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GABA-transaminase, the liver and infantile autism
Medical Hypotheses (2001) 57(6), 673±674 & 2001 Harcourt Publishers Ltd 1
doi: 10.1054/mehy.2001.1350, available online at http://www.idealibrary.com on
GABA-transaminase, the liver and infantile autism B. I. Cohen ED Laboratories, 89 Leuning Street, S. Hackensack, New Jersey, USA
Summary Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the mammalian brain and the enzyme responsible for catabolism (breakdown in the liver during regulation) is GABA-Transaminase (GABA-T). Recently, Cohen (1) has shown that extremely high GABA levels in the urine and blood were observed for an autistic child. The finding that elevated levels of GABA in the urine and blood are present for an autistic child could explain why autistic features (such as self-stimulatory behavior and language delays, etc.) are found. Increasing the GABA-T enzyme activity for this autistic patient could result in less plasma GABA (after liver regulation) entering into the bloodsteam and brain and it is postulated that this could result in a reduction of the autistic features (such as selfstimulatory behavior and language delays, etc.) due to abnormal development of the axon(s) in the corpus callosum. & 2001 Harcourt Publishers Ltd
INTRODUCTION Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the mammalian brain and the enzyme responsible for its synthesis is glutamic acid decarboxylase (GAD, EC 4.1.1.15) and the enzyme responsible for catabolism (breakdown in the liver during regulation) is GABA-transaminase (GABA-T, EC 2.6.1.19). Recently, Cohen (1) has illustrated that extremely high GABA levels in the urine and blood were observed for an autistic child. Cohen (1) also illustrated that the corpus callosum in the brain is responsible for intelligence, language and speech and that GABA as a major inhibitory neurotransmitter is responsible for axon(s)-to-oligodendrocyte signaling in the corpus callosum. The corpus callosum is located in the center of the brain and is the major communication pathway between the two cerebral hemispheres. The finding that elevated levels of GABA in the Received 23 October 2000 Accepted 23 January 2001 Published online 16 October 2001 Correspondence to: B. I. Cohen Director of Research, ED Laboratories, 89 Leuning Street, S. Hackensack, New Jersey 07606, USA. Phone: 1-201-487-9090; Fax: 1-201-487-5120; E-mail: [email protected]
urine and blood are present for an autistic child could explain why autistic features (such as self-stimulatory behavior and language delays, etc.) are found. This is possibly due to abnormal development of the axon(s) in the corpus callosum. Cohen (2) has also illustrated a possible link between the liver and infantile autism via the measurement of elevated levels of plasma GABA and ammonia that were observed for the same autistic patient. Studies have shown that elevated levels of ammonia in the plasma results in a decrease in the efficiency for the enzyme GABA-T and this results in higher GABA concentrations in the blood after regulation in the liver (3). Jayakumar (3) also illustrated that elevated levels of nitric oxide (NO) (an oxygen derivative of ammonia) in the brain suppresses the activity of GABA-T and this also resulted in elevated levels of plasma GABA. Therefore, extremely high levels of plasma GABA are observed for the patient with a liver disorder. Interestingly, for epileptic disorders the opposite effect on the enzyme GABA-T is observed. Armijo et al. (4) illustrated that the GABA-T enzyme activity was approximately 60% higher for epileptic patients (adults and children) than for the control group. Since GABA-T is responsible for catabolism of GABA, the end result of a highly efficient or active enzyme results in lower plasma
673
674 Cohen
GABA. This is consistent for the disorder epilepsy where lower plasma GABA is usually found (4). The purpose of this study was to measure the GABA-T enzyme activity for an autistic child (this child had previously elevated levels of GABA and ammonia (1,2)) and to relate the activity to the regulation of GABA in the liver. This study also theorizes that high serum plasma and urine GABA levels is possibly the root cause for the developmental disorder of autism. The patient is a 9-year-old white male diagnosed with infantile autism. Diagnosis of infantile autism was made by DSM-IIIR criteria. TEST FOR GABA-TRANSAMINASE (GABA-T) ACTIVITY A plasma sample was drawn (15 mL) in a green top tube and frozen for leucocytes while cells separation. The GABA-T enzyme activity assay was measured versus a control and reported in pmol/min/mg of protein. The GABA-T activity for the control group ranged from 110± 147 pmol/min/mg of protein (with an average GABA-T activity of 128.5 pmol/min/mg of protein). The value measured for the autistic patient was 70 pmol/min/mg of protein. The autistic patient had a value for the GABA-T enzyme activity which represents 54.5% compared to 100% for the control group. Therefore, the enzyme activity for the autistic patient is approximately 45.5% lower (approximately half) then the average control group GABA-T enzyme activity [(70 pmol/min/mg divided by 128 pmol/ min/mg 100) ÿ 100 45.5%]. White et al. (5) illustrated that GABA-T inhibition (with 1-(n-decyl-)3-pyrazolidinone, BW357U (a potent, selective inhibitor of GABA-T in vitro)) of approximately 50% from oral administration to rats resulted in elevated plasma
