Neuroscience Letters, 127 (1991) 105-107
105
© 1991 Elsevier Scientific Publishers Ireland Ltd. 0304-3940/91/$ 03.50 ADONIS 030439409100281Z NSL 07798
Aluminum chloride stimulates the release of endogenous glutamate, taurine and adenosine from cultured rat cortical astrocytes Jan Albrecht 1,*, M a r t h a Simmons 2, G a r y R. D u t t o n 2 and Michael D. Norenberg ~ 1Veteran Administration Medical Center, Department of Pathology, University of Miami School of Medicine, Jackson Memorial Hospital, Miami, FL 33131 (U.S.A.) and ZDepartment of Pharmacology, University of lowa College of Medicine, Iowa City, 1.4 52242 (U.S.A.) (Received 3 August 1991; Revised version received 7 March 1991; Accepted 9 March 1991)
Key words." Cultured astrocyte; Aluminum toxicity; Taurine; Cerebral cortex Primary astrocyte cultures derived from neonatal rat cerebral cortex were treated for 5 min with 0.5 mM or 5.0 mM A1C13, and the incubation medium was analyzed by HPLC for the content of released glutamate (Glu), taurine (Tau), serine (Ser) and the nucleoside adenosine (Ade). At 0.5 mM, AICI3 stimulated Tau release to about 170% of basal levels, but did not affect the release of the other compounds. Treatment with 5.0 mM AIC13 enhanced the release of Tau, Glu and Ade, to 800%, 1000% and 250%, respectively, but decreased the release of Ser to 70% compared to basal levels. The enhanced release of these neuroactive compounds from astrocytes may contribute to changes in neural transmission known to accompany exposure to aluminum.
Aluminum is a potent neurotoxin and its excessive accumulation in the CNS, whether from endogenous sources or from environmental exposure, has been implicated in a variety of neurological disorders. These include dialysis encephalopathy, Alzheimer's disease and the amyotrophic lateral sclerosis-dementia complex of Guam (see review ref. 27). While neurodegenerative changes produced in CNS neurons following chronic exposure to aluminum salts in vivo or in vitro have been analyzed extensively [27], little is known about the more immediate neurochemical effects after acute exposure. In vitro experiments have revealed that aluminum chloride inhibits the uptake of the amino acid neurotransmitters glutamate (Glu) and 7-aminobutyric acid (GABA) [29], and that it interferes with calcium transport in rat brain synaptosomes [11]. These effects are likely to underlie aluminum-induced disturbances of neurotransmission. However, though nerve cells are the eventual functional target of aluminum toxicity, morphological evidence suggests that astrocytes are the cellular CNS compartment that is most strongly affected by aluminum. This appears to be true regardless of whether aluminum is administered in vivo [9], enters the brain in the course of
*Permanent address: Department of Neuropathology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. Correspondence: G.R. Dutton, Department of Pharmacology, University of Iowa College of Medicine, Iowa City, IA 52242, U.S.A.
dialysis encephalopathy [7, 28], or is added in vitro to primary astrocyte cultures [17]. Astrocytes react to a variety of extracellular stimuli with the enhanced release of neuroactive compounds, including the neuromodulators taurine (Tau) [14, 15, 18-21, 26] and adenosine (Ade) [25], and the neurotransmitters Glu and GABA [2, 3, 23, 24]. Since such an increased release may affect the functioning of adjacent neurons, we examined whether aluminum chloride acts as a stimulus of the release of these substances from cultured astrocytes. This study was performed using five-week-old cultures of neonatal cortical astrocytes grown in the presence of dibutyryl cAMP (not less than 95 % of the cells were glial fibrillary acidic protein (GFAP)-positive) as previously reported [8]. Cells maintained in 35-mm dishes were washed twice with buffered Krebs-Ringer medium (in mM: NaC1 140, KC1 3, CaC12 1, MgCI2 0.6, glucose 10 and HEPES 50, pH 7.4) and then incubated in 1 ml of the same medium for 15 min at 37°C. The cells were then incubated for 5 min at 37°C, either in Krebs-Ringer medium alone (control cells) or in Krebs-Ringer medium containing 0.5 mM or 5.0 mM aluminum chloride. Following incubation, 0.9 ml samples of the medium were collected. Thereafter, 1 ml of Krebs-Ringer medium was added, the 5-min incubation was repeated and 0.9 ml samples were again collected. The second incubation step was included to account for possible delay in the maximal release response known from previous studies to occur with Tau and Ade [1, 18, 20, 22].
