Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria

Glushakov, Alexander V.; Dennis, Donn M.; Morey, Timothy E.; Sumners, Colin; Cucchiara, Roy F.; Seubert, Christoph N.; Martynyuk, Anatoly E.

doi:10.1038/sj.mp.4000976

Cited by 39 publications

(40 citation statements)

References 32 publications

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“…This action of L-Phe is unique in that 3 distinct mechanisms combine to mediate depression of glutamatergic synaptic transmission (GST): (1) competition for the glycine-binding site of N-methyl-D-aspartate receptors (NMDARs); (2) competition for the glutamate-binding site of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors (non-NMDARs); and (3) attenuation of glutamate release. 7,8 Furthermore, as observed in patients with phenylketonuria or in experiments with neuronal cultures, temporary increases in the concentration of L-Phe are not likely to cause permanent changes in neuronal and brain function. [7][8][9] The objectives of the present study were 2-fold.…”

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confidence: 99%

“…7,8 Furthermore, as observed in patients with phenylketonuria or in experiments with neuronal cultures, temporary increases in the concentration of L-Phe are not likely to cause permanent changes in neuronal and brain function. [7][8][9] The objectives of the present study were 2-fold. First, to identify endogenous derivatives of L-Phe that exhibit a similar pattern of antiglutamatergic activity, but are more potent.…”

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confidence: 99%

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Neuroprotective Action of Halogenated Derivatives of L-Phenylalanine

Kagiyama

Glushakov

Sumners

et al. 2004

Stroke

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Background and Purpose-The aromatic amino acid L-Phenylalanine (L-Phe) significantly and reversibly depresses excitatory glutamatergic synaptic transmission (GST) via a unique set of presynaptic and postsynaptic mechanisms. Therefore, we hypothesized that endogenous derivatives of L-Phe, which display potent antiglutamatergic activity, may safely and efficaciously protect the brain during conditions characterized by overactivation of glutamate receptors. Methods-We tested this hypothesis in vitro with a combination of patch-clamp and lactate dehydrogenase (LDH) analyses in rat cultured neurons exposed to simulated ischemia, and in vivo using a rat model of experimental stroke caused by transient middle cerebral artery occlusion (MCAO). Results-3,5-diiodo-L-tyrosine (DIT) and 3,5-dibromo-L-tyrosine (DBrT), endogenous halogenated derivatives of L-Phe, attenuated GST by similar mechanisms as L-Phe, but with greater potency. For example, the IC 50 s for DIT and DBrT to depress the frequency of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptormediated mEPSCs were 104.6Ϯ14.1 mol/L and 127.5Ϯ13.3 mol/L, respectively. Depression of GST by DIT and DBrT persisted during energy deprivation. Furthermore, DBrT significantly reduced LDH release in neuronal cultures exposed to oxygen glucose deprivation. In rats subjected to transient MCAO, DBrT decreased the brain infarct volume and neurological deficit score to 52.7Ϯ14.1% and 57.1Ϯ12.0% of control values, respectively. DBrT neither altered atrioventricular nodal and intraventricular conduction in isolated heart, nor heart rate and blood pressure in vivo. Conclusion-DBrT, an endogenous halogenated derivative of L-Phe, shows promise as a representative of a novel class of neuroprotective agents by exerting significant neuroprotection in both in vitro and in vivo models of brain ischemia.

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confidence: 99%

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confidence: 99%

Neuroprotective Action of Halogenated Derivatives of L-Phenylalanine

Kagiyama

Glushakov

Sumners

et al. 2004

Stroke

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“…The binding sites for glycine and glutamate are located on subunits 1 and 2, respectively (Laube et al, 1997). Previously, we have demonstrated that L-Phe depressed NMDA receptor function by competing for the glycine-binding site of NMDA receptors and depressed non-NMDA receptor activity by competing for the glutamatebinding site of these receptors (Glushakov et al, 2002(Glushakov et al, , 2003. Similar to L-Phe, 3,5-DBr-L-Phe also is a competitive antagonist of AMPA/kainate receptors.…”

Section: Discussionmentioning

confidence: 94%

“…During investigation of the cellular mechanisms of brain dysfunction seen in phenylketonuria, we found that L-Phe selectively depresses glutamatergic synaptic transmission by a combination of pre-and postsynaptic actions (Glushakov et al, 2002(Glushakov et al, , 2003. Specifically, L-Phe depresses glutamatergic synaptic transmission by 1) competing for the glycine-binding site of NMDA receptors, 2) competing for the glutamate-binding site of AMPA/kainate receptors, and 3) attenuating glutamate release.…”

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confidence: 99%

Differential Modulation of Glutamatergic Transmission by 3,5-Dibromo-L-phenylalanine

