Effects of ammonia and hepatic failure on the net efflux of endogenous glutamate, aspartate and taurine from rat cerebrocortical slices: modulation by elevated K+ concentrations

Neurochemistry International 41 (2002) 87–93

Effects of ammonia and hepatic failure on the net efflux of endogenous glutamate, aspartate and taurine from rat cerebrocortical slices: modulation by elevated K+ concentrations M. Zieli´nska a , W. Hilgier a , R.O. Law b , P. Gorynski c , J. Albrecht a,∗ a

Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Pawi´nskiego St. 5, 02-106 Warsaw, Poland b Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK c Department of Medical Statistics, National Institute of Hygiene, Warsaw, Poland

Abstract Cerebrocortical minislices derived from control rats (“control slices”) and from rats with thioacetamide (TAA)-induced hepatic failure showing moderate hyperammonemia and symptoms of hepatic encephalopathy (HE) (“HE slices”), were incubated with physiological saline in the absence or presence of 5 mM ammonium acetate (“ammonia”), at potassium ion (K+ ) concentrations ranging from 5 to 15 mM. The efflux of endogenous aspartate (Asp), glutamate (Glu) and taurine (Tau) to the incubation medium was assayed by HPLC. At 5 mM K+ , perfusion of control slices with ammonia did not affect Glu and slightly depressed Asp efflux. Raising K+ concentrations in the incubation medium to 7.5 led to inhibition of Glu and Asp efflux by ammonia and the inhibitory effect was further potentiated at10 mM K+ . The inhibition was also significant at 15 mM K+ . This suggests that, depression of excitatory neurotransmission associated with acute hyperammonemia is more pronounced under conditions of intense neuronal activity than in the resting state. HE moderately increased the efflux of Glu and Asp, and the stimulatory effect of HE on Glu and Asp efflux showed virtually no variation upon changing K+ concentration up to 15 mM. Ammonia strongly, and HE moderately, increased Tau efflux at 5 mM K+ . However, both the ammonia- and HE-dependent Tau efflux decreased with increasing K+ concentration in the medium and was no longer significant at 10 mM concentration, indicating that intense neuronal activity obliterates the neuroprotective functions of this amino acid triggered by hyperammonemia. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Ammonia; Hepatic encephalopathy; Excitatory amino acids; Taurine; Efflux; Potassium

1. Introduction Ammonia is a neurotoxin whose excessive accumulation in the brain is a pathogenetic factor in the hyperammonemic encephalopathies including hepatic encephalopathy (HE) (Cooper and Plum, 1987; Fan et al., 1990). Symptoms of ammonia neurotoxicity are due to the imbalance between the excitatory and inhibitory neurotransmission (Fan et al., 1990; Iles and Jack, 1980; Raabe, 1992; Szerb and Butterworth, 1992). The imbalance is usually attributed to changes in the functioning of the amino acid neurotransmitter systems: the excitatory glutamatergic and aspartatergic system and the inhibitory GABAergic system, with a contribution of the inhibitory amino acid taurine (Tau) which Abbreviations: IM, incubation medium; HEPES, N-2-hydroxyethylpiperazine-N -2-ethanesulphonic acid; HPLC, high performance liquid chromatography; PCA, perchloric acid; HE, hepatic encephalopathy ∗ Corresponding author. Tel.: +48-22-6685323; fax: +48-22-6685532. E-mail address: [email protected] (J. Albrecht).

exerts cell membrane protective functions (reviewed in Albrecht, 1998; Albrecht and Jones, 1999). While changes in GABAergic tone accompanying hyperammonemia are largely due to its altered modulation by central and peripheral benzodiazepine receptors (Basile et al., 1991; Desjardin et al., 1997; Itzhak et al., 1995; Lavoie et al., 1990), involvement of glutamate (Glu), aspartate (Asp) and taurine (Tau) is mainly related to changes in their extracellular concentrations (Bosman et al., 1992; Butterworth, 1996; Hilgier et al., 1999; Michalak et al., 1996; Raghavendra Rao et al., 1995; Tossman et al., 1987). These changes are associated with ammonia-induced disturbances in the synthesis and degradation of the amino acids (Hertz et al., 2000; Sonnewald et al., 1996), and with changes in the amino acid efflux from and/or reuptake by astrocytes, the ammonia-sensitive cells in the CNS. Evidence suggesting the role of changes in amino acid transport in hyperammonemic conditions has been derived from studies on the effects of ammonia or HE on the uptake or efflux of individual radiolabelled amino acids in bulk isolated or cultured CNS cells (Albrecht et al.,