106
Mean values of these two samples were used in determining the stimulated levels of release in five separate experiments. Samples were freeze-dried and subjected to reverse HPLC analysis as detailed in ref. 22. In keeping with earlier observations on cerebellar astrocytes [20], incubation of cerebral cortical astrocyte cultures for 5 min in the Krebs-Ringer buffer led to measurable basal release levels of Tau (Fig. 1A), Ade (Fig. I C) and of Glu (Fig. 1B). No GABA was detected, confirming the extremely low content of this amino acid in cultured astrocytes. Basal release levels of the neuroinert amino acid serine (Ser) were highest in the medium after incubation (Fig. 1D). Five-minute treatment with 0.5 mM A1C13 increased Tau release to approximately 170 % of basal levels (Fig. 1A), but had no effect on Glu, Ade or Ser basal levels (Fig. 1B-D). Treatment with 5.0 mM A1C13 increased the basal release of Tau to more than 800% (Fig. 1A), that of Glu to more than 10-fold (Fig. 1B), and the release of Ade to 250% of control levels (Fig. 1C). By contrast, 5.0 mM AIC13 caused an approximately 30% inhibition of Ser basal release (Fig. 1D). Taken together, these results confirm the assumption that toxic concentrations of AIC13 enhance the release of neuroactive compounds from astrocytes. The absence of A1Cls-stimulated Ser release, plus the marked quantitative differences between the responses of the particular neuroactive compounds, suggest that the effects of AICI3 were not simply due to general cell membrane damage, such as lysis. Furthermore, only morphological changes are seen in these cells even after 24 h in 5 mM A1C13 [16]. 800
200
c 600
150
"~400
100 50
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0 0.0
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5.0
0.0
600
2500
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2000
E 400
0.5
5.0
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~-~300 1000
~ 200
500
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0 0.0 0.5 5.0 AICI3 (raM)
0.0 0.5 5.0 AICi3 (mM)
Fig. I. Effect of aluminum chloride on the release of (A) Tau, (B) Glu, (C) Ade and (D) Ser, from cultured cerebral cortex astrocytes. Results are mean ___ S.D. of 5 experiments. For detailed description of the methods see text. * P < 0 . 0 5 compared to controls (Student's paired t-test).
The selective stimulation of Tau release at the lower concentration (0.5 mM) of A1Cl3 is consistent with a greater sensitivity of astrocytes to changes in the extracellular ionic milieu [15, 18, 19]. While the mechanism that mediates Tau release remains to be conclusively identified, it is possibly, at least in part, due to cell swelling which might be caused by aluminum, although this was not measured directly. It is noteworthy in this context that long-term treatment of astrocytes with low millimolar concentrations of A1CI3 results in cytoplasmic vacuolization [17]. The mechanism by which 5 mM A1C13 evokes release of Glu is difficult to deduce, however, interference with the astrocytic Glu transporter cannot be excluded. It is also possible that A1C13 induces metabolic changes in astrocytes favoring Glu release, as was recently reported for cerebellar astroglial cell clones which differ in spontaneous Gtu release levels [4]. While the increased release of neuroactive compounds may result in functional changes in the adjacent neurons, massive release of Glu, which has well documented neurotoxic properties, appears to be of particular significance. For example, it has been shown that CNS explants cultured in the presence of Glu develop neurodegenerative changes similar to those observed in Alzheimer's disease [6]. The experiments presented here support the possibility that in vivo aluminum neurotoxicity may to some degree be mediated by the release of Glu from astrocytes. Glu release has been observed by Kimelberg and co-workers to accompany astrocyte swelling [10], and this phenomenon may occur as a result of exposure to A1C13. Ade has been ascribed a role of an inhibitory neurotransmitter and/or neuromodulator (references in ref. 24). Recently it has been shown that cerebellar granular neurons cultured in vitro co-release Ade with Glu, and it has been speculated that this may represent the way in which Ade controls transmission at glutamatergic synapses [24]. The present results demonstrate that what appears to be co-release can also be evoked from astrocytes. However, it is not known from these experiments if the Ade and Glu originate from the same, or different cells within these cultures. The aluminum chloride concentrations used in this and our previous studies [1], are close to the lower and upper limits of the concentrations of aluminum salts applied in chronic paradigms to induce neurodegenerative changes in mixed [13], neoplastic [16], or astroglial cell cultures [17]. However, the compatibility of the in vitro model with the clinical aspects of aluminum-related neurological disorders remains to be examined. As measured globally, brain aluminum concentrations in such disorders do not exceed 0.25 mM [5, 12], however, they may reach higher values locally [4].
