Evidence for carrier-mediated transport of glutathione across the blood-brain barrier in the rat.

Kannan, Ram; Kuhlenkamp, John; Jeandidier, Éric; Trinh, Hoang M.; Ookhtens, Murad; Kaplowitz, Neil

doi:10.1172/jci114666

Cited by 148 publications

(97 citation statements)

References 35 publications

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“…Mouse studies have shown that NAC completely crosses the capillary wall to enter brain tissue and extracellular space, and that the amount of NAC transported across the BBB is well within the therapeutic range of CNS-active agents (Farr et al, 2003). Also, an increase of plasma GSH should increase brain GSH since the tripeptide also crosses the BBB, possibly by Na + -dependent GSH transport (Kannan et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Impairment in Consolidation of Learned Place Preference Following Dopaminergic Neurotoxicity in Mice is Ameliorated by N-acetylcysteine but not D1 and D2 Dopamine Receptor Agonists

Achat-Mendes

Anderson

Itzhak

2006

Neuropsychopharmacol

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Some of the major concerns related to methamphetamine (METH) abuse are the neuronal damage inflicted at dopamine (DA) nerve terminals and the cognitive deficits observed in human METH abusers. We have shown that a high dose of METH selectively depleted dopaminergic markers in striatum, frontal cortex and amygdala of Swiss Webster mice, and impaired learned place preference. In this study, we investigated whether deficits in consolidation of place learning, as a consequence of METH neurotoxicity, underlie the underperformance of cocaine conditioned place preference (CPP). Administration of METH (5 mg/kg Â 3) to Swiss Webster mice decreased striatal tyrosine hydroxylase (TH) immunoreactive neurons and significantly increased glial fibrillary acidic protein (GFAP) expression, confirming the neurotoxic potential of METH in mice. This treatment significantly attenuated the establishment of cocaine (15 mg/kg) CPP compared to control. To investigate whether manipulation of the consolidation phase improves learned place preference, mice were trained by cocaine and received daily post-training injections of DA receptor agonists or N-acetylcysteine (NAC). As memory consolidation occurs shortly after training, drugs were administered either immediately or 2 h post-training. Immediate posttraining administration of the D1 DA receptor agonist SKF38393 (5, 10, and 20 mg/kg) or the D2 DA receptor agonist quinpirole (0.25, 0.5, and 1.0 mg/kg) did not improve the establishment of CPP following METH neurotoxicity. However, immediate but not delayed NAC administration (50 and 100 mg/kg) enhanced cocaine CPP following METH neurotoxicity and had no effect on control CPP. The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of CPP training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls. Results suggest that METH-induced dopaminergic neurotoxicity is associated with impairment of consolidation of learned place preference, and that this impairment is improved by immediate posttraining administration of the glutathione precursor NAC and not by D1 or D2 DA receptor agonists. Restoration of brain glutathione levels immediately post-training may facilitate the consolidation process.

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Section: Discussionmentioning

confidence: 99%

Impairment in Consolidation of Learned Place Preference Following Dopaminergic Neurotoxicity in Mice is Ameliorated by N-acetylcysteine but not D1 and D2 Dopamine Receptor Agonists

Achat-Mendes

Anderson

Itzhak

2006

Neuropsychopharmacol

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“…Recent findings Brain uptake of glutathione, a tripeptide, measured by the BUI method showed saturation with a Km value of 5.8 mM, and is specific for the reduced form of glutathione, GSH. 81,82 Significant transport of GSH in intact form was also demonstrated by the brain perfusion method. 83 When mRNA obtained from brain capillaries was injected into oocytes, GSH transport activity, via both sodium-dependent and -independent mechanisms, was observed with a Km for sodium-dependent transport of 0.4 mM, demonstrating that the transporter protein is present at the BBB.…”

Section: Peptidesmentioning

confidence: 97%

Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems

Tsuji

2005

Neurotherapeutics

193

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Summary:Because of the physiological nature of the bloodbrain barrier (BBB), transport of chemical compounds between blood and brain has been widely believed to occur by means of passive diffusion, depending upon the lipophilicity of the compounds. However, discrepancies exist between the lipophilicity and apparent BBB permeation properties in many cases, and these discrepancies can be ascribed to the existence