Medical Hypotheses (2001) 57(6), 673±674
GABA levels in the brain of approximately threefold. Here, the GABA-T enzyme activity for an autistic patient was found to be inhibited or inefficient by approximately 45.5% or half and this results in measured plasma GABA level of approximately 2.25 fold (two and a quarterfold) more than the norm (1). Therefore, increasing the GABA-T enzyme activity for this autistic patient could result in less plasma GABA (after liver regulation) entering into the bloodstream and brain. In other words, a GABA-T agonist can be used to selectively activate GABA-T enzyme activity and this can result in a lowering of the plasma GABA in the brain. A reduction of the plasma GABA will probably result in more axon(s)-to-oligodendrocyte signaling in the corpus callosum and it is postulated that this could result in a reduction of the autistic features (such as self-stimulatory behavior and language delays, etc.) due to abnormal development of the axon(s) in the corpus callosum. More work is warranted in this area. REFERENCES 1. Cohen B. I. Elevated levels of plasma and urine gammaaminobutyric acid ± a case study for an autistic child. Autism 1999; 3: 437±440. 2. Cohen B. I. Infantile autism and the liver ± a possible connection. Autism 2000; 4: 441±442. 3. Jayakumar A. R., Sujatha R., Paul V., Asokan C., Govindasamy S., Jayakumar R. Role of nitric oxide on GABA, glutamic acid, activities of GABA-T and GAD in rat brain cerebral cortex. Brain Res 1999; 837: 229±235. 4. Armijo J. A., Arteaga R., Valiente R., Herranz J. L. Platelet GABAaminotransferase in epileptic patients. Inter J Clin Pharm Res 1989; 9: 283±285. 5. White H. L., Howard J. L., Cooper B. R., Soroko F. E., McDermed J. D., Ingold K. J., Maxwell R. A. A novel inhibitor of gammaaminobutyrate aminotransferase with anorectic activity. J Neurochemistry 1982; 39: 271±273.
& 2001 Harcourt Publishers Ltd
doi: 10.1054/mehy.2001.1350, available online at http://www.idealibrary.com on
GABA-transaminase, the liver and infantile autism B. I. Cohen ED Laboratories, 89 Leuning Street, S. Hackensack, New Jersey, USA
Summary Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the mammalian brain and the enzyme responsible for catabolism (breakdown in the liver during regulation) is GABA-Transaminase (GABA-T). Recently, Cohen (1) has shown that extremely high GABA levels in the urine and blood were observed for an autistic child. The finding that elevated levels of GABA in the urine and blood are present for an autistic child could explain why autistic features (such as self-stimulatory behavior and language delays, etc.) are found. Increasing the GABA-T enzyme activity for this autistic patient could result in less plasma GABA (after liver regulation) entering into the bloodsteam and brain and it is postulated that this could result in a reduction of the autistic features (such as selfstimulatory behavior and language delays, etc.) due to abnormal development of the axon(s) in the corpus callosum. & 2001 Harcourt Publishers Ltd
INTRODUCTION Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the mammalian brain and the enzyme responsible for its synthesis is glutamic acid decarboxylase (GAD, EC 4.1.1.15) and the enzyme responsible for catabolism (breakdown in the liver during regulation) is GABA-transaminase (GABA-T, EC 2.6.1.19). Recently, Cohen (1) has illustrated that extremely high GABA levels in the urine and blood were observed for an autistic child. Cohen (1) also illustrated that the corpus callosum in the brain is responsible for intelligence, language and speech and that GABA as a major inhibitory neurotransmitter is responsible for axon(s)-to-oligodendrocyte signaling in the corpus callosum. The corpus callosum is located in the center of the brain and is the major communication pathway between the two cerebral hemispheres. The finding that elevated levels of GABA in the Received 23 October 2000 Accepted 23 January 2001 Published online 16 October 2001 Correspondence to: B. I. Cohen Director of Research, ED Laboratories, 89 Leuning Street, S. Hackensack, New Jersey 07606, USA. Phone: 1-201-487-9090; Fax: 1-201-487-5120; E-mail: [email protected]