107
The authors would like to thank Marilynn Kirkpatrick and Kathryn Andrews for manuscript preparation. This work was supported by the Veteran Administration and an NIH Grant DK 38153, a grant from the University of Miami (M.D.N.), by NIH Grant NS 20632 (G.R.D.), and the Life and Health Insurance Medical Research Fund (M.L.S.). 1 Albrecht, J. and Norenberg, M.D., Aluminum chloride stimulates NaCl-dependent release of taurine and 7-aminobutyric acid in rat cortical astrocytes, Neurochem. Int., 18 (1991) 125-130. 2 Albrecht, J. and Rafalowska, U., Enhanced potassium-stimulated y-aminobutyric acid release by astrocytes derived from rats with early hepatogenic encephalopathy, J. Neurochem., 49 (1987) 9-11. 3 Bowery, N.G., Brown, D.A. and Marsh, S., y-Aminobutyric acid ettlux from sympathetic glial ceils: effect of 'depolarizing' agents, J. Physiol., 293 (1979) 75-101. 4 Cambier, D. and Pessac, G., Spontaneous glutamate release by a 'fibrous'-like cerebellar astroglial cell clone, J. Neurochem., 53 (1989) 551-555. 5 Cropper, D.R., Krishnan, S.S. and Quitkat, S., Aluminum, neurofibrillary degeneration and Alzheimer's disease, Brain, 99 (1976) 67-80. 6 DeBoni, U. and Crapper-McLachlan, D.R., Controlled induction of paired helical filaments of the Alzheimer type in cultured human neurons, by glutamate and aspartate, J. Neurol. Sci., 68 (1985) 105118. 7 Good, P.F. and Perl, D.P., A laser microprobe mass analysis (LAMMA): study of aluminum distribution in the cerebral cortex in dialysis encephalopathy, J. Neuropathol. Exp. Neurol., 47 (1988) 321. 8 Gregorios, J.B., Mozes, L.W., Norenberg, L.O.B. and Norenberg, M.D., Morphologic effects of ammonia on primary astrocyte cultures. I. Light microscopic studies, J. Neuropathol. Exp. Neurol., 44 (1985) 397-403. 9 Harris, A.B., Cortical neuroglia in experimental epilepsy, Exp. Neurol., 49 (1975) 691-715. 10 Kimelberg, H.K., Gooderie, S.K., Higman, S., Pang, S. and Waniewski, R.A., Swelling-induced release of glutamate, aspartate and taurine from astrocyte cultures, J. Neurosci., 10 (1990) 15831591. 11 Koenig, M.L. and Jope, R.S., Aluminum inhibits the fast phase of voltage-dependent calcium influx into synaptosomes, J. Neurochem., 49 (1987) 316-320. 12 Lai, J.C.K. and Blass, J.P., Inhibition of brain glycolysis by aluminum, J. Neurochem., 42 (1984) 438-446. 13 Langui, D., Anderton, B.H., Brion, J.-P. and Ulrich, J., Effects of aluminum chloride on cultured cells from rat brain hemispheres, Brain Res., 438 (1988) 67-76. 14 Madelian, V., Martin, D.L., Lepore, R., Perrone, M. and Shain,
