R.J. Huxtable, Higher susceptibility of taurine-deficient rats to seizures induced by 4-aminopyridine, Neuropharmacology 26 (1987) 1721–1725. [35] T.L. Perry, P.J. Bratty, S. Hansen, J. Kennedy, N. Urquhart, C.L. Dolman, Hereditary mental depression and Parkinsonism with taurine deficiency, Arch. Neurol. 32 (1975) 108–113. [36] P. Saransaari, S.S. Oja, Taurine and neural cell damage, Amino Acids 19 (2000) 509–526. [37] H. Satoh, Cardiac actions of taurine as a modulator of the ion channels, Adv. Exp. Med. Biol. 442 (1998) 121–128. [38] A. Sawamura, H. Sada, J. Azuma, S. Kishimoto, N. Sperelakis, Taurine modulates ion influx through cardiac Ca2+ channels, Cell Calcium 11 (1990) 251–259. [39] J.C. Seidel, N. Nath, A.E. Harper, Diet and cholesterolemia. V. Effects of sulfurcontaining amino acids and protein, J. Lipid Res. 1 (1960) 474–481. [40] H.K. Shin, H.M. Linkswiler, Tryptophan and methionine metabolism of adult females as affected by vitamin B-6 deficiency, J. Nutr. 104 (1974) 1348–1355. [41] E. Sykova, T. Mazel, L. Vargova, I. Vorisek, S. Prokopova-Kubinova, Extracellular space diffusion and pathological states, Prog. Brain Res. 125 (2000) 155–178. [42] J.A. Timbrell, V. Seabra, C.J. Waterfield, The in vivo and in vitro protective properties of taurine, Gen. Pharmacol. 26 (1995) 453–462. [43] N. Van Gelder, Neuronal discharge hypersynchrony and the intracranial water balance in relation to glutamic acid and taurine redistribution: migraine and epilepsy, in: H. Pasantes-Morales, D. Martin, W. Shain (Eds.), Taurine: Functional Neurochemistry, Physiology, and Cardiology, vol. 351, Wiley-Liss, New York City, NY, 1990. [44] N.M. Van Gelder, A.L. Sherwin, C. Sacks, F. Anderman, Biochemical observations following administration of taurine to patients with epilepsy, Brain Res. 94 (1975) 297–306. [45] J.V. Wade, J.P. Olson, F.E. Samson, S.R. Nelson, T.L. Pazdernik, A possible role for taurine in osmoregulation within the brain, J. Neurochem. 51 (1988) 740–745. [46] R.J. Ward, M. Francaux, C. Cuisinier, X. Sturbois, P. De Witte, Changes in plasma taurine levels after different endurance events, Amino Acids 16 (1999) 71–77. [47] C.J. Waterfield, J.A. Turton, M.D. Scales, J.A. Timbrell, Taurine, a possible urinary marker of liver damage: a study of taurine excretion in carbon tetrachloridetreated rats, Arch. Toxicol. 65 (1991) 548–555. [48] A.A Wong, S.J. Read, Early changes in physiological variables after stroke, Ann. Indian Acad. Neurol. 11 (2008) 207–220.