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1988; Albrecht et al., 1994; Bender and Norenberg, 1996; Faff et al., 1996, 1997), and/or from analysis of the expression of amino acid transporters in experimental HE models (Knecht et al., 1997; Norenberg et al., 1997), or from studies with ammonia-treated astrocytes in culture (Chan et al., 2000). However, the effects of ammonia or HE on the balance between the efflux and uptake of Glu, Asp and Tau simultaneously and in a relatively intact CNS preparation have not been studied before. We recently analysed the net efflux of endogenous amino acids from rat cerebrocortical minislices in the presence of a pathophysiologically relevant (5 mM) ammonia concentration. Ammonia strongly stimulated taurine (Tau) efflux, but was much less effective in inducing the efflux of glutamate (Glu) under these conditions (Zieli´nska et al., 1999). In the previous study, however, the effect of ammonia was examined at a 5 mM K+ concentration, a condition which simulates the resting state of the brain in vitro. In the present study we set out to determine whether and in what way ammonia modulates the efflux of the amino acids at increased K+ concentrations in the medium, in the range of 7.5–15 mM. The 7.5–15 mM K+ concentrations were intended to mimic [K+ ] attainable in brain during intense neuronal activity (Somjen, 1979). While ammonia is a pathogenetic factor in HE, multiple toxic compounds that are released from the injured liver in addition to ammonia may also contribute to HE (Zieve, 1987). A 3-day treatment of rats with a hepatotoxin, thioacetamide (TAA), which induces the precomatous stage of HE (reviewed in Albrecht et al., 1988), is accompanied by a protracted but only moderate (∼0.6 mM) increase of brain ammonia (Hilgier and Olson, 1994). It was thus reasonable to assume that hepatic failure will affect the efflux of the amino acids differently than exposure of the slices to high concentrations of ammonia. In this study, therefore, we measured the efflux of Asp, Glu and Tau in slices derived from rats with TAA-induced liver failure.

2. Experimental procedures 2.1. Animals and HE model Male Wistar rats weighing 180–250 g were kept under standard conditions (light from 7 a.m. to 7 p.m., ambient temperature 19–21 ◦ C, humidity 35%, and given food and water ad libitum). Liver failure was induced by three i.p. injections of 250 mg/kg of thioacetamide (TAA) at 24 h intervals. The animals were sacrificed 24 h after the last injection. The treatment produces behavioral and biochemical alterations typical of acute HE (Albrecht et al., 1988; Hilgier and Olson, 1994; Hilgier et al., 1996).The experiments were approved by the University of Leicester Ethical Committee.

2.2. Preparation of rat cerebral cortical minislices and efflux assay This was done exactly as described earlier (Law, 1994; Zieli´nska et al., 1999). Briefly, rats were killed by cervical dislocation, and cerebral hemispheres were excised and placed in ice-cold aerated incubation medium (IM) containing (mmol/l): NaCl 126, MgSO4 1.29, NaH2 PO4 1.29, KCl 5, CaCl2 0.8, HEPES 15, d-glucose 10, NaOH 11.7, pH 7.4. Slices (300–400 ␮m thickness, 4 out of each brain hemisphere) were cut freehand with a chilled razor blade from the frontal part of the cortex. Each slice (5–10 mg) was weighed to the nearest 50 ␮g on a torsion balance, placed separately in 350 ␮l of either a standard IM or a medium in which KCl concentration was increased to 7.5, 10, 15 or 25 mM, with the NaCl concentration adjusted to maintain isotonicity, and supplemented or not with 5 mM ammonium acetate (“ammonia”), The slices were incubated at 18–21 ◦ C with gentle shaking. At 20 min and again at 40 min slices were gently transferred to a fresh buffer, and incubation was terminated at 60 min. The buffer aliquots containing effluxed amino acid were freeze-dried for HPLC analysis of the amino acids. The slices after incubation were supended in 0.25 ml of 0.3 M PCA, sonicated thrice for 10 s, and neutralized to pH 7.0 with 3 M KOH. Precipitates was spun down (15 min, 10 000 × g), and supernatants were subjected to HPLC analysis as described. 2.3. HPLC analysis of amino acids Amino acids were analysed using HPLC with fluorescence detection after derivatisation in a timed reaction with o-phthalaldehyde (OPA) plus mercaptoethanol, as described earlier (Zieli´nska et al., 1999). Derivatised samples (50 ␮l) were injected onto 5 ␮m Bio-Sil C18 Hl column (250 × 4.6 mM, BIO-RAD), with a mobile phase of 0.075 M KH2 PO4 solution containing 10% (v/v) methanol, pH 6.2 (solvent A), and methanol (solvent B). The methanol gradient was 20–70%, and the elution time was 20 min. 2.4. Calculation and expression of the results of amino acid efflux tests Only the efflux during the first 20 min of incubation was analysed because, in agreement with previous observations (Zieli´nska et al., 1999), the efflux of the amino acids late during incubation was very low and inconsistent (data not shown). The efflux was expressed as a fraction of the total amino acid lost during the first 20 min of incubation (“fractional efflux”), the “total amino acid” being the sum of the amino acid eluted plus that residing in the pellet after elution. The “fractional efflux” gives a measure of net efflux irrespective of the fluctuations of the total tissue content of the amino acids. The complex issue of the effects of superfusion of the slices with ammonia on the amino acid content in the slices is not dealt with in this paper.

