Amino Acids in Human Epileptogenic Foci Thomas L. Perry, MD; Shirley Hansen; Janet Kennedy; Juhn A. Wada, MD, FRCP (C); Gordon B. Thompson, MD, FRCS \s=b\ Free amino compounds were measured in 16 rapidly frozen epileptogenic foci excised from temporal or frontal cortex of nine patients with focal epilepsy, and in single cortical biopsy specimens obtained from 16 nonepileptic patients. Unlike the findings of a previous study, glutamic and aspartic acids were not diminished in the foci, nor was there a decrease in \g=g\-aminobutyric acid (GABA) or taurine levels. Glycine content was markedly elevated in two of 16 epileptogenic foci. These results do not suggest that deficiencies of GABA or of taurine, amino acids that may act physio-
logically
as
inhibitory
neurotransmitters
modulators of inhibition, are causes of focal epilepsy, nor do they provide a logical basis for clinical trials of taurine in treatment of human epilepsy. (Arch Neurol 32:752-754, 1975) or
Many
attempts have been made to find biochemical causes that might explain epilepsy in man. These have included studies designed to ex¬ plore the possibility that excessive amounts of amino acids believed to act as excitatory synaptic transmit¬ ters in brain, or deficient brain lev¬ els of amino acids believed to act as
inhibitory neurotransmitters, might the abnormal neuronal activity in epileptogenic foci. Interest in this field was recently stimulated by the cause
report of Van Gelder et al1 that levels
of taurine and of glutamic acid are low in human epileptogenic foci, that levels of glycine are strikingly high in Accepted for publication Sept 1, 1974. From the departments of pharmacology, psychiatry, and surgery, University of British Columbia, Vancouver. Reprint requests to Department of Pharmacology, University of British Columbia, Vancouver, BC V6T 1W5, Canada (Dr. Perry).
(C)
such foci, and that levels of aspartic acid and of -aminobutyric acid (GABA) are diffusely low in the cere¬ bral cortex of patients with epilepsy. This subject has become of more than just theoretical interest, since propos¬ als are now appearing that suggest that clinical evaluation of the anti¬ epileptic effects of taurine should be undertaken.24 We compared the amino acid con¬ tents of rapidly frozen human epilep¬ togenic foci with those of cortical biopsy specimens from nonepileptic patients. No deficiencies of taurine, GABA, glutamic acid, or aspartic acid were found in epileptogenic foci, and in only two such foci was there an ab¬
normally high glycine
content.
PATIENTS AND METHODS Epileptic Patients
During a four-year period, 16 epilepto¬ genic foci were obtained from nine con¬ secutive patients who underwent neuro¬ surgical removal of cortical tissue because of intractable focal epilepsy. These pa¬ tients had failed to respond adequately to various combinations of the usual anti¬ epileptic drugs, and their clinical manifes¬ tations, besides frequent seizures, usually included behavior that seriously interfered with education or employment. The pa¬ tients ranged in age from 8 to 44 years (mean age, 23). Five brain specimens (two patients) were obtained from the frontal cortex, and 11 specimens (seven patients) from the temporal cortex. These speci¬ mens were obtained from epileptogenic foci that were defined by direct cortical and depth electrographic recordings, while the patients were under halothane-induced anesthesia. The area or areas of maximal
spontaneous
epileptiform
abnormality
also verified by intravenous methohexital activation,'' which frequently pro¬ duced a localized and sustained electrowere
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/12/2015
graphie discharge. Cortical specimens removed at surgery were immersed in liq¬ uid nitrogen within ten seconds of the cut¬ ting of the blood supply. The subsequent substantial clinical and electrographic im¬ provement of the patients suggested that localization of the epileptogenic foci had been accurate.
Control
Subjects
A single cortical biopsy specimen was obtained during neurosurgical exploration from each of 16 nonepileptic patients who underwent surgical removal of a deepseated brain tumor or brain abscess. This surgery necessitated sacrifice of a small area of apparently normal cerebral cortex in order to reach the deeper pathological lesion. The 16 subjects ranged in age from 16 to 67 years (mean age, 49). Seven of the 16 cortical biopsy specimens were from the frontal lobe, and four were from the tem¬ poral lobe. As in the case of the epilepto¬ genic foci, each specimen was immersed in liquid nitrogen within ten seconds of the severing of its blood supply.