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Changes in plasma concentration of taurine in stroke Mohammadreza Ghandforoush-Sattari a,b , Simin O. Mashayekhi c,∗ , Mahboob Nemati d , Hormoz Ayromlou a a
Neurosciences Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran Infectious and Tropical Diseases Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran NPMC, Tabriz University of Medical Sciences, Tabriz, Iran d Applied Drug Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran b c
a r t i c l e
i n f o
Article history: Received 14 January 2011 Received in revised form 10 March 2011 Accepted 6 April 2011 Keywords: Stroke Biomarker Taurine HPLC Amino acid
a b s t r a c t Taurine is critical for proper brain functioning. Increase in plasma taurine concentration has already been shown in many diseases [1,2,5,10,12,14,17,22,25,47]. The plasma concentrations of taurine in 60 patients, suffering from stroke, were compared with that of 54 healthy volunteers. The plasma samples of the patients were obtained three times in the first five days of hospitalization. A Student’s t-test showed a significant difference (P < 0.0001) between the plasma concentrations of taurine of the patients group (136.5 ± 8.2 mmol/L) and the control group (41.9 ± 2.5 mmol/L). In addition, a one-way repeated measures ANOVA test showed that the mean plasma concentration of taurine in the patients during the first five days of hospitalization declined significantly from 136.9 ± 8.2 mmol/L in the first day of hospitalization to 120.1 ± 5.9 mmol/L on the third day and 110.2 ± 7.0 mmol/L by the fifth day (P > 0.05). The plasma concentration of taurine was increased in the patients with stroke probably because of brain tissue damage. Although, according to the result of the study, mean plasma taurine concentration in stroke patients declined during five days of hospitalization. Further studies are needed to introduce taurine as a biomarker of recovery in stroke. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Taurine (2-aminoethanesulfonic acid) is a -amino acid, not incorporated into proteins and is found free in the body. Taurine is also one of the most abundant free amino acids in the mammalian brain and is critical for proper brain functioning [22,21]. Taurine is possibly the only free amino acid, which is found extensively in unicellular bacteria to complex humans and in organs particularly liver, heart, bone and brain [15]. Taurine is widely involved in neurological activities leading to neuroprotection; modulation of neural excitability, maintenance of cerebellar function, motor behaviour modulation through dopaminergic, adrenergic, serotonergic, cholinergic regulation and interaction with glutamate [15]. It has been shown to inhibit seizures in some experimental models [7,44]. Taurine acts as a low affinity agonist for GABA(A) receptors, protects neurons against kainate excitotoxic insults and modulates calcium homeostasis. Therefore, taurine is potentially capable of treating seizure-
∗ Corresponding author at: Dept. Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences. Tel.: +98 411 3341315; fax: +98 411 3344798. E-mail address: [email protected] (S.O. Mashayekhi). 0304-3940/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2011.04.010
associated brain damage [8]. The anticonvulsant effect of taurine might be mediated by 4-aminopyridine–calcium–taurine interactions [33]. Raised taurine concentration in plasma and urine have already been reported after surgical trauma, X-radiation, muscle necrosis, carbon tetrachloride-induced liver damage [47], heroin addiction [12] and paracetamol overdose [10,17]. Changes in taurine concentrations typically occur in stress states, e.g. osmotic changes, anoxia, prolonged illumination of photoreceptors, cell proliferation, brain development [22], pneumococcal meningitis [14], lung cancer [25], myocardial infarction [1], epilepsy [5,13,29,44] and hepatic encephalopathy [2]. Ward et al. showed elevation of plasma taurine concentration after speedy exercise indicating its possible release from muscle fibers [46]. Taurine is produced by liver, heart, brain, and lung cells in response to a toxic insult and subsequent leakage from damaged cells leads to increased concentrations in the plasma and urine. There are also other factors, which may influence the concentrations of taurine in tissue, blood and urine. Plasma and urinary taurine concentrations may decrease in patients receiving salbutamol and clenbuterol [3] and chemotherapy [6]. Gut flora may also modulate taurine concentrations [42]. Vitamin B6 deficiency [40], also depresses taurine formation with reducing intake of total protein or methionine [9]. Dietary content of methyl donors, may also influence taurine biosynthesis [39]. The range of
M. Ghandforoush-Sattari et al. / Neuroscience Letters 496 (2011) 172–175
