Brain Amino Acid Levels Research Articles

The effect of phencyclidine-mediated blockade of NMDA receptors in the early postnatal period on glutathione and sulfur amino acid levels in the rat brain as a potential causative factor of schizophrenia-like behavior in adulthood

BackgroundPhencyclidine, an NMDA receptor antagonist, is frequently used to model behavioral and neurochemical changes correlated with schizophrenia in laboratory animals. The present study aimed to examine the effects of repeated administration of phencyclidine during early postnatal development on the contents of glutathione and sulfur-containing amino acids, as well as the activity of antioxidant enzymes in the brain of 12-day-old rats, and schizophrenia-like symptoms in adulthood.MethodsMale Sprague-Dawley pups were administered phencyclidine (10 mg/kg) or saline subcutaneously on the postnatal days p2, p6, p9 and p12. In 12-day-old pups, 4 h after the last dose of phencyclidine, the levels of glutathione, cysteine, methionine, and homocysteine, and the enzymatic activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were measured in the frontal cortex, hippocampus, and striatum. In 70-72-day-old rats, schizophrenia-like symptoms were assessed using behavioral tests.ResultsBiochemical data showed that perinatal phencyclidine treatment significantly reduced glutathione and cysteine levels in all brain structures studied, methionine was diminished in the striatum, and homocysteine in both the frontal cortex and striatum. GR activity was increased in the frontal cortex while SODactivity was decreased in the hippocampus. Behaviorally, perinatal phencyclidine induced long-term deficits in social and cognitive function and a decrease in locomotor activity assessed as the time of walking. Finally, perinatal treatment with phencyclidine resulted in a significant reduction in body weight gain over time.ConclusionOur research provides further evidence for the usefulness of the phencyclidine-induced neurodevelopmental model of schizophrenia for studying the pathogenesis of schizophrenia.

Dysregulation of Amino Acid Transporters in a Rat Model of TLR7-Mediated Maternal Immune Activation.

Maternal immune activation (MIA) during pregnancy is linked to neurodevelopmental disorders in humans. Similarly, the TLR7 agonist imiquimod alters neurodevelopment in rodents. While the mechanisms underlying MIA-mediated neurodevelopmental changes are unknown, they could involve dysregulation of amino acid transporters essential for neurodevelopment. Therefore, we sought to determine the nature of such transporter changes in both imiquimod-treated rats and human placentas during infection. Pregnant rats received imiquimod on gestational day (GD)14. Transporter expression was measured in placentas and fetal brains via qPCR (GD14.5) and immunoblotting (GD16). To monitor function, fetal brain amino acid levels were measured by HPLC on GD16. Gene expression in the cortex of female fetal brains was further examined by RNAseq on GD19. In human placentas, suspected active infection was associated with decreased ASCT1 and SNAT2 protein expression. Similarly, in imiquimod-treated rats, ASCT1 and SNAT2 protein was also decreased in male placentas, while EAAT2 was decreased in female placentas. CAT3 was increased in female fetal brains. Consistent with this, imiquimod altered amino acid levels in fetal brains, while RNAseq demonstrated changes in expression of several genes implicated in autism. Thus, imiquimod alters amino acid transporter levels in pregnant rats, and similar changes occur in human placentas during active infection. This suggests that changes in expression of amino acid transporters may contribute to effects mediated by MIA toward altered neurodevelopment.

Regional contributions of D-serine to Alzheimer's disease pathology in male AppNL-G-F/NL-G-F mice.