urine and blood are present for an autistic child could explain why autistic features (such as self-stimulatory behavior and language delays, etc.) are found. This is possibly due to abnormal development of the axon(s) in the corpus callosum. Cohen (2) has also illustrated a possible link between the liver and infantile autism via the measurement of elevated levels of plasma GABA and ammonia that were observed for the same autistic patient. Studies have shown that elevated levels of ammonia in the plasma results in a decrease in the efficiency for the enzyme GABA-T and this results in higher GABA concentrations in the blood after regulation in the liver (3). Jayakumar (3) also illustrated that elevated levels of nitric oxide (NO) (an oxygen derivative of ammonia) in the brain suppresses the activity of GABA-T and this also resulted in elevated levels of plasma GABA. Therefore, extremely high levels of plasma GABA are observed for the patient with a liver disorder. Interestingly, for epileptic disorders the opposite effect on the enzyme GABA-T is observed. Armijo et al. (4) illustrated that the GABA-T enzyme activity was approximately 60% higher for epileptic patients (adults and children) than for the control group. Since GABA-T is responsible for catabolism of GABA, the end result of a highly efficient or active enzyme results in lower plasma
673
674 Cohen
GABA. This is consistent for the disorder epilepsy where lower plasma GABA is usually found (4). The purpose of this study was to measure the GABA-T enzyme activity for an autistic child (this child had previously elevated levels of GABA and ammonia (1,2)) and to relate the activity to the regulation of GABA in the liver. This study also theorizes that high serum plasma and urine GABA levels is possibly the root cause for the developmental disorder of autism. The patient is a 9-year-old white male diagnosed with infantile autism. Diagnosis of infantile autism was made by DSM-IIIR criteria. TEST FOR GABA-TRANSAMINASE (GABA-T) ACTIVITY A plasma sample was drawn (15 mL) in a green top tube and frozen for leucocytes while cells separation. The GABA-T enzyme activity assay was measured versus a control and reported in pmol/min/mg of protein. The GABA-T activity for the control group ranged from 110± 147 pmol/min/mg of protein (with an average GABA-T activity of 128.5 pmol/min/mg of protein). The value measured for the autistic patient was 70 pmol/min/mg of protein. The autistic patient had a value for the GABA-T enzyme activity which represents 54.5% compared to 100% for the control group. Therefore, the enzyme activity for the autistic patient is approximately 45.5% lower (approximately half) then the average control group GABA-T enzyme activity [(70 pmol/min/mg divided by 128 pmol/ min/mg 100) ÿ 100 45.5%]. White et al. (5) illustrated that GABA-T inhibition (with 1-(n-decyl-)3-pyrazolidinone, BW357U (a potent, selective inhibitor of GABA-T in vitro)) of approximately 50% from oral administration to rats resulted in elevated plasma
Medical Hypotheses (2001) 57(6), 673±674
GABA levels in the brain of approximately threefold. Here, the GABA-T enzyme activity for an autistic patient was found to be inhibited or inefficient by approximately 45.5% or half and this results in measured plasma GABA level of approximately 2.25 fold (two and a quarterfold) more than the norm (1). Therefore, increasing the GABA-T enzyme activity for this autistic patient could result in less plasma GABA (after liver regulation) entering into the bloodstream and brain. In other words, a GABA-T agonist can be used to selectively activate GABA-T enzyme activity and this can result in a lowering of the plasma GABA in the brain. A reduction of the plasma GABA will probably result in more axon(s)-to-oligodendrocyte signaling in the corpus callosum and it is postulated that this could result in a reduction of the autistic features (such as self-stimulatory behavior and language delays, etc.) due to abnormal development of the axon(s) in the corpus callosum. More work is warranted in this area. REFERENCES 1. Cohen B. I. Elevated levels of plasma and urine gammaaminobutyric acid ± a case study for an autistic child. Autism 1999; 3: 437±440. 2. Cohen B. I. Infantile autism and the liver ± a possible connection. Autism 2000; 4: 441±442. 3. Jayakumar A. R., Sujatha R., Paul V., Asokan C., Govindasamy S., Jayakumar R. Role of nitric oxide on GABA, glutamic acid, activities of GABA-T and GAD in rat brain cerebral cortex. Brain Res 1999; 837: 229±235. 4. Armijo J. A., Arteaga R., Valiente R., Herranz J. L. Platelet GABAaminotransferase in epileptic patients. Inter J Clin Pharm Res 1989; 9: 283±285. 5. White H. L., Howard J. L., Cooper B. R., Soroko F. E., McDermed J. D., Ingold K. J., Maxwell R. A. A novel inhibitor of gammaaminobutyrate aminotransferase with anorectic activity. J Neurochemistry 1982; 39: 271±273.
& 2001 Harcourt Publishers Ltd