Methods
specimens remained frozen at they were homogenized and deproteinized in 0.4M perchloric acid. The procedures used were those that we have previously described,6·' except that homogenizations were carried out in a Tef¬ lon-pestle glass tissue grinder. Free amino acids and other ninhydrinpositive com¬ pounds were then identified and quantitated with a amino acid analyzer, with the Brain
-196 C until
of a lithium citrate elution buffer sys¬ tem" that makes it possible to measure ac¬ curately 36 different amino compounds present in human brain. Student t test was used to calculate the statistical signifi¬ cance of differences in the mean levels of amino compounds in the two groups of pa¬ tients. Where group variances were un¬ equal, as indicated by the F test, the ¿-like use
statistic
was
used."
RESULTS The Table lists the mean contents of eight amino compounds of special interest in cortical epileptogenic foci and in nonepileptic cerebral cortex. Values for 27 additional compounds that were present in both groups of brain tissue in approximately equal concentrations are not shown in the Table. Our findings do not concur with those reported by Van Gelder et al.1 The neuroexcitatory compounds, aspartic acid and glutamic acid, were not decreased in epileptogenic foci, but were present in normal concen¬ trations. The inhibitory amino acids, taurine and GABA, were not de¬ creased in foci. Indeed, their mean content was significantly higher than in nonepileptic cortex. Individual values for taurine, GABA, and glycine in epileptogenic foci are presented in the Figure, where they are compared with the mean values for these three amino acids in nonepileptic cerebral cortex. The contents of taurine and GABA, rather than being decreased in foci, actually fell in almost all instances in or above the upper range of normal for these compounds. Most glycine values in foci were also in the high normal range, but in two foci the con¬ tent of glycine was markedly ele¬ vated. The mean content of glutathione was higher in epileptogenic foci than in control cortex (Table). This dif¬ ference could not have been caused by relative dehydration of brain in the epileptic patients, since most amino acids were present in the same amounts as found in the cortex of the
nonepileptic patients. Cystathionine content was significantly reduced in the epileptogenic foci. Homocarno-
sine levels are shown in the Table as an indicator that GABA levels were not diminished in the epileptogenic foci prior to neurosurgery. Brain GABA levels rise markedly within a few minutes of the onset of cerebral anoxia,1" while levels of homocarnosine, its histidyl dipeptide, remain un¬ changed. Thus, any delay in dis¬ secting out and in freezing and the excised foci could not have produced an artifactually high mean GABA value for the epileptogenic foci since
Taurine
GABA
Glycine
Distribution of individual values for the three inhibitory amino acids—taurine, GABA, and glycine—in cortical epilepto¬ genic foci. Mean +2 SD for each com-
in nonepileptic human cortex is in¬ dicated to left of individual values by solid bars and broken lines.
their homocarnosine content was also higher than that in nonepileptic cor¬
naturally
tex.
COMMENT
Taurine has been reported to have anticonvulsant activity against vari¬ ous models of epilepsy produced in mice, rats, and cats by topical appli¬ cation of substances such as cobalt or penicillin, or by intraventricular in¬ jection of ouabain.3·4·11 Adminis¬ tration of taurine has also been re¬ ported to reduce seizure activity in
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/12/2015
pound
occurring epilepsy in dispute the possi¬
man.'·4 We do not
that taurine may possess antiseizure activity. A wide variety of drugs have such activity. However, the finding of elevated levels of tau¬ rine in epileptogenic foci, rather than depressed levels as has been re¬ ported,1 does not support a deficiency of brain taurine as a possible bio¬ chemical cause of epilepsy, and does not suggest the administration of taurine as a logical therapeutic mea¬
bility
sure.