Yarotskyy

Glushakov²,

Sumners³

et al. 2005

Molecular Pharmacology

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An increasing body of evidence supports the hypothesis that diminished function of N-methyl-D-aspartate (NMDA) receptors and the associated increase in glutamate release and overstimulation of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors are critical elements of the pathophysiology of schizophrenia. Here, we describe a halogenated derivative of the aromatic amino acid L-phenylalanine that 1) activates NMDA receptors, 2) depresses presynaptic glutamate release, and 3) blocks AMPA/kainate receptors. The experiments were conducted in rat cerebrocortical cultured neurons by using the patch-clamp technique. 3,5-Dibromo-Lphenylalanine (3,5-DBr-L-Phe) augmented NMDA miniature excitatory postsynaptic currents (mEPSCs) and activated the steady-state current, effects that were eliminated by NMDA receptor antagonists DL-2-amino-5-phosphonopentanoic acid and MK-801 (dizocilpine maleate; 5H-dibenzo

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“…Moreover, some neurotransmitters such as serotonin and dopamine were deficient in PKU animal models (9). Glushakov et al (10) found that a high concentration of phenylalanine attenuated NMDA-activated currents in cultured hippocampal neurons. In vivo 31 P-MRS demonstrated abnormalities of cerebral energy metabolism in PKU, indicating a link between phenylalanine neurotoxicity and imbalances of cerebral energy metabolism (11).…”

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confidence: 99%

Differential Effects of Phenylalanine on Rac1, Cdc42, and RhoA Expression and Activity in Cultured Cortical Neurons

Zhang

Yuan

et al. 2007

Pediatr Res

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Phenylketonuria (PKU) is characterized by a high concentration of phenylalanine, which can lead to mental retardation. One of the characteristic pathologic changes in untreated phenylketonuria patients is a reduction in the number of axons, dendrites, and synapses in the brain. This is thought to be due to the toxic effects of phenylalanine and/or its metabolites, however, the underlying mechanism remains unclear. In this study, we observed that phenylalanine reduced the number of dendrites and dendritic spines in cultured neurons. We further demonstrated that phenylalanine down-regulated Rac1, Cdc42, and RhoA mRNA and protein expression. Pull-down assays indicated that phenylalanine caused a decrease in Rac1/Cdc42 activity but increased RhoA activity. Expression of a dominant negative RhoA or treatment with a Rho-associated kinase specific inhibitor, Y-27632, partly inhibited the phenylalanine-induced decrease in dendrite numbers. In conclusion, we have demonstrated that phenylalanine affects the expression and activity of Rac1, Cdc42, and RhoA. Furthermore, RhoA signaling is involved in the inhibitory effect of phenylalanine on dendritic branching. These results may provide an important insight into the molecular mechanism underlying phenylalanine-induced abnormalities of dendrites, specifically in phenylketonuria neuronal injury. (Pediatr Res 62: 8-13, 2007) P henylketonuria (PKU) is one of the most frequent inborn disorders of amino acid metabolism. It is caused by a deficiency in phenylalanine hydroxylase (PAH), resulting in an accumulation of its upstream metabolite phenylalanine, mainly in brain tissue and the cerebrospinal fluid of PKU patients. Phenylalanine interferes with brain development and results in severe MR, microcephaly, epilepsy, and behavioral problems. These symptoms appear to be the direct consequence of neuronal cell loss, white matter abnormalities, dendritic simplification, and synaptic density reduction (1-5). Previous studies demonstrated that phenylalanine reduced Naϩ, Kϩ-ATPase and creatine kinase activity in rat brain (6 -8). Moreover, some neurotransmitters such as serotonin and dopamine were deficient in PKU animal models (9). Glushakov et al. (10) found that a high concentration of phenylalanine attenuated NMDA-activated currents in cultured hippocampal neurons. In vivo 31 P-MRS demonstrated abnormalities of cerebral energy metabolism in PKU, indicating a link between phenylalanine neurotoxicity and imbalances of cerebral energy metabolism (11). Lately, Horster et al. (5) revealed that phenylalanine reduced synaptic density and simultaneously inhibited pyruvate kinase in mixed cortical cultures. Our laboratory reported that phenylalanine and its metabolites caused neuronal cell apoptosis in vitro (12,13). Although these observations demonstrate that phenylalanine is probably the main causative agent of brain injury in PKU, the pathophysiological mechanisms of its actions in brain injury are multiple and not fully understood.As dendrites are the site of most synaptic c...

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Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria

Cited by 39 publications

References 32 publications

Neuroprotective Action of Halogenated Derivatives of L-Phenylalanine

Neuroprotective Action of Halogenated Derivatives of L-Phenylalanine

Differential Modulation of Glutamatergic Transmission by 3,5-Dibromo-L-phenylalanine

Differential Effects of Phenylalanine on Rac1, Cdc42, and RhoA Expression and Activity in Cultured Cortical Neurons

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