W., t-Receptor-stimulated and cyclic adenosine 3-,5-monophosphate-mediated taurine release from LRM55 glial cells, J. Neurosci., 5 (1985) 3154-3160. 15 Martin, D.L., Madelian, V., Seligmann, B. and Shain, W., The role of osmotic pressure and membrane potential in K+-stimulated taurine release from cultured astrocytes and LRM55 cells, J. Neurosci., 10 (1990) 571-577. 16 Miller, C.A. and Levine, E.M., Effect of aluminum salts on cultured neuroblastoma cells, J. Neurochem., 22 (1974) 751-758. 17 Norenberg, M.D., Norenberg, L.O.B., Cowman, G.A., McCarthy, M. and Neary, J.T., Effect of aluminum on astrocytes in primary culture, J. Neuropathol. Exp. Neurol., 48 (1989) 374. 18 Pasantes-Morales, H. and Schousboe, A., Volume regulation in astrocytes: a role of taurine as osmoeffector, J. Neurosci. Res., 20 (1988) 505-509. 19 Pasantes-Morales, H. and Schousboe, A., Release of taurine from astrocytes during potassium-induced swelling, Glia, 2 (1989) 45-50. 20 Philibert, R.A., Rogers, K.L., Allen, A.J. and Dutton, G.R., Dosedependent, K +-stimulated efflux of endogenous taurine from primary astrocyte cultures is Ca2+-dependent, J. Neurochem., 51 (1988) 122-126. 21 Philibert, R.A., Rogers, K.L. and Dutton, G.R., K+-evoked taufine ettlux from cerebeUar astrocytes: on the roles of Ca 2+ and Na ÷, Neurochem. Res., 14 (1988) 43-48. 22 Rogers, K.L., Philibert, R.A., Allen, A.J., Molitor, J., Wilson, E.J. and Dutton, G.R., HPLC analysis of putative amino acid neurotransmitters released from primary cerebellar cultures, J. Neurosci. Methods, 22 (1987) 173-179. 23 Sarthy, P.V., Release of [3H]7-aminobutyric acid from glial (Muller) cells of the rat retina: effects of K ÷, veratridine and ethylenediamine, J. Neurosci., 3 (1983) 2494-2452. 24 Schousboe, A., Frandsen, A. and Drejer, J., Evidence for evoked release of adenosine and glutamate from cultured cerebellar granule cells, Neurochem. Res., 14 (1989) 871-875. 25 Schousboe, A., Larsson, O.M., Krogsgaard-Larsen, P., Drejer, J. and Hertz, L., Uptake and release processes for neurotransmitter amino acids in astrocytes. In M.D. Norenberg, L. Hertz and A. Schousboe (Eds.), The Biochemical Pathology of Astrocytes, A.R. Liss, New York, 1988, pp. 3811-394. 26 Shain, W., Madelian, V., Martin, D.L., Kimelberg, H., Perrone, M. and Lepore, R., Activation of beta-adrenergic receptors stimulates release of an inhibitory transmitter from astrocytes, J. Neurochem., 46 (1986) 1298-1303. 27 Sturman, J.A. and Wisniewski, H.M., Aluminum. In S.C. Bondy and L.L. Prasad (Eds.), Metal Neurotoxicity, CRC Press, Boca Raton, Florida, 1988, pp. 61-85. 28 Winkelman, M.D. and Ricanati, E.S., Dialysis encephalopathy: neuropathologic aspects, Hum. Pathol., 17 (1986) 823-833. 29 Wong, P.C.L., Lai, J.C.K., Lim, L. and Davison, A.N., Selective inhibition of L-glutamate and gamma-aminobutyrate transport in nerve ending particles by aluminum, manganese and cadmium chloride, J. Inorg. Biochem., 14 (1981) 253-260.