Neurodegenerative processes in Alzheimer's disease (AD) are associated with excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR). D-Serine is an endogenous co-agonist necessary for NMDAR-mediated excitotoxicity. In the mammalian brain, it is produced by serine racemase (SRR) from L-serine, suggesting that dysregulation of L-serine, D-serine, or SRR may contribute to AD pathogenesis. We examined the contributions of D-serine to AD pathology in the AppNL-G-F/NL-G-F gene knock-in (APPKI) mouse model of AD. We first examined brain SRR expression levels and neuropathology in APPKI mice and then assessed the effects of long-term D-serine supplementation in drinking water on neurodegeneration. To further confirm the involvement of endogenous D-serine in AD progression, we generated Srr gene-deleted APPKI (APPKI-SRRKO) mice. Finally, to examine the levels of brain amino acids, we conducted liquid chromatography-tandem mass spectrometry. Expression of SRR was markedly reduced in the retrosplenial cortex (RSC) of APPKI mice at 12 months of age compared with age-matched wild-type mice. Neuronal density was decreased in the hippocampal CA1 region but not altered significantly in the RSC. D-Serine supplementation exacerbated neuronal loss in the hippocampal CA1 of APPKI mice, while APPKI-SRRKO mice exhibited attenuated astrogliosis and reduced neuronal death in the hippocampal CA1 compared with APPKI mice. Furthermore, APPKI mice demonstrated marked abnormalities in the cortical amino acid levels that were partially reversed in APPKI-SRRKO mice. These findings suggest that D-serine participates in the regional neurodegenerative process in the hippocampal CA1 during the amyloid pathology of AD and that reducing brain D-serine can partially attenuate neuronal loss and reactive astrogliosis. Therefore, regulating SRR could be an effective strategy to mitigate NMDAR-dependent neurodegeneration during AD progression.

DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.

SUMMARYCaloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling. Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine, which are dependent on DEPDC5, a component of the GATOR1 complex. Metabolomic analysis reveals that Depdc5 neuronal-specific knockout mice are resistant to sensing significant fluctuations in brain amino acid levels after fasting. Depdc5 neuronal-specific knockout mice are resistant to the protective effects of fasting on seizures or seizure-induced death. These results establish that acute fasting reduces seizure susceptibility in a DEPDC5-dependent manner. Modulation of nutrients upstream of GATOR1 and mTORC1 could offer a rational therapeutic strategy for epilepsy treatment.

Anticancer and Neuroprotective Activities of Ethyl Acetate Fractions from Morus macroura Miq. Plant Organs with Ultraperformance Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry Profiling.

Column chromatography afforded the isolation of seven secondary metabolites (1-(2,4,6-trihydroxy phenyl)-ethanone-4-O-β-d-glucopyranoside, naringenin-7-O-β-d-glucopyranoside, kaempferol-3-O-α-l-rhamnoside, kaempferol-3-O-β-d-glucopyranoside, quercetin-3-O-β-d-glucopyranoside, quercetin-3-O-β-d-galactopyranoside, rutin) from the ethyl acetate (ET) fractions of Morus macroura Miq. stems (S), leaves (L), and fruits (F). Their identification based on ultraviolet (UV), electron ionization (EI), electrospray ionization-mass spectrometry (ESI-MS), and 1D and 2D NMR data. In addition, profiling of ET fractions using ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) resulted in the identification of 82 compounds belonging to different classes, mainly polyphenolic constituents. Chemical profiling as well as molecular docking directed us to biological evaluation. Interestingly, the ET-L fraction exhibited a robust cytotoxic activity against HepG-2, MCF-7, and HELA cell lines. Also, it displayed a neuromodulatory activity against cisplatin neurotoxicity in rats by ameliorating the neurobehavioral dysfunction visualized in the open field and Y-maze test and modulating the neurochemical parameters such as brain amino acid levels (glutamate, aspartate, serine, and histidine), oxidative stress markers (GSH, MDA, and 8-hydroxy-2′-deoxyguanosine), and purinergic cell energy (adenosine triphosphate (ATP) and adenosine monophosphate (AMP)). In conclusion, the isolated compounds (kaempferol-3-O-β-glucoside and quercetin-3-O-β-glucoside) from the ET-L fraction could serve as potent anticancer agents due to their strong antioxidant, in vitro cytotoxicity, and in vivo neuroprotective activity.

GABAB Receptor Agonist R-Baclofen Reverses Altered Auditory Reactivity and Filtering in the Cntnap2 Knock-Out Rat.