Brain Amino
Compounds
Compound
in
Nonepileptic
Cortex and in
Control Cortex 1.16 ±0.12*
Taurine
Epileptogenic Foci 1.67 ±0.08
acid_1.08 ±± 0.07_1.01 Glutathionel
Aspartic
2.02 6.72 0.46 1.78 0.53
Glutamic acid
Glycine Cystathionine GABA
Epileptogenic Foci
0.14
2.46 8.42 0.69 0.38 0.79
±
0.47 ± 0.05
±0.39 ±0.05
Homocarnosine_0.28 ± 0.04_0.42
< .005 ± .40 0.05_< ± 0.06 < .02+ ± 0.44 < .02 ±0.11 < .10+ ± 0.08 < .005+ ± 0.05 < .005 ± 0.04_< .02
*
Values shown are mean ±SE, expressed in micromols per gram wet weight, t Total of oxidized and reduced glutathione. expressed as reduced glutathione. +
The f-like statistic used
to
calculate
significance.
Some years ago GABA also was ad¬ ministered to patients with severe ep¬ ilepsy in an effort to control seizure activity.1'2 It is now clear that exoge¬ nous GABA, unlike exogenous tau¬ rine," ·14 fails to cross the blood-brain barrier in adult mammals. Our find¬ ing that the content of GABA is high, rather than low in epileptogenic foci, does not suggest that other methods of elevating brain GABA levels15·16 would be effective in human epilepsy. As was the case with Van Gelder et al,1 we found glycine levels to be rela¬ tively high in epileptogenic foci, al¬ though in only two foci was the in¬ crease in glycine content striking. One possible explanation for this phe¬ nomenon is that drugs may have pro¬ duced the elevation in brain glycine content. Phenytoin and other anti-
convulsant drugs frequently cause moderate folate deficiency in epilep¬ tic patients.17 Since the glycine cleav¬ age enzyme system in brain requires tetrahydrofolate as a cofactor,18 fo¬ late deficiency might result in eleva¬ tion of brain glycine. We fed pheny¬ toin to rats in a dosage ten times higher than that customarily used in treating human epilepsy without pro¬ ducing any increase in glycine levels in whole rat brain. However, the fail¬ ure of phenytoin to inhibit the gly¬ cine cleavage enzyme system in rat brain does not prove that this or other anticonvulsant drugs might not have such an effect in human brain. It is also conceivable that local ac¬ cumulations of glycine may occur in some epileptogenic foci and be of etiological importance. One might de-
tect tent was
strikingly elevated glycine con¬ only if an epileptogenic focus precisely located and if it had
been removed with a minimum of sur¬ normal tissue. Removal of a minute biochemically abnormal focus, surrounded by ten times the volume of electrographically abnormal, but chemically nor¬ mal tissue, as must frequently occur in such neurosurgery, could easily lead to dilution of any abnormal bio¬ chemical factor being measured. We are unable to explain the sig¬ nificantly decreased cystathionine content found in epileptogenic foci, other than to suggest that this may also have been a drug effect. Cyst¬ athionine content varies widely from patient to patient in biopsy speci¬ mens of normal cortex, and we doubt that the low levels of cystathionine found in the epileptogenic foci were causally related to the epilepsy. Fur¬ ther biochemical studies of excised epileptogenic foci seem indicated. These should include, but not be lim¬ ited to amino acids. We anticipate that multiple biochemical aberra¬ tions, rather than a single one, will likely be shown to produce epilepsy in
rounding chemically
This work was supported by a grant to Dr. from the Medical Research Council of Canada.