105
© 1991 Elsevier Scientific Publishers Ireland Ltd. 0304-3940/91/$ 03.50 ADONIS 030439409100281Z NSL 07798
Aluminum chloride stimulates the release of endogenous glutamate, taurine and adenosine from cultured rat cortical astrocytes Jan Albrecht 1,*, M a r t h a Simmons 2, G a r y R. D u t t o n 2 and Michael D. Norenberg ~ 1Veteran Administration Medical Center, Department of Pathology, University of Miami School of Medicine, Jackson Memorial Hospital, Miami, FL 33131 (U.S.A.) and ZDepartment of Pharmacology, University of lowa College of Medicine, Iowa City, 1.4 52242 (U.S.A.) (Received 3 August 1991; Revised version received 7 March 1991; Accepted 9 March 1991)
Key words." Cultured astrocyte; Aluminum toxicity; Taurine; Cerebral cortex Primary astrocyte cultures derived from neonatal rat cerebral cortex were treated for 5 min with 0.5 mM or 5.0 mM A1C13, and the incubation medium was analyzed by HPLC for the content of released glutamate (Glu), taurine (Tau), serine (Ser) and the nucleoside adenosine (Ade). At 0.5 mM, AICI3 stimulated Tau release to about 170% of basal levels, but did not affect the release of the other compounds. Treatment with 5.0 mM AIC13 enhanced the release of Tau, Glu and Ade, to 800%, 1000% and 250%, respectively, but decreased the release of Ser to 70% compared to basal levels. The enhanced release of these neuroactive compounds from astrocytes may contribute to changes in neural transmission known to accompany exposure to aluminum.
Aluminum is a potent neurotoxin and its excessive accumulation in the CNS, whether from endogenous sources or from environmental exposure, has been implicated in a variety of neurological disorders. These include dialysis encephalopathy, Alzheimer's disease and the amyotrophic lateral sclerosis-dementia complex of Guam (see review ref. 27). While neurodegenerative changes produced in CNS neurons following chronic exposure to aluminum salts in vivo or in vitro have been analyzed extensively [27], little is known about the more immediate neurochemical effects after acute exposure. In vitro experiments have revealed that aluminum chloride inhibits the uptake of the amino acid neurotransmitters glutamate (Glu) and 7-aminobutyric acid (GABA) [29], and that it interferes with calcium transport in rat brain synaptosomes [11]. These effects are likely to underlie aluminum-induced disturbances of neurotransmission. However, though nerve cells are the eventual functional target of aluminum toxicity, morphological evidence suggests that astrocytes are the cellular CNS compartment that is most strongly affected by aluminum. This appears to be true regardless of whether aluminum is administered in vivo [9], enters the brain in the course of
*Permanent address: Department of Neuropathology, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. Correspondence: G.R. Dutton, Department of Pharmacology, University of Iowa College of Medicine, Iowa City, IA 52242, U.S.A.
dialysis encephalopathy [7, 28], or is added in vitro to primary astrocyte cultures [17]. Astrocytes react to a variety of extracellular stimuli with the enhanced release of neuroactive compounds, including the neuromodulators taurine (Tau) [14, 15, 18-21, 26] and adenosine (Ade) [25], and the neurotransmitters Glu and GABA [2, 3, 23, 24]. Since such an increased release may affect the functioning of adjacent neurons, we examined whether aluminum chloride acts as a stimulus of the release of these substances from cultured astrocytes. This study was performed using five-week-old cultures of neonatal cortical astrocytes grown in the presence of dibutyryl cAMP (not less than 95 % of the cells were glial fibrillary acidic protein (GFAP)-positive) as previously reported [8]. Cells maintained in 35-mm dishes were washed twice with buffered Krebs-Ringer medium (in mM: NaC1 140, KC1 3, CaC12 1, MgCI2 0.6, glucose 10 and HEPES 50, pH 7.4) and then incubated in 1 ml of the same medium for 15 min at 37°C. The cells were then incubated for 5 min at 37°C, either in Krebs-Ringer medium alone (control cells) or in Krebs-Ringer medium containing 0.5 mM or 5.0 mM aluminum chloride. Following incubation, 0.9 ml samples of the medium were collected. Thereafter, 1 ml of Krebs-Ringer medium was added, the 5-min incubation was repeated and 0.9 ml samples were again collected. The second incubation step was included to account for possible delay in the maximal release response known from previous studies to occur with Tau and Ade [1, 18, 20, 22].