Altered sensory information processing, and auditory processing, in particular, is a common impairment in individuals with autism spectrum disorder (ASD). One prominent hypothesis for the etiology of ASD is an imbalance between neuronal excitation and inhibition. The selective GABAB receptor agonist R-Baclofen has been shown previously to improve social deficits and repetitive behaviors in several mouse models for neurodevelopmental disorders including ASD, and its formulation Arbaclofen has been shown to ameliorate social avoidance symptoms in some individuals with ASD. The present study investigated whether R-Baclofen can remediate ASD-related altered sensory processing reliant on excitation/inhibition imbalance in the auditory brainstem. To assess a possible excitation/inhibition imbalance in the startle-mediating brainstem underlying ASD-like auditory-evoked behaviors, we detected and quantified brain amino acid levels in the nucleus reticularis pontis caudalis (PnC) of rats with a homozygous loss-of-function mutation in the ASD-linked gene Contactin-associated protein-like 2 (Cntnap2) and their wildtype (WT) littermates using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (MALDI MS). Abnormal behavioral read-outs of brainstem auditory signaling in Cntnap2 KO rats were accompanied by increased levels of GABA, glutamate, and glutamine in the PnC. We then compared the effect of R-Baclofen on behavioral read-outs of brainstem auditory signaling in Cntnap2 KO and WT rats. Auditory reactivity, sensory filtering, and sensorimotor gating were tested in form of acoustic startle response input-output functions, short-term habituation, and prepulse inhibition before and after acute administration of R-Baclofen (0.75, 1.5, and 3 mg/kg). Systemic R-Baclofen treatment improved disruptions in sensory filtering in Cntnap2 KO rats and suppressed exaggerated auditory startle responses, in particular to moderately loud sounds. Lower ASR thresholds in Cntnap2 KO rats were increased in a dose-dependent fashion, with the two higher doses bringing thresholds close to controls, whereas shorter ASR peak latencies at the threshold were further exacerbated. Impaired prepulse inhibition increased across various acoustic prepulse conditions after administration of R-Baclofen in Cntnap2 KO rats, whereas R-Baclofen did not affect prepulse inhibition in WT rats. Our findings suggest that GABAB receptor agonists may be useful for pharmacologically targeting multiple aspects of sensory processing disruptions involving neuronal excitation/inhibition imbalances in ASD.

Withdrawal Effects Following Methionine Exposure in Adult Zebrafish.

Methionine (Met) has important functions for homeostasis of various species, including zebrafish. However, the increased levels of this amino acid in plasma, a condition known as hypermethioninemia, can lead to cell alterations. Met is crucial for the methylation process and its excesses interfere with the cell cycle, an effect that persists even after the removal of this amino acid. Some conditions may lead to a transient increase of this amino acid with unexplored persistent effects of Met exposure. In the present study, we investigated the behavioral and neurochemical effects after the withdrawal of Met exposure. Zebrafish were divided into two groups: control and Met-treated group (3mM) for 7days and after maintained for 8days in tanks containing only water. In the eighth day post-exposure, we evaluated locomotion, anxiety, aggression, social interaction, and memory, as well as oxidative stress parameters, amino acid, and neurotransmitter levels in the zebrafish brain. Our results showed that 8days after Met exposure, the treated group showed decreased locomotion and aggressive responses, as well as impaired aversive memory. The Met withdrawal did not change thiobarbituric acid reactive substances, reactive oxygen species, and nitrite levels; however, we observed a decrease in antioxidant enzymes superoxide dismutase, catalase, and total thiols. Epinephrine and cysteine levels were decreased after the Met withdrawal whereas carnitine and creatine levels were elevated. Our findings indicate that a transient increase in Met causes persistent neurotoxicity, observed by behavioral and cognitive changes after Met withdrawal and that the mechanisms underlying these effects are related to changes in antioxidant system, amino acid, and neurotransmitter levels.

Comparison of transitional vs surgical menopause on monoamine and amino acid levels in the rat brain.