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plasma taurine in healthy humans is between 65 and 179 mmol/L (8–22 mg/L) [27]. Taurine has been shown to regulate osmotic pressure in the cell, maintain homeostasis of intracellular ions, inhibit phosphorylation of membrane proteins, and prevent lipid peroxidation. As an osmotic regulator, it has been suggested that taurine, along with glutamic acid, is instrumental in the transport of metabolically generated water from the brain [43]. Other evidences suggest that taurine may function as a potent candidate of inhibitory neurotransmitter or modulator to regulate neuronal activity in many cerebral areas [16,20,22,23]. Previous studies have also demonstrated release of taurine after middle cerebral artery occlusion in rats [28], in human cerebral cortex during membrane depolarization and simulated ischemia [19] and patients with headache during the acute phase of cerebrovascular ischemic disease [4]. It is suggestive that taurine is released from astrocyte cells by a variety of external stimuli including hypoosmotic stress, elevated extracellular potassium, and ammonia [45]. Therefore, we hypothesized that taurine could be suggested as a possible biomarker of stroke. There are several types of cellular release of taurine, of which the basal release described as ‘leaking of taurine’ through membrane is the commonest one. Such leaking depends on the permeability of the membrane to taurine, which in turn depends on lipid composition and several other factors [15]. Fig. 1. Mean of plasma taurine concentration in 60 stroke patients compared with 54 healthy control subjects (P < 0.0001)
2. Materials and methods Sixty patients [48 males and 12 females, aged 58–89 (Median 78)], suffering from stroke, were recruited for the study after giving fully informed written consent. The approval for the study was attained from the ethics committee of Tabriz University of Medical Sciences. The subjects who had Red Bull energy drink or sea food in the last 24 h, were excluded from the study because Red Bull and sea food contain large amount of taurine. Three blood samples (5 mL each) were taken from the brachial vain in the first, third, and fifth days of hospitalization and collected into heparinized tubes. The samples were immediately centrifuged at 4 ◦ C at 2000 rpm. Plasma was removed using a Pasteur pipette and transferred into 5 ml glass tubes and kept frozen at −20 ◦ C until analysis and when thawed, diluted (1:10, v/v) in methanol. On each assay day. 200 L of plasma samples was mixed in 2 mL methanol in glass tubes and centrifuged at 2000 rpm. Supernatants were decanted and stored at −20 ◦ C until required. 250 L of methanolic solution of calibrator or pre-treated samples was treated with 250 L boric acid buffer (618 mg boric acid in 100 mL water, pH 10 with NaOH), 250 L methanol, 250 L OPA (20 mg/mL in methanol), 50 L of a 25 mg/L ␣-amino-butyric acid (internal standard), and 50 L of MPA reagent (in fume hood) and then incubated for 10 min in the dark at −20 ◦ C. 20 L of prepared samples was injected onto the HPLC system which included a Genesis C18 4 15 cm column and disodium hydrogen phosphate 0.0125 M: acetonitrile (94:6) pH 7.2 as mobile phase using fluorescence detection [11]. The data were statistically analysed using Student’s unpaired t-test and one-way repeated measures ANOVA by Graph Pad Prism (ver. 2).
and control groups respectively. Plasma taurine concentrations of the first (before treatment) (mean ± SEM: 136.9 ± 8.2 mmol/L), third (120.1 ± 5.9 mmol/L), and fifth day (110.2 ± 7.0 mmol/L) of hospitalization were also compared using a one-way ANOVA test. There was a significant decline (P < 0.05) in the mean plasma taurine during the five day period of hospitalization (Fig. 2). The correlations between plasma taurine with plasma sodium and potassium concentrations which might be involved in osmorgulation were also analysed but there was no significant correlation (P > 0.05) (Figs. 3 and 4). Wong and Read [48] suggested that several aspects of physiology, notably blood pressure, body temperature, blood glucose, and blood oxygen saturation, might be
3. Results Plasma taurine concentrations of 60 patients, suffering from stroke, in the first (before treatment) (mean ± SEM: 136.9 ± 8.2 mmol/L) day of hospitalization were compared with those of 54 healthy control subjects (mean ± SEM: 41.9 ± 2.5 mmol/L) by two-tailed unpaired Student’s t-test. The mean plasma taurine concentration in the stroke group was significantly different from the control group (P < 0.0001) (Fig. 1). Plasma taurine concentrations ranged from 9.9 to 394.9 mmol/L (median 134.5) and 13.8 to 72.8 mmol/L (median 36.8) in the stroke
Fig. 2. Mean of plasma taurine concentration in 60 stroke patients during five days of hospitalization (P < 0.05).