106
Mean values of these two samples were used in determining the stimulated levels of release in five separate experiments. Samples were freeze-dried and subjected to reverse HPLC analysis as detailed in ref. 22. In keeping with earlier observations on cerebellar astrocytes [20], incubation of cerebral cortical astrocyte cultures for 5 min in the Krebs-Ringer buffer led to measurable basal release levels of Tau (Fig. 1A), Ade (Fig. I C) and of Glu (Fig. 1B). No GABA was detected, confirming the extremely low content of this amino acid in cultured astrocytes. Basal release levels of the neuroinert amino acid serine (Ser) were highest in the medium after incubation (Fig. 1D). Five-minute treatment with 0.5 mM A1C13 increased Tau release to approximately 170 % of basal levels (Fig. 1A), but had no effect on Glu, Ade or Ser basal levels (Fig. 1B-D). Treatment with 5.0 mM A1C13 increased the basal release of Tau to more than 800% (Fig. 1A), that of Glu to more than 10-fold (Fig. 1B), and the release of Ade to 250% of control levels (Fig. 1C). By contrast, 5.0 mM AIC13 caused an approximately 30% inhibition of Ser basal release (Fig. 1D). Taken together, these results confirm the assumption that toxic concentrations of AIC13 enhance the release of neuroactive compounds from astrocytes. The absence of A1Cls-stimulated Ser release, plus the marked quantitative differences between the responses of the particular neuroactive compounds, suggest that the effects of AICI3 were not simply due to general cell membrane damage, such as lysis. Furthermore, only morphological changes are seen in these cells even after 24 h in 5 mM A1C13 [16]. 800
200
c 600
150
"~400
100 50
200
0 0.0
0.5
5.0
0.0
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2500
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2000
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1500
~-~300 1000
~ 200
500
100
0 0.0 0.5 5.0 AICI3 (raM)
0.0 0.5 5.0 AICi3 (mM)
Fig. I. Effect of aluminum chloride on the release of (A) Tau, (B) Glu, (C) Ade and (D) Ser, from cultured cerebral cortex astrocytes. Results are mean ___ S.D. of 5 experiments. For detailed description of the methods see text. * P < 0 . 0 5 compared to controls (Student's paired t-test).
The selective stimulation of Tau release at the lower concentration (0.5 mM) of A1Cl3 is consistent with a greater sensitivity of astrocytes to changes in the extracellular ionic milieu [15, 18, 19]. While the mechanism that mediates Tau release remains to be conclusively identified, it is possibly, at least in part, due to cell swelling which might be caused by aluminum, although this was not measured directly. It is noteworthy in this context that long-term treatment of astrocytes with low millimolar concentrations of A1CI3 results in cytoplasmic vacuolization [17]. The mechanism by which 5 mM A1C13 evokes release of Glu is difficult to deduce, however, interference with the astrocytic Glu transporter cannot be excluded. It is also possible that A1C13 induces metabolic changes in astrocytes favoring Glu release, as was recently reported for cerebellar astroglial cell clones which differ in spontaneous Gtu release levels [4]. While the increased release of neuroactive compounds may result in functional changes in the adjacent neurons, massive release of Glu, which has well documented neurotoxic properties, appears to be of particular significance. For example, it has been shown that CNS explants cultured in the presence of Glu develop neurodegenerative changes similar to those observed in Alzheimer's disease [6]. The experiments presented here support the possibility that in vivo aluminum neurotoxicity may to some degree be mediated by the release of Glu from astrocytes. Glu release has been observed by Kimelberg and co-workers to accompany astrocyte swelling [10], and this phenomenon may occur as a result of exposure to A1C13. Ade has been ascribed a role of an inhibitory neurotransmitter and/or neuromodulator (references in ref. 24). Recently it has been shown that cerebellar granular neurons cultured in vitro co-release Ade with Glu, and it has been speculated that this may represent the way in which Ade controls transmission at glutamatergic synapses [24]. The present results demonstrate that what appears to be co-release can also be evoked from astrocytes. However, it is not known from these experiments if the Ade and Glu originate from the same, or different cells within these cultures. The aluminum chloride concentrations used in this and our previous studies [1], are close to the lower and upper limits of the concentrations of aluminum salts applied in chronic paradigms to induce neurodegenerative changes in mixed [13], neoplastic [16], or astroglial cell cultures [17]. However, the compatibility of the in vitro model with the clinical aspects of aluminum-related neurological disorders remains to be examined. As measured globally, brain aluminum concentrations in such disorders do not exceed 0.25 mM [5, 12], however, they may reach higher values locally [4].