Perry
References 1. Van Gelder NM, Sherwin AL, Rasmussen T: Amino acid content of epileptogenic human brain: Focal versus surrounding regions. Brain Res 40:385-393, 1972. 2. Barbeau A, Donaldson J: Taurine in epilepsy. Lancet 2:387, 1973. 3. Barbeau A, Donaldson J: Zinc, taurine, and epilepsy. Arch Neurol 30:52-58, 1974. 4. Mutani R, Bergamini L, Fariello R, et al: Effects of taurine on cortical epileptic foci. Brain Res 70:170-173, 1974. 5. Wada JA, Ferguson R, Thompson GB, et al: Intracarotid and intravenous Brietal activation: Sphenoidal and corticographic exploration in patients with temporal lobe seizures. Epilepsia 12:283, 1971. 6. Perry TL, Berry K, Hansen S, et al: Regional distribution of amino acids in human brain obtained at autopsy. J Neurochem 18:513\x=req-\ 519, 1971. 7. Perry TL, Hansen S, Berry K, et al: Free
amino acids and related compounds in biopsies of human brain. J Neurochem 18:521-528, 1971. 8. Perry TL, Stedman D, Hansen S: A versatile lithium buffer elution system for single column automatic amino acid chromatography. J Chromatogr 38:460-466, 1968. 9. Li CC: Introduction to Experimental Statistics, ed 1. New York, McGraw-Hill Book Co, 1964, p 431. 10. Minard
FN, Mushahwar IK: Synthesis of \g=g\aminobutyric acid from a pool of glutamic acid in brain after decapitation. Life Sci 5:1409-1413, 1966. 11. Van Gelder NM:
Antagonism by taurine of
cobalt-induced epilepsy in cat and mouse. Brain Res 47:157-165, 1972. 12. Tower DB: The administration of gammaaminobutyric acid to man: Systemic effects and anticonvulsant action in Roberts E, Baxter CF, van Harreveld A, et al (eds): Inhibition in the Nervous System and Gamma- Aminobutyric Acid.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/12/2015
New York, Pergamon Press, 1960, pp 562-578. 13. Peck EJ Jr, Awapara J: Formation of taurine and isethionic acid in rat brain. Biochim Biophys Acta 141:499-506, 1967. 14. Urquhart N, Perry TL, Hansen S, et al: Passage of taurine into adult mammalian brain. J Neurochem 22:871-872, 1974. 15. Perry TL, Hansen S: Sustained druginduced elevation of brain GABA in the rat. Neurochem 21:1167-1175, 1973. 16. Perry TL, Urquhart N, Hansen S, et al: \g=g\ Aminobutyric acid: Drug-induced elevation in monkey brain. J Neurochem 23:443-445, 1974. 17. Herbert V: Drugs effective in mrhslonlsdtic anemias, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics, ed 4. New York, Macmillan Co, 1970, p 1438. 18. Bruin WJ, Frantz BM, Sallach HJ: The occurrence of glycine cleavage system in mammalian brain. J Neurochem 20:1649-1658, 1973.
logically
as
inhibitory
neurotransmitters
modulators of inhibition, are causes of focal epilepsy, nor do they provide a logical basis for clinical trials of taurine in treatment of human epilepsy. (Arch Neurol 32:752-754, 1975) or
Many
attempts have been made to find biochemical causes that might explain epilepsy in man. These have included studies designed to ex¬ plore the possibility that excessive amounts of amino acids believed to act as excitatory synaptic transmit¬ ters in brain, or deficient brain lev¬ els of amino acids believed to act as
inhibitory neurotransmitters, might the abnormal neuronal activity in epileptogenic foci. Interest in this field was recently stimulated by the cause
report of Van Gelder et al1 that levels
of taurine and of glutamic acid are low in human epileptogenic foci, that levels of glycine are strikingly high in Accepted for publication Sept 1, 1974. From the departments of pharmacology, psychiatry, and surgery, University of British Columbia, Vancouver. Reprint requests to Department of Pharmacology, University of British Columbia, Vancouver, BC V6T 1W5, Canada (Dr. Perry).
(C)
such foci, and that levels of aspartic acid and of -aminobutyric acid (GABA) are diffusely low in the cere¬ bral cortex of patients with epilepsy. This subject has become of more than just theoretical interest, since propos¬ als are now appearing that suggest that clinical evaluation of the anti¬ epileptic effects of taurine should be undertaken.24 We compared the amino acid con¬ tents of rapidly frozen human epilep¬ togenic foci with those of cortical biopsy specimens from nonepileptic patients. No deficiencies of taurine, GABA, glutamic acid, or aspartic acid were found in epileptogenic foci, and in only two such foci was there an ab¬
normally high glycine
content.