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Fig. 1. Net efflux of Asp in cerebrocortical minislices derived from healthy rats, incubated in physiological saline (“control”) or 5 mM ammonium acetate (“ammonia”), and in slices derived from rats with thioacetamide-induced HE incubated in physiological saline (“HE”), at different concentrations of potassium ions (K+ ) in the medium. Results are mean ± S.D. for eight experiments. ∗ P < 0.05 or less vs. “control” at the same [K+ ].

Fig. 2. Net efflux of Glu in cerebrocortical minislices derived from healthy rats, incubated in physiological saline (“control”) or 5 mM ammonium acetate (“ammonia”), and in slices derived from rats with thioacetamide-induced HE incubated in physiological saline (“HE”), at different concentrations of potassium ions (K+ ) in the medium. Results are mean ± S.D. for eight experiments. ∗ P < 0.05 or less vs. “control” at the same [K+ ].

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Fig. 3. Net efflux of Tau in cerebrocortical minislices derived from healthy rats, incubated in physiological saline (“control”) or 5 mM ammonium acetate (“ammonia”), and in slices derived from rats with thioacetamide-induced HE incubated in physiological saline (“HE”), at different concentrations of potassium ions (K+ ) in the medium. Results are mean ± S.D. for eight experiments. ∗ P < 0.05 or less vs. “control” at the same [K+ ].

2.5. Statistical evaluation Statistical analysis of the data was performed using one way analysis of variance followed by the Duncan’s multiple comparisons test. 3. Results 3.1. Effects of ammonia or HE on the amino acid efflux Superfusion with ammonia significantly decreased Asp efflux at all K+ concentrations except 15 mM. The decreases at the individual K+ concentrations were: 68% at 5 mM K+ ; 84% at 7.5 mM K+ ; and 92% at 10 mM K+ (Fig. 1). In slices from rats with TAA-induced liver failure, an increase of Asp efflux was consistently found at all the K+ concentrations studied. The increases at the individual K+ concentrations were: 59% at 5 mM K+ ; 52% at 7.5 mM K+ ; 115% at 10 mM K+ ; and 106% at 15 mM K+ (Fig. 1). Ammonia did not significantly alter Glu efflux at 5 mM K+ , but decreased the efflux at all the remaining K+ concentrations studied. The decreases at the individual K+ concentrations were: 65% at 7.5 mM K+ , 73% at 10 mM K+ , and 62% at 15 mM K+ (Fig. 2). In slices from rats with TAA-induced liver failure, an increase of Glu efflux was observed at 5 mM and 10 mM K+ , and a tendency towards increase was noted at 7.5 mM. The efflux at 15 mM K+ was not significantly different from control efflux (Fig. 2).

Ammonia increased Tau efflux at 5 mM K+ from 0 to 1.1%, and at 7.5 mM by 11-fold. Ammonia produced no significant effect on Tau efflux at 10 mM or 15 mM K+ (Fig. 3). In slices from rats with TAA-induced liver failure, Tau efflux was significantly higher than in control slices at 5, 7.5 and 15 mM K+ , but was not significantly different from control at 10 mM K+ . The increases at the individual K+ concentrations were: from 0 to the fractional efflux of 0.24 at 5 mM K+ ; 278% at 7.5 mM K+ and 105% at 15 mM K+ (Fig. 3).