107
The authors would like to thank Marilynn Kirkpatrick and Kathryn Andrews for manuscript preparation. This work was supported by the Veteran Administration and an NIH Grant DK 38153, a grant from the University of Miami (M.D.N.), by NIH Grant NS 20632 (G.R.D.), and the Life and Health Insurance Medical Research Fund (M.L.S.). 1 Albrecht, J. and Norenberg, M.D., Aluminum chloride stimulates NaCl-dependent release of taurine and 7-aminobutyric acid in rat cortical astrocytes, Neurochem. Int., 18 (1991) 125-130. 2 Albrecht, J. and Rafalowska, U., Enhanced potassium-stimulated y-aminobutyric acid release by astrocytes derived from rats with early hepatogenic encephalopathy, J. Neurochem., 49 (1987) 9-11. 3 Bowery, N.G., Brown, D.A. and Marsh, S., y-Aminobutyric acid ettlux from sympathetic glial ceils: effect of 'depolarizing' agents, J. Physiol., 293 (1979) 75-101. 4 Cambier, D. and Pessac, G., Spontaneous glutamate release by a 'fibrous'-like cerebellar astroglial cell clone, J. Neurochem., 53 (1989) 551-555. 5 Cropper, D.R., Krishnan, S.S. and Quitkat, S., Aluminum, neurofibrillary degeneration and Alzheimer's disease, Brain, 99 (1976) 67-80. 6 DeBoni, U. and Crapper-McLachlan, D.R., Controlled induction of paired helical filaments of the Alzheimer type in cultured human neurons, by glutamate and aspartate, J. Neurol. Sci., 68 (1985) 105118. 7 Good, P.F. and Perl, D.P., A laser microprobe mass analysis (LAMMA): study of aluminum distribution in the cerebral cortex in dialysis encephalopathy, J. Neuropathol. Exp. Neurol., 47 (1988) 321. 8 Gregorios, J.B., Mozes, L.W., Norenberg, L.O.B. and Norenberg, M.D., Morphologic effects of ammonia on primary astrocyte cultures. I. Light microscopic studies, J. Neuropathol. Exp. Neurol., 44 (1985) 397-403. 9 Harris, A.B., Cortical neuroglia in experimental epilepsy, Exp. Neurol., 49 (1975) 691-715. 10 Kimelberg, H.K., Gooderie, S.K., Higman, S., Pang, S. and Waniewski, R.A., Swelling-induced release of glutamate, aspartate and taurine from astrocyte cultures, J. Neurosci., 10 (1990) 15831591. 11 Koenig, M.L. and Jope, R.S., Aluminum inhibits the fast phase of voltage-dependent calcium influx into synaptosomes, J. Neurochem., 49 (1987) 316-320. 12 Lai, J.C.K. and Blass, J.P., Inhibition of brain glycolysis by aluminum, J. Neurochem., 42 (1984) 438-446. 13 Langui, D., Anderton, B.H., Brion, J.-P. and Ulrich, J., Effects of aluminum chloride on cultured cells from rat brain hemispheres, Brain Res., 438 (1988) 67-76. 14 Madelian, V., Martin, D.L., Lepore, R., Perrone, M. and Shain,
