Stereospecificity of blood-brain barrier permeability to amino acids

Oldendorf, WH

doi:10.1152/ajplegacy.1973.224.4.967

Cited by 155 publications

(67 citation statements)

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“…Not surprisingly, system L is considered a major carrier of large neutral amino acids into the substance of the brain. In addition, this transporter has a broad substrate-specificity (Oldendorf, 1973), which may allow it to utilize CH 3 Hg-S-Cys as a substrate. Indeed, in vivo studies in rats (Kerper et al, 1992) and in vitro studies utilizing primary cultures of rat astrocytes (Aschner et al, 1990(Aschner et al, , 1991 provided evidence that CH 3 Hg-S-Cys is a transportable substrate of system L. The involvement of this transporter in the uptake of CH 3 Hg-S-Cys was also demonstrated in another study utilizing cultured endothelial cells from the brain (Mokrzan et al, 1995).…”

Section: Molecular Mimicry and The Transport Of Ch 3 Hg + In Brainmentioning

confidence: 99%

Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

677

460

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Despite many scientific advances, human exposure to, and intoxication by, toxic metal species continues to occur. Surprisingly, little is understood about the mechanisms by which certain metals and metal-containing species gain entry into target cells. Since there do not appear to be transporters designed specifically for the entry of most toxic metal species into mammalian cells, it has been postulated that some of these metals gain entry into target cells, through the mechanisms of ionic and/or molecular mimicry, at the site of transporters of essential elements and/or molecules. The primary purpose of this review is to discuss the transport of selective toxic metals in target organs and provide evidence supporting a role of ionic and/or molecular mimicry. In the context of this review, molecular mimicry refers to the ability of a metal ion to bond to an endogenous organic molecule to form an organic metal species that acts as a functional or structural mimic of essential molecules at the sites of transporters of those molecules. Ionic mimicry refers to the ability of a cationic form of a toxic metal to mimic an essential element or cationic species of an element at the site of a transporter of that element. Molecular and ionic mimics can also be sub-classified as structural or functional mimics. This review will present the established and putative roles of molecular and ionic mimicry in the transport of mercury, cadmium, lead, arsenic, selenium, and selected oxyanions in target organs and tissues.

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Section: Molecular Mimicry and The Transport Of Ch 3 Hg + In Brainmentioning

confidence: 99%

Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

677

460

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“…D-Serine is moderately better than glycine in penetrating the blood-brain barrier when administered systemically (Oldendorf 1973). In our in vivo studies, we tested whether the GlyB site of the NMDA receptor in the PFC was saturated by using the GlyB site agonist D-serine to probe at this issue.…”

Section: Effects Of D-serine and Nfps On Iontophoretic Nmda-evoked Exmentioning

confidence: 99%

“…One therapeutic strategy is to administer daily a large glycine dose (e.g., in grams per day, due to its poor CNS penetrance) (Oldendorf 1973), or GlyB site agonist D-serine, or a partial agonist cycloserine. These treatment approaches led to reported improvement of neuropsychiatric symptoms, presumably via potentiation of NMDA-R functions (Goff et al 1999;Heresco-Levy and Javitt 1999;Javitt et al 1994;Tsai et al 1998Tsai et al , 1999.…”

Section: Introductionmentioning

confidence: 99%

Glycine Tranporter-1 Blockade Potentiates NMDA-Mediated Responses in Rat Prefrontal Cortical Neurons In Vitro and In Vivo