PATIENTS AND METHODS Epileptic Patients
During a four-year period, 16 epilepto¬ genic foci were obtained from nine con¬ secutive patients who underwent neuro¬ surgical removal of cortical tissue because of intractable focal epilepsy. These pa¬ tients had failed to respond adequately to various combinations of the usual anti¬ epileptic drugs, and their clinical manifes¬ tations, besides frequent seizures, usually included behavior that seriously interfered with education or employment. The pa¬ tients ranged in age from 8 to 44 years (mean age, 23). Five brain specimens (two patients) were obtained from the frontal cortex, and 11 specimens (seven patients) from the temporal cortex. These speci¬ mens were obtained from epileptogenic foci that were defined by direct cortical and depth electrographic recordings, while the patients were under halothane-induced anesthesia. The area or areas of maximal
spontaneous
epileptiform
abnormality
also verified by intravenous methohexital activation,'' which frequently pro¬ duced a localized and sustained electrowere
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/12/2015
graphie discharge. Cortical specimens removed at surgery were immersed in liq¬ uid nitrogen within ten seconds of the cut¬ ting of the blood supply. The subsequent substantial clinical and electrographic im¬ provement of the patients suggested that localization of the epileptogenic foci had been accurate.
Control
Subjects
A single cortical biopsy specimen was obtained during neurosurgical exploration from each of 16 nonepileptic patients who underwent surgical removal of a deepseated brain tumor or brain abscess. This surgery necessitated sacrifice of a small area of apparently normal cerebral cortex in order to reach the deeper pathological lesion. The 16 subjects ranged in age from 16 to 67 years (mean age, 49). Seven of the 16 cortical biopsy specimens were from the frontal lobe, and four were from the tem¬ poral lobe. As in the case of the epilepto¬ genic foci, each specimen was immersed in liquid nitrogen within ten seconds of the severing of its blood supply.
Methods
specimens remained frozen at they were homogenized and deproteinized in 0.4M perchloric acid. The procedures used were those that we have previously described,6·' except that homogenizations were carried out in a Tef¬ lon-pestle glass tissue grinder. Free amino acids and other ninhydrinpositive com¬ pounds were then identified and quantitated with a amino acid analyzer, with the Brain
-196 C until
of a lithium citrate elution buffer sys¬ tem" that makes it possible to measure ac¬ curately 36 different amino compounds present in human brain. Student t test was used to calculate the statistical signifi¬ cance of differences in the mean levels of amino compounds in the two groups of pa¬ tients. Where group variances were un¬ equal, as indicated by the F test, the ¿-like use
statistic
was
used."
RESULTS The Table lists the mean contents of eight amino compounds of special interest in cortical epileptogenic foci and in nonepileptic cerebral cortex. Values for 27 additional compounds that were present in both groups of brain tissue in approximately equal concentrations are not shown in the Table. Our findings do not concur with those reported by Van Gelder et al.1 The neuroexcitatory compounds, aspartic acid and glutamic acid, were not decreased in epileptogenic foci, but were present in normal concen¬ trations. The inhibitory amino acids, taurine and GABA, were not de¬ creased in foci. Indeed, their mean content was significantly higher than in nonepileptic cortex. Individual values for taurine, GABA, and glycine in epileptogenic foci are presented in the Figure, where they are compared with the mean values for these three amino acids in nonepileptic cerebral cortex. The contents of taurine and GABA, rather than being decreased in foci, actually fell in almost all instances in or above the upper range of normal for these compounds. Most glycine values in foci were also in the high normal range, but in two foci the con¬ tent of glycine was markedly ele¬ vated. The mean content of glutathione was higher in epileptogenic foci than in control cortex (Table). This dif¬ ference could not have been caused by relative dehydration of brain in the epileptic patients, since most amino acids were present in the same amounts as found in the cortex of the
nonepileptic patients. Cystathionine content was significantly reduced in the epileptogenic foci. Homocarno-
sine levels are shown in the Table as an indicator that GABA levels were not diminished in the epileptogenic foci prior to neurosurgery. Brain GABA levels rise markedly within a few minutes of the onset of cerebral anoxia,1" while levels of homocarnosine, its histidyl dipeptide, remain un¬ changed. Thus, any delay in dis¬ secting out and in freezing and the excised foci could not have produced an artifactually high mean GABA value for the epileptogenic foci since
Taurine
GABA
Glycine
Distribution of individual values for the three inhibitory amino acids—taurine, GABA, and glycine—in cortical epilepto¬ genic foci. Mean +2 SD for each com-
in nonepileptic human cortex is in¬ dicated to left of individual values by solid bars and broken lines.