W., t-Receptor-stimulated and cyclic adenosine 3-,5-monophosphate-mediated taurine release from LRM55 glial cells, J. Neurosci., 5 (1985) 3154-3160. 15 Martin, D.L., Madelian, V., Seligmann, B. and Shain, W., The role of osmotic pressure and membrane potential in K+-stimulated taurine release from cultured astrocytes and LRM55 cells, J. Neurosci., 10 (1990) 571-577. 16 Miller, C.A. and Levine, E.M., Effect of aluminum salts on cultured neuroblastoma cells, J. Neurochem., 22 (1974) 751-758. 17 Norenberg, M.D., Norenberg, L.O.B., Cowman, G.A., McCarthy, M. and Neary, J.T., Effect of aluminum on astrocytes in primary culture, J. Neuropathol. Exp. Neurol., 48 (1989) 374. 18 Pasantes-Morales, H. and Schousboe, A., Volume regulation in astrocytes: a role of taurine as osmoeffector, J. Neurosci. Res., 20 (1988) 505-509. 19 Pasantes-Morales, H. and Schousboe, A., Release of taurine from astrocytes during potassium-induced swelling, Glia, 2 (1989) 45-50. 20 Philibert, R.A., Rogers, K.L., Allen, A.J. and Dutton, G.R., Dosedependent, K +-stimulated efflux of endogenous taurine from primary astrocyte cultures is Ca2+-dependent, J. Neurochem., 51 (1988) 122-126. 21 Philibert, R.A., Rogers, K.L. and Dutton, G.R., K+-evoked taufine ettlux from cerebeUar astrocytes: on the roles of Ca 2+ and Na ÷, Neurochem. Res., 14 (1988) 43-48. 22 Rogers, K.L., Philibert, R.A., Allen, A.J., Molitor, J., Wilson, E.J. and Dutton, G.R., HPLC analysis of putative amino acid neurotransmitters released from primary cerebellar cultures, J. Neurosci. Methods, 22 (1987) 173-179. 23 Sarthy, P.V., Release of [3H]7-aminobutyric acid from glial (Muller) cells of the rat retina: effects of K ÷, veratridine and ethylenediamine, J. Neurosci., 3 (1983) 2494-2452. 24 Schousboe, A., Frandsen, A. and Drejer, J., Evidence for evoked release of adenosine and glutamate from cultured cerebellar granule cells, Neurochem. Res., 14 (1989) 871-875. 25 Schousboe, A., Larsson, O.M., Krogsgaard-Larsen, P., Drejer, J. and Hertz, L., Uptake and release processes for neurotransmitter amino acids in astrocytes. In M.D. Norenberg, L. Hertz and A. Schousboe (Eds.), The Biochemical Pathology of Astrocytes, A.R. Liss, New York, 1988, pp. 3811-394. 26 Shain, W., Madelian, V., Martin, D.L., Kimelberg, H., Perrone, M. and Lepore, R., Activation of beta-adrenergic receptors stimulates release of an inhibitory transmitter from astrocytes, J. Neurochem., 46 (1986) 1298-1303. 27 Sturman, J.A. and Wisniewski, H.M., Aluminum. In S.C. Bondy and L.L. Prasad (Eds.), Metal Neurotoxicity, CRC Press, Boca Raton, Florida, 1988, pp. 61-85. 28 Winkelman, M.D. and Ricanati, E.S., Dialysis encephalopathy: neuropathologic aspects, Hum. Pathol., 17 (1986) 823-833. 29 Wong, P.C.L., Lai, J.C.K., Lim, L. and Davison, A.N., Selective inhibition of L-glutamate and gamma-aminobutyrate transport in nerve ending particles by aluminum, manganese and cadmium chloride, J. Inorg. Biochem., 14 (1981) 253-260.