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Fig. 3. Correlation between plasma taurine and sodium concentrations in 60 stroke patients before treatment.
Fig. 4. Correlation between plasma taurine and potassium concentrations in 60 stroke patients before treatment.
altered after an ischemic stroke and intracerebral hemorrhage. Generally, blood pressure and temperature rise acutely after a stroke, before returning to normal. Five of the patients who had high level of plasma taurine, died in a week because of a second stroke, 14 patients had high level of blood sugar, 26 patients had hyperthermia and 12 had hypothermia, 32 patients were hypoxic at the first day of hospitalization. There was only a week significant correlation between plasma taurine and systolic blood pressures of patients at the first day of hospitalization (Fig. 5). There was not any difference between the mean of plasma taurine concentrations in men and women. 4. Discussion There are a number of electrophysiological studies indicating that taurine exerts its actions by interacting with different ion channels [37,38]. The inhibitory amino acid taurine is an osmoregulator and neuromodulator, also exerting neuroprotective actions in neural tissue [36]. Findings have indicated that different transport mechanisms and/or distinct cellular sources mediate hypoosmotic medium induced release of the excitatory amino acids and taurine in vivo [18]. Several neural pathologies, most particularly cerebral ischemia, hyponatremia, hepatic encephalopathy and traumatic brain injury, are associated with pronounced cell
Fig. 5. Correlation between plasma taurine and systolic blood pressures in 60 stroke patients before treatment.
swelling [24,30,41] followed by releasing taurine. Since taurine is a putative inhibitory synaptic transmitter, deficiency of brain taurine may possibly have caused the psychiatric and neurological manifestations of this disorder [35]. Reuptake of taurine to brain cells plays a significant role in determining taurine’s volume in brain tissue and plasma. Oja and Saransaari [31,32] suggested that transport of taurine into cells occurs by Na+ and Cl− -dependent mechanisms and it may be presumed that when external Na+ is reduced from 142 to 122 mmol/L (accompanied by a corresponding reduction in Cl− concentration) the rate of uptake is reduced. The reduction in the net rate of taurine efflux during chronic hyponatraemia may reflect a gradual readjustment of the influx/efflux balance, the effect of which is to maintain the osmotically determined cell water content and hence volume. This contrasts with the acceleration of taurine efflux that is seen in normal cells acutely exposed to hyposmotic media in which efflux occurs in response to sudden swelling following osmotic water entry [26]. We could not found any significant correlation between taurine with sodium and potassium plasma concentrations which might be involved in osmorgulation probably because of low sample size or difference between their plasma half-lives. There was also no correlation between plasma taurine and other biochemical parameters such as Mg, Ca, and phosphate. Pasanet-Morales et al. [34] showed a greater susceptibility to seizures in taurine-deficient rats, as demonstrated by a lowered latency for clonic seizures, an increased incidence of tonic seizures and a higher postseizure mortality. They suggested an involvement of endogenous taurine in nervous excitability. We showed that the plasma concentration of taurine increases in the patients with stroke probably because of brain tissue damage. However, the correlation between plasma taurine and changes in physiological aspects after stroke remains incomplete. Further studies are needed to evaluate plasma and CSF’s taurine concentrations in both ischemic and hemorrhagic strokes on extra patients. Acknowledgments We wish to thank to Dr. Derek Buss (Cardiff University) for his collaboration in writing this paper and the personnel and academic staff of the neurology department of Imam Reza Hospital of Tabriz University of Medical Sciences for their cooperation. References [1] S.K. Bhatnagar, J.D. Welty, A.R. al Yusuf, Significance of blood taurine levels in patients with first time acute ischaemic cardiac pain, Int. J. Cardiol. 27 (1990) 361–366.
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