their homocarnosine content was also higher than that in nonepileptic cor¬
naturally
tex.
COMMENT
Taurine has been reported to have anticonvulsant activity against vari¬ ous models of epilepsy produced in mice, rats, and cats by topical appli¬ cation of substances such as cobalt or penicillin, or by intraventricular in¬ jection of ouabain.3·4·11 Adminis¬ tration of taurine has also been re¬ ported to reduce seizure activity in
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/12/2015
pound
occurring epilepsy in dispute the possi¬
man.'·4 We do not
that taurine may possess antiseizure activity. A wide variety of drugs have such activity. However, the finding of elevated levels of tau¬ rine in epileptogenic foci, rather than depressed levels as has been re¬ ported,1 does not support a deficiency of brain taurine as a possible bio¬ chemical cause of epilepsy, and does not suggest the administration of taurine as a logical therapeutic mea¬
bility
sure.
Brain Amino
Compounds
Compound
in
Nonepileptic
Cortex and in
Control Cortex 1.16 ±0.12*
Taurine
Epileptogenic Foci 1.67 ±0.08
acid_1.08 ±± 0.07_1.01 Glutathionel
Aspartic
2.02 6.72 0.46 1.78 0.53
Glutamic acid
Glycine Cystathionine GABA
Epileptogenic Foci
0.14
2.46 8.42 0.69 0.38 0.79
±
0.47 ± 0.05
±0.39 ±0.05
Homocarnosine_0.28 ± 0.04_0.42
< .005 ± .40 0.05_< ± 0.06 < .02+ ± 0.44 < .02 ±0.11 < .10+ ± 0.08 < .005+ ± 0.05 < .005 ± 0.04_< .02
*
Values shown are mean ±SE, expressed in micromols per gram wet weight, t Total of oxidized and reduced glutathione. expressed as reduced glutathione. +
The f-like statistic used
to
calculate
significance.
Some years ago GABA also was ad¬ ministered to patients with severe ep¬ ilepsy in an effort to control seizure activity.1'2 It is now clear that exoge¬ nous GABA, unlike exogenous tau¬ rine," ·14 fails to cross the blood-brain barrier in adult mammals. Our find¬ ing that the content of GABA is high, rather than low in epileptogenic foci, does not suggest that other methods of elevating brain GABA levels15·16 would be effective in human epilepsy. As was the case with Van Gelder et al,1 we found glycine levels to be rela¬ tively high in epileptogenic foci, al¬ though in only two foci was the in¬ crease in glycine content striking. One possible explanation for this phe¬ nomenon is that drugs may have pro¬ duced the elevation in brain glycine content. Phenytoin and other anti-
convulsant drugs frequently cause moderate folate deficiency in epilep¬ tic patients.17 Since the glycine cleav¬ age enzyme system in brain requires tetrahydrofolate as a cofactor,18 fo¬ late deficiency might result in eleva¬ tion of brain glycine. We fed pheny¬ toin to rats in a dosage ten times higher than that customarily used in treating human epilepsy without pro¬ ducing any increase in glycine levels in whole rat brain. However, the fail¬ ure of phenytoin to inhibit the gly¬ cine cleavage enzyme system in rat brain does not prove that this or other anticonvulsant drugs might not have such an effect in human brain. It is also conceivable that local ac¬ cumulations of glycine may occur in some epileptogenic foci and be of etiological importance. One might de-
tect tent was
strikingly elevated glycine con¬ only if an epileptogenic focus precisely located and if it had
been removed with a minimum of sur¬ normal tissue. Removal of a minute biochemically abnormal focus, surrounded by ten times the volume of electrographically abnormal, but chemically nor¬ mal tissue, as must frequently occur in such neurosurgery, could easily lead to dilution of any abnormal bio¬ chemical factor being measured. We are unable to explain the sig¬ nificantly decreased cystathionine content found in epileptogenic foci, other than to suggest that this may also have been a drug effect. Cyst¬ athionine content varies widely from patient to patient in biopsy speci¬ mens of normal cortex, and we doubt that the low levels of cystathionine found in the epileptogenic foci were causally related to the epilepsy. Fur¬ ther biochemical studies of excised epileptogenic foci seem indicated. These should include, but not be lim¬ ited to amino acids. We anticipate that multiple biochemical aberra¬ tions, rather than a single one, will likely be shown to produce epilepsy in
rounding chemically
This work was supported by a grant to Dr. from the Medical Research Council of Canada.