Loss of ovarian function has important effects on neurotransmitter production and release with corresponding effects on cognitive performance. To date, there has been little direct comparison of the effects of surgical and transitional menopause on neurotransmitter pathways in the brain. In this study, effects on monoamines, monoamine metabolites, and the amino acids tryptophan (TRP) and tyrosine (TYR) were evaluated in adult ovariectomized (OVX) rats and in rats that underwent selective and gradual ovarian follicle depletion by daily injection of 4-vinylcyclohexene-diepoxide (VCD). Tissues from the hippocampus (HPC), frontal cortex (FCX), and striatum (STR) were dissected and analyzed at 1- and 6-weeks following OVX or VCD treatments. Tissues from gonadally intact rats were collected at proestrus and diestrus to represent neurochemical levels during natural states of high and low estrogens. In gonadally intact rats, higher levels of serotonin (5-HT) were detected at proestrus than at diestrus in the FCX. In addition, the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5HT in the FCX and HPC was lower at proestrus than at diestrus, suggesting an effect on 5-HT turnover in these regions. No other significant differences between proestrus and diestrus were observed. In OVX- and VCD-treated rats, changes were observed which were both brain region- and time point-dependent. In the HPC levels of norepinephrine, 5-HIAA, TRP and TYR were significantly reduced at 1 week, but not 6 weeks, in both OVX and VCD-treated rats relative to proestrus and diestrus. In the FCX, dopamine levels were elevated at 6 weeks after OVX relative to diestrus. A similar trend was observed at 1 week (but not 6 weeks) following VCD treatment. In the STR, norepinephrine levels were elevated at 1 week following OVX, and HVA levels were elevated at 1 week, but not 6 weeks, following VCD treatment, relative to proestrus and diestrus. Collectively, these data provide the first comprehensive analysis comparing the effects of two models of menopause on multiple neuroendocrine endpoints in the brain. These effects likely contribute to effects of surgical and transitional menopause on brain function and cognitive performance that have been reported.

Differences in activity levels as well as in brain amino acid levels and monoamine metabolisms, that exist between the Djungarian hamster（P. sungorus）and the Roborovskii hamster（P. roborovskii）are scarcely influenced by social isolation

Differences in activity levels as well as in brain amino acid levels and monoamine metabolisms, that exist between the Djungarian hamster（P. sungorus）and the Roborovskii hamster（P. roborovskii）are scarcely influenced by social isolation

Balancing Act: Maintaining Amino Acid Levels in the Autistic Brain

The ever-expanding number of genes that are mutated in autism is showing us how imbalances in fundamental cellular processes can lead to disease. A recent study by Tărlungeanu etal. (2016) identifies a form of ASD resulting from a failure of the brain to properly import amino acids.

Attentional performance, impulsivity, and related neurotransmitter systems in apoE2, apoE3, and apoE4 female transgenic mice.

The apolipoprotein E (apoE) genotype influences cognitive performance in humans depending on age and sex. While the detrimental role of the apoE4 isoform on spatial learning and memory has been well-established in humans and rodents, less is known on its impact on the executive functions. We aimed to evaluate the effect of apoE isoforms (apoE2, apoE3, apoE4) on visuospatial attention and inhibitory control performance in female transgenic mice, and to determine the neurochemical and neuropharmacological basis of this potential relationship. Female mice carrying apoE2, apoE3, and apoE4 were trained in the five-choice serial reaction time task (5-CSRTT). Upon a stable performance, we manipulated the inter-trial interval and the stimulus duration to elicit impulsive responding and engage attention respectively. We further performed a pharmacological challenge by administering cholinergic and GABAergic agents. Finally, we analyzed the levels of brain amino acids and monoamines by using reversed phase high-performance liquid chromatography (HPLC). ApoE4 mice showed a deficient inhibitory control as revealed by increased perseveration and premature responding. When attention was challenged, apoE4 mice also showed a higher drop in accuracy. The adverse effect of scopolamine on the task was attenuated in apoE4 mice compared to apoE2 and apoE3. Furthermore, apoE4 mice showed less dopamine in the frontal cortex than apoE2 mice. We confirmed that the apoE genotype influences attention and inhibitory control in female transgenic mice. The influence of apoE isoforms in the brain neuromodulatory system may explain the cognitive and behavioral differences attributable to the genotype.

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats.