4. Discussion Changes in the extracellular concentrations of Glu, Asp and Tau, neuroactive amino acids which have a role in the pathogenesis of hyperammonemic encephalopathies, may reflect in part, an imbalance between the amino acid efflux and reuptake (reviewed in Albrecht, 1998; Albrecht and Jones, 1999). A previous study from our laboratories have shown a robust stimulation of Tau efflux, an inhibitory amino acid, but very little effect on Glu efflux, in cerebral cortical minislices of rats incubated with 5 mM ammonia (Zieli´nska et al., 1999). An increased efflux of newly loaded radiolabelled Tau was also measured in slices derived from rats with TAA-induced HE (Hilgier et al., 1996); the efflux of endogenous amino acids was not studied in much detail in this model. In these previous studies elution was carried out with a buffer containing a low, nondepolarizing (5 mM) concentration of K+ ions, which in an in vitro system

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simulates the resting state of the CNS. In the present study, the analysis of the effects of ammonia or HE was extended to elevated K+ concentrations in the range of 7.5–15 mM, mimicking the depolarizing conditions which occur during intense neuronal activity (Somjen, 1979; Sykova, 1983; Walz and Hertz, 1983). The principal effects found at increased K+ concentrations in the incubation medium were: (a) inhibition of Glu and Asp efflux by ammonia, but stimulation by HE and (b) a gradual reduction with increasing K+ concentration and, eventually, suppression of the stimulation of Tau efflux, by ammonia treatment or HE. The observed changes in the amino acid efflux are considered in the light of the current views on the causes and pathophysiologic effects of amino acid imbalance during acute hyperammonemia and liver failure. 4.1. Opposite effects of ammonia and liver failure on Glu and Asp efflux The most prominent finding of the present study was that ammonia treatment in vivo and hepatic failure produced opposite effects on the efflux of Glu and Asp. At all K+ concentrations above 5 mM, ammonia depressed whereas HE stimulated the efflux of the two amino acids. While depression of Glu and Asp efflux by ammonia was deepened with increasing K+ concentration in the 7.5–10 mM range, and tended to be less pronounced at 15 mM K+ , the stimulatory effect of HE was relatively uniform throughout the whole K+ concentration range. The contrasting effects of ammonia and HE on Asp and Glu efflux are consistent with the previously reported opposite effects of short term versus long term exposure to ammonia in vitro or in vivo on the astrocytic transport of these amino acids. A 20 min exposure of cultured cerebrocortical astrocytes to 1–5 mM ammonia inhibited the efflux of newly loaded radiolabelled Glu analogue—d-asp (Albrecht et al., 1994). By contrast, a few-days’ treatment of the cultures with ammonia, mimicking protracted exposure of CNS tissues to ammonia characteristic of HE, inhibited d-asp uptake (Bender and Norenberg, 1996; Chan et al., 2000). The inhibition of uptake was correlated with decreased expression of an astroglia specific Glu carrier, GLAST (Chan et al., 2000). In agreement with the effects of long-term treatment of cultured astrocytes with ammonia, the present model of thioacetamide-induced HE (a few-days’ exposure to slightly elevated ammonia concentration (∼0.6 mM, Hilgier and Olson, 1994) caused inhibition of d-asp uptake into astrocytes bulk-isolated from HE-affected animals (Albrecht et al., 1988), and a decreased expression of an astroglia specific Glu transporter—GLT-1 (Norenberg et al., 1997). However, neurons may also participate in the ammonia- and HE-induced changes in the net efflux of Asp and Glu. Hertz et al. (2000) reported an ammonia-induced decrease of endogenous Glu efflux from cultured cerebellar granule neurons at depolarizing K+ concentrations. Moreover, increased net efflux of Glu