Perry
References 1. Van Gelder NM, Sherwin AL, Rasmussen T: Amino acid content of epileptogenic human brain: Focal versus surrounding regions. Brain Res 40:385-393, 1972. 2. Barbeau A, Donaldson J: Taurine in epilepsy. Lancet 2:387, 1973. 3. Barbeau A, Donaldson J: Zinc, taurine, and epilepsy. Arch Neurol 30:52-58, 1974. 4. Mutani R, Bergamini L, Fariello R, et al: Effects of taurine on cortical epileptic foci. Brain Res 70:170-173, 1974. 5. Wada JA, Ferguson R, Thompson GB, et al: Intracarotid and intravenous Brietal activation: Sphenoidal and corticographic exploration in patients with temporal lobe seizures. Epilepsia 12:283, 1971. 6. Perry TL, Berry K, Hansen S, et al: Regional distribution of amino acids in human brain obtained at autopsy. J Neurochem 18:513\x=req-\ 519, 1971. 7. Perry TL, Hansen S, Berry K, et al: Free
amino acids and related compounds in biopsies of human brain. J Neurochem 18:521-528, 1971. 8. Perry TL, Stedman D, Hansen S: A versatile lithium buffer elution system for single column automatic amino acid chromatography. J Chromatogr 38:460-466, 1968. 9. Li CC: Introduction to Experimental Statistics, ed 1. New York, McGraw-Hill Book Co, 1964, p 431. 10. Minard
FN, Mushahwar IK: Synthesis of \g=g\aminobutyric acid from a pool of glutamic acid in brain after decapitation. Life Sci 5:1409-1413, 1966. 11. Van Gelder NM:
Antagonism by taurine of
cobalt-induced epilepsy in cat and mouse. Brain Res 47:157-165, 1972. 12. Tower DB: The administration of gammaaminobutyric acid to man: Systemic effects and anticonvulsant action in Roberts E, Baxter CF, van Harreveld A, et al (eds): Inhibition in the Nervous System and Gamma- Aminobutyric Acid.
Downloaded From: http://archneur.jamanetwork.com/ by a University of Michigan User on 06/12/2015
New York, Pergamon Press, 1960, pp 562-578. 13. Peck EJ Jr, Awapara J: Formation of taurine and isethionic acid in rat brain. Biochim Biophys Acta 141:499-506, 1967. 14. Urquhart N, Perry TL, Hansen S, et al: Passage of taurine into adult mammalian brain. J Neurochem 22:871-872, 1974. 15. Perry TL, Hansen S: Sustained druginduced elevation of brain GABA in the rat. Neurochem 21:1167-1175, 1973. 16. Perry TL, Urquhart N, Hansen S, et al: \g=g\ Aminobutyric acid: Drug-induced elevation in monkey brain. J Neurochem 23:443-445, 1974. 17. Herbert V: Drugs effective in mrhslonlsdtic anemias, in Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics, ed 4. New York, Macmillan Co, 1970, p 1438. 18. Bruin WJ, Frantz BM, Sallach HJ: The occurrence of glycine cleavage system in mammalian brain. J Neurochem 20:1649-1658, 1973.