Phenylketonuria and hyperphenylalanemia are inborn errors in metabolism of phenylalanine arising from defects in steps to convert phenylalanine to tyrosine. Phe accumulation causes severe mental retardation that can be prevented by timely identification of affected individuals and their placement on a Phe-restricted diet. In spite of many studies in patients and animal models, the basis for acquisition of mental retardation during the critical period of brain development is not adequately understood. All animal models for human disease have advantages and limitations, and characteristics common to different models are most likely to correspond to the disorder. This study established similar levels of Phe exposure in developing rats between 3 and 16 days of age using three models to produce chronic hyperphenylalanemia, and identified changes in brain amino acid levels common to all models that persist for ~16 h of each day. In a representative model, local rates of glucose utilization (CMRglc) were determined at 25-27 days of age, and only selective changes that appeared to depend on Phe exposure were observed. CMRglc was reduced in frontal cortex and thalamus and increased in hippocampus and globus pallidus. Behavioral testing to evaluate neuromuscular competence revealed poor performance in chronically-hyperphenylalanemic rats that persisted for at least 3 weeks after cessation of Phe injections and did not occur with mild or acute hyperphenylalanemia. Thus, the abnormal amino acid environment, including hyperglycinemia, in developing rat brain is associated with selective regional changes in glucose utilization and behavioral abnormalities that are not readily reversed after they are acquired.

Voluntary Exercise Prevents Oxidative Stress in the Brain of Phenylketonuria Mice.

High phenylalanine levels in phenylketonuria (PKU) have been associated with brain oxidative stress and amino acid imbalance. Exercise has been shown to improve brain function in hyperphenylalaninemia and neurodegenerative diseases. This study aimed to verify the effects of exercise on coordination and balance, plasma and brain amino acid levels, and brain oxidative stress markers in PKU mice. Twenty wild-type (WT) and 20 PAH(enu2) (PKU) C57BL/6 mice were placed in cages with (exercise, Exe) or without (sedentary, Sed) running wheels during 53 days. At day 43, a balance beam test was performed. Plasma and brain were collected for analyses of amino acid levels and the oxidative stress parameters superoxide dismutase (SOD) activity, sulfhydryl and reduced glutathione (GSH) contents, total radical-trapping antioxidant potential (TRAP), and total antioxidant reactivity (TAR). SedPKU showed poor coordination (p < 0.001) and balance (p < 0.001), higher plasma and brain phenylalanine (p < 0.001), and increased brain oxidative stress (p < 0.05) in comparison to SedWT. ExePKU animals ran less than ExeWT (p = 0.018). Although no improvement was seen in motor coordination and balance, exercise in PKU restored SOD, sulfhydryl content, and TRAP levels to controls. TAR levels were increased in ExePKU in comparison to SedPKU (p = 0.012). Exercise decreased plasma and brain glucogenic amino acids in ExePKU, but did not change plasma and brain phenylalanine in both WT and PKU. Exercise prevents oxidative stress in the brain of PKU mice without modifying phenylalanine levels. Hence, exercise positively affects the brain, demonstrating its value as an intervention to improve brain quality in PKU.

Control of protein and energy intake - brain mechanisms

The protein content of the diet has long been investigated for its influence on food behavior. High-protein diets promote satiety and reduce calorie intake, whereas results for low-protein diets are more contradictory and less established. Protein sensing might take place in the oral cavity or in the post-oral gastrointestinal tract, where specific receptors have been found. Protein signaling to the brain may act through the vagal nerve and involve gastric hormones, such as cholecystokinin and peptide YY. Other pathways are post-absorptive signaling and the direct influence of brain levels of amino acids. High-protein diet enhances the activity of brain satiety centers, mainly the nucleus of the solitary tract and arcuate nucleus, although the activity of brain reward centers might also be modified. A better understanding of the role of both homeostatic and hedonic systems is needed to fully describe the influence of protein on food intake.

Differential levels of brain amino acids in rat models presenting learned helplessness or non-learned helplessness

Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model). We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression. LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography. The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals. The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression.

Improved Amino Acid, Bioenergetic Metabolite and Neurotransmitter Profiles following Human Amnion Epithelial Cell Transplant in Intermediate Maple Syrup Urine Disease Mice