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in TAA-induced hepatic failure could also be partly due to inhibition of Glu uptake by synaptosomes, which is a characteristic feature of HE in this model (Oppong et al., 1995). The opposite effects of short-term treatment with ammonia and of toxic liver failure on the efflux of the excitatory amino acids may in part account for the contrasting pathophysiologic characteristics of acute hyperammonemia as compared to prolonged, moderate hyperammonemia accompanying HE. In acute hyperammonemia, decreased net efflux of Glu and Asp is likely to contribute to decreased excitatory transmission and coma often seen in these conditions (Fan et al., 1990; Iles and Jack, 1980; Raabe, 1992; Szerb and Butterworth, 1992). Increased efflux of Glu and Asp during prolonged hyperammonemia accompanying liver failure may be a contributory factor in downregulation of Glu receptors (Maddison et al., 1991; Michalak and Butterworth, 1997; Peterson et al., 1990; Saransaari et al., 1997), which on one hand would decrease excitatory transmission, and on the other hand may offer extra protection against glutamate and/or ammonia neurotoxicity (Kosenko et al., 1993; Marcaida et al., 1995; Minana et al., 1995). 4.2. Ammonia- and liver failure-dependent Tau efflux becomes less pronounced at increased K+ concentrations Tau is a neuroprotective amino acid acting at nerve cell membranes and subcellular targets (Huxtable, 1992; Nakada et al., 1991; Saransaari and Oja, 2000). The neuroprotective functions of Tau are promoted by its controlled inter- and intracellular movements (reviewed in Saransaari and Oja, 1992, 1997, 2000). Previous studies have shown that ammonia strongly stimulates the efflux of newly loaded radiolabelled Tau from cultured astrocytes (Albrecht et al., 1994) and Müller glia (Faff et al., 1996; Faff et al., 1997), and of endogenous Tau from cerebrocortical slices (Zieli´nska et al., 1999). Also, HE in the TAA model increased spontaneous efflux of radiolabelled or endogenous Tau from cerebrocortical slices (Hilgier et al., 1996). The increased Tau efflux could enhance its neuroinhibitory and/or neuroprotective action. However, in the above quoted studies, the experiments were performed at 5 mM K+ . The decreased ability of both ammonia in vitro and HE to promote Tau efflux at elevated potassium concentrations usually associated with intense neuronal activity suggest that the neuroprotective function of Tau in hyperammonemic encephalopathy is less pronounced when the neurons are activated than in the resting state. At 10 mM K+ , a concentration which is considered to be still within the physiological limit (Somjen, 1979), ammonia did not stimulate Tau efflux, and HE produced only moderate stimulation (24%). These observations are in agreement with the results of in vivo tests using microdialysis technique. Mild HE, with a moderate increase of blood ammonia, as seen in the present model, was not associated with any changes in the basal extracellular Tau levels (Albrecht et al., 2000; Bosman et al., 1992; Raghavendra Rao et al., 1995; Tossman et al., 1987). One mechanism by

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which K+ ions may counteract Tau efflux evoked by direct ammonia treatment and render the two effects nonadditive, is by competition of K+ and NH4 + ions for entry into the cell via K+ -selective channels or transporters (Hille, 1992). In agreement with this interpretation, in cultured Müller glia, ammonia-induced Tau efflux was not potentiated by K+ concentrations in the pathophysiological range (Faff et al., 1997). This simple interpretation is unlikely to be valid for the effect of K+ on HE-induced Tau efflux, where the efflux is secondary to water redistribution between the intra- and extracellular compartments (Hilgier and Olson, 1994; Hilgier et al., 1996). Irrespective of the mechanism involved, this effect is likely to have occurred in astrocytes: protracted treatment of cerebellar astrocytes with ammonia increased basal Tau efflux in these cells, at the same time abolishing the K+ -induced Tau efflux (Wysmyk et al., 1994). In conclusion, the present study demonstrated that ammonia-induced alterations in the net efflux of the excitatory amino acids Asp and Glu and of the inhibitory amino acid Tau from brain slices, are modulated by increasing K+ concentration in the medium to levels mimicking depolarizing conditions. Raising K+ concentration within the physiological range potentiated the inhibitory effects of ammonia on Glu and Asp efflux, and markedly reduced the stimulatory effect of ammonia on Tau efflux. This suggests that under conditions of intense neuronal activity, ammonia-induced depression of excitatory neurotransmission becomes more-, and the neuroprotective function of Tau less pronounced than in the resting state. In contrast to ammonia treatment in vitro, HE potentiated the net efflux of the excitatory amino acids irrespective of actual K+ concentration, which could contribute to downregulation of excitatory amino acid receptors and to a tonic decrease of excitatory transmission. However, HE-induced efflux of Tau became less effective with increasing K+ , indicating that, like during acute exposure to ammonia, the neuroprotective response of Tau in HE is less effective in the brain under conditions of stimulated neuronal activity than in the resting state.

Acknowledgements The study was supported by a statutory grant of the Medical Research Centre, Polish Academy of Sciences, and a SCSR grant no 4P05A05519 (to J.A.), and by the Wellcome Trust Grant (to R.O.L). We thank Professor Janusz Sadowski for constructive comments on the manuscript. References Albrecht, J., 1998. Roles of neuroactive amino acids in ammonia neurotoxicity. J. Neurosci. Res. 51, 133–138. Albrecht, J., Jones, E.A., 1999. Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome. J. Neurol. Sci. 170, 138–146.

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