Chen

Muhlhauser

Yang

2003

Journal of Neurophysiology

218

149

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Chen, Long, Mark Muhlhauser, and Charles R. Yang. Glycine tranporter-1 blockade potentiates NMDA-mediated responses in rat prefrontal cortical neurons in vitro and in vivo. J Neurophysiol 89: 691-703, 2003. First published October 30, 2002 10.1152/jn.00680. 2002 receptor (NMDA-R) has pivotal roles in neural development, learning, memory, and synaptic plasticity. Functional impairment of NMDA-R has been implicated in schizophrenia. NMDA-R activation requires glycine to act on the glycine-B (GlyB) site of the NMDA-R as an obligatory co-agonist with glutamate. Extracellular glycine near NMDA-R is regulated effectively by a glial glycine transporter (GlyT1). Using whole-cell voltage-clamp recordings in prefrontal cortex (PFC) slices, we have shown that exogenous GlyB site agonists glycine and D-serine, or a specific GlyT1 inhibitor N[3-(4Ј-fluorophenyl)-3-(4Ј-phenylphenoxy)-propyl]sarcosine (NFPS) in the presence of exogenous glycine (10 M), potentiated synaptically evoked NMDA excitatory postsynaptic currents (EPSCs) in vitro. Furthermore, in urethan-anesthetized rats, microiontophoretic NMDA pulses excite single PFC neurons. When these responses were blocked by approximately 50% to approximately 90% on continuous iontophoretic application of the GlyB site, antagonist (ϩ)HA-966, intravenous NFPS (5 mg/kg), or a GlyB site agonist D-serine (50 mg/kg iv) reversed this (ϩ)HA-966 block. NFPS may elevate endogenous glycine levels sufficiently to displace (ϩ)HA-966 from the GlyB sites of the NMDA-R, thus enabling reactivation of the NMDA-Rs by iontophoretic NMDA applications. D-Serine (50 -100 mg/kg iv) or NFPS (1-2 mg/kg iv) alone also augmented NMDAevoked excitatory responses. These data suggest that direct GlyB site stimulation by D-serine, or blockade of GLYT1 to elevate endogenous glycine to act on unsaturated GlyB sites on NMDA-Rs, potentiated NMDA-R-mediated firing responses in rat PFC. Hence, blockade of GlyT1 to elevate glycine near the NMDA-R may activate hypofunctional NMDA-R, which has been implicated to play a critical role in the pathophysiology of schizophrenia.

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“…An alternative intervention, tyrosine-phenylalanine depletion (TPD), entails ingestion of an amino-acid beverage lacking catecholamine precursor L-tyrosine (Tyr) as well as L-phenylalanine (Phe), which is peripherally converted into Tyr by phenylalanine hydroxylase. Large neutral amino acids (LNAAs) compete with Tyr for CNS uptake (Oldendorf, 1973) and stimulate hepatic protein synthesis to incorporate extant Tyr into proteins (Harper et al, 1970). This markedly lowers concentrations of Tyr in the plasma (Moja et al, 1996;Palmour et al, 1998) as well as catecholamine metabolites in the CSF (Palmour et al, 1998) and striatum (Biggio et al, 1976) within hours.…”

Section: Introductionmentioning

confidence: 99%

Dietary Tyrosine/Phenylalanine Depletion Effects on Behavioral and Brain Signatures of Human Motivational Processing

Bjork

Grant

Chen

et al. 2013

Neuropsychopharmacol

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Dopamine (DA) neurotransmission is critical for motivational processing. We assessed whether disruption of DA synthesis in healthy controls using an amino-acid beverage devoid of catecholamine precursors (tyrosine-phenylalanine depletion (TPD)) would blunt recruitment of the nucleus accumbens (NAcc) by rewards. Sixteen controls ingested each of a tyr/phe-depleting beverage (DEP) or a tyr/ phe-balanced (BAL) control beverage in two laboratory visits. Five hours after consumption of each drink, subjects underwent functional magnetic resonance imaging while they viewed anticipatory cues to respond to a target to either win money or avoid losing money. TPD did not exert main effects on mood or on task behavior, but affected brain activation. In right NAcc, TPD blunted activation by anticipation of high rewards. In left NAcc, recruitment anticipating high rewards was modulated by individual differences in mood change across the DEP drink day, where subjects whose mood worsened following TPD (relative to within-day mood change under BAL conditions) also showed lower activation under DEP conditions relative to BAL conditions. Exploratory analysis indicated that TPD qualitatively blunted the voxel-wise spatial extent of suprathreshold activation by reward anticipation. Finally, loss outcomes activated anterior insula under DEP conditions but not under BAL conditions. These data indicate that: (1) dietary depletion of catacholamine precursors will blunt dopaminergic mesolimbic activity, and (2) in controls, synthetic pathways of this neurocircuitry maintain sufficient buffering capacity to resist an effect on motivated behavior. Additional studies are needed to determine if clinical populations would show similar resistance to behavioral effects of TPD.

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Stereospecificity of blood-brain barrier permeability to amino acids

Cited by 155 publications

References 0 publications

Molecular and ionic mimicry and the transport of toxic metals

Molecular and ionic mimicry and the transport of toxic metals

Glycine Tranporter-1 Blockade Potentiates NMDA-Mediated Responses in Rat Prefrontal Cortical Neurons In Vitro and In Vivo

Dietary Tyrosine/Phenylalanine Depletion Effects on Behavioral and Brain Signatures of Human Motivational Processing

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