Orthotopic liver transplant (OLT) significantly improves patient outcomes in maple syrup urine disease (MSUD; OMIM: 248600), yet organ shortages point to the need for alternative therapies. Hepatocyte transplantation has shown both clinical and preclinical efficacy as an intervention for metabolic liver diseases, yet the availability of suitable livers for hepatocyte isolation is also limited. Conversely, human amnion epithelial cells (hAEC) may have utility as a hepatocyte substitute, and they share many of the characteristics of pluripotent embryonic stem cells while lacking their safety and ethical concerns. We reported that like hepatocytes, transplantation of hAEC significantly improved survival and lifespan, normalized body weight, and significantly improved branched-chain amino acid (BCAA) levels in sera and brain in a transgenic murine model of intermediate maple syrup urine disease (imsud). In the current report, we detail the neural and peripheral metabolic improvements associated with hAEC transplant in imsud mice, including amino acids associated with bioenergetics, the urea cycle, as well as the neurotransmitter systems for serotonin, dopamine, and gamma-aminobutyric acid (GABA). This stem cell therapy results in significant global correction of the metabolic profile that characterizes the disease, both in the periphery and the central nervous system, the target organ for toxicity in iMSUD. The significant correction of the disease phenotype, coupled with the theoretical benefits of hAEC, particularly their lack of immunogenicity and tumorigenicity, suggests that human amnion epithelial cells deserve serious consideration for clinical application to treat metabolic liver diseases.

Comparison of phenelzine and geometric isomers of its active metabolite, β-phenylethylidenehydrazine, on rat brain levels of amino acids, biogenic amine neurotransmitters and methylamine

Phenelzine is a monoamine oxidase (MAO) inhibitor used in treatment of depression and anxiety disorders. It also elevates brain levels of γ-aminobutyric acid (GABA) and inhibits primary amine oxidase (PrAO), an enzyme whose activity and/or expression has been reported to be increased in diabetes mellitus, Alzheimer's disease and cardiovascular disorders. Phenelzine is not only an inhibitor of, but also a substrate for, MAO and it has been suggested that an active metabolite, namely β-phenylethylidenehydrazine (PEH), is responsible for phenelzine's effects on amino acids. PEH is also a strong inhibitor of PrAO but has weak effects on MAO. PEH has a double bond and can thus exist as (E)- and (Z)-geometric isomers, but to date the two isomers have not been compared with regard to their neurochemical effects. We have investigated the effects of phenelzine, (E)- and (Z)-PEH on rat whole brain levels of amino acids, biogenic amine neurotransmitters and methylamine (an endogenous substrate of PrAO). Under the conditions used in the study, (E)- and (Z)-PEH appear to be equivalent in their neurochemical properties. Both PEH isomers and phenelzine produced marked increases in rat brain levels of GABA and alanine while decreasing brain levels of glutamine. Phenelzine increased brain levels of biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin), whereas neither PEH isomer altered levels of these neurotransmitters to a considerable extent. All three drugs significantly increased rat brain levels of methylamine, with (E)- and (Z)-PEH causing a greater increase than phenelzine. These results are discussed in relation to the possible therapeutic applications of these drugs.

Taurine Implicated in Bromocriptine Induced Hallucination: Glycine-Glutamic-Aspartic Implicated in Bromocriptine Induced Schizophrenia

Problem statement: The literature is reviewed and supports a strong anecdotal relationship between bromocriptine use and psychosis. It is well known that any interference with brain amino acid levels is likely to lead to disorder. Our previous research has shown that bromocriptine produced significant changes in the heart and kidneys amino acid contents. It has been confirmed that the brain amino acids concentrations are influenced by plasma amino acid levels. Therefore, it is the thought of interest to investigate the effect of bromocriptine, sulpiride or their combination on the brain and plasma amino acid concentrations of rat. Approach: The influence of chronic treatment with bromocriptine 20 mg kg day-1 i.p, sulpiride 20 mg kg day-1 i.p. or their combination bromocriptine 20 mg kg day-1 i.p + sulpiride 20 mg kg day-1 i.p. for 6 weeks on free amino acids in the brain and the plasma of rats were carried out. The amino acids were quantified using the LKB 4400 Amino Acid Analyzer and the Hami1ton’s amino acid calibration standards. Results: Bromocriptine significantly decreased the plasma content of glutamic acid, glycine and alanine. (p<0.05, n = 7). Sulpiride did not affect basal or bromocriptine-induced changes in the plasma amino acid concentrations. Also, results indicate that bromocriptine decreased the brain content of taurine, glycine and aspartic acid. The mean % decreases were 40±3, 55±6 and 30±4 respectively (p<0.01, n = 7). Sulpiride prevented the decreases in glycine and aspartic acid only. Conclusion: This study provided evidence for the possible involvement of some amino acids in mediating some actions of bromocriptine. Our previous results presented evidence for the antagonistic effect of taurine on some bromocriptine-induced actions that probably involve activation of 5-HT receptors. As a result, bromocriptine-induced depletion of brain taurine, which involved activation seretonergic receptors, may underlie the appearance of some side effects of bromocriptine such as hallucinations in Parkinson’s patients. Thus, bromocriptine induced hallucination is related to non dopaminergic action. Further, the results direct the attention to the possible involvement of glycine, aspartic and glutamic in bromocriptine induced schizophrenia. This study indicates that different mechanisms of the etiology of schizophrenia which are not possible based upon dopaminergic mechanism alone.

Comparison of amino add levels in brain during different anesthesias in patients undergoing coronary artery bypass grafting under CPB

Objective To compare the amino acid levels in brain during different anesthesias in patients undergoing coronary artery bypass grafting (CABG) under CPB. Methods Eighty ASA Ⅱ or Ⅲ patients aged 45-64 yr undergoing CABG under CPB were randomly divided into 2 groups (n=40 each) : group Ⅰ propefol (P) and group Ⅱ sevoflurane (S). The patients were premeditated with intransuscular morphine 0.2 mg/kg and scopolamine 0.3 mg. Anesthesia was induced with midazolam, etomidate, fentanyl and vecuronium. The patients were mechanically ventilated after tracheal intubation. Anesthesia was maintained with TCI of propofol (target plasma concentration was set at 1-2 μg/ml) in group P or sevoflurane inhalation (end-tidal concentration 0.5%-1.0% ) in group S combined with remifentanil infusion at 0.2-0.4 μg·kg-1 ·min-1 and intermittent iv boluses of vecuronium.Radial artery was cannulated for BP monitoring. Right internal jugular vein was retrogradely cannulated for blood sampling. BIS was maintained at 40-50. Blood samples were taken from right jugular bulb immediately before incision (T1), at 5 min after the beginning of CPB (T2), at 5 min after termination of cooling (T3), immediately and at 30 and 60 min after nasepharyngeal temperature was rewarmed to 37℃(T4-6) for determination of plasma concentrations of glutamic acid (Glu),γ-aminobytyric acid (GABA) and glycine (Gly). The excitatory toxicity index (ETI) was calculated. Results Glu concentration and ETI were significantly lower, GABA concentration was significantly higher at T4-6 and Gly concentration higher at T4 in group P than in group S (P<0.01).Conclusion Propofol can inhibit the release of excitatory amino acids in the brain leading to a new balance between excitatory and inhibitory amino acids. Key words: Propofol; Amino acids; Brain; Cardiopulmonary bypass; Coronary artery bypass

Fetal Down Syndrome Brains Exhibit Aberrant Levels of Neurotransmitters Critical for Normal Brain Development

In the immature developing fetal brain, amino acids (such as gamma-aminobutyric acid, and taurine) and monoamines (serotonin, noradrenaline, and dopamine) act as developmental signals or regulators. In subjects with Down syndrome, dysfunctional brain development is evident from birth as reduction in brain weight, as well as volume reductions in specific brain regions, and an altered number of neurons, dendrites, and dendritic branching is observed. However, mechanisms that underlie the observed dysfunctional brain development in Down syndrome are not clear. Because diverse amino acids and monoamines are critical for normal brain development, we wanted to determine whether dysfunctional brain development observed in subjects with Down syndrome is associated with altered brain amino acid and/or monoamine levels. We quantified tissue concentrations of diverse amino acids, including gamma-aminobutyric acid and taurine, and the monoamines serotonin, noradrenaline, and dopamine in the frontal cortex of fetal Down syndrome tissue at a gestational age of approximately 20 weeks versus age-matched control aborted fetuses. Fetal Down syndrome brains showed reductions in the levels of serotonin, gamma-aminobutyric acid, taurine, and dopamine in the frontal cortex. No alteration in the levels of arginine, aspartate, glutamine, glutamate, glycine, histidine, serine, or noradrenaline was observed. Serotonin, gamma-aminobutyric acid, taurine, and dopamine are critical for the acquisition of brain morphologic features, neuronal and glia proliferation, and synapse formation. The detected reductions in the levels of these neurotransmitters may indicate potential mechanisms for the observed dysfunctional neuronal development in the Down syndrome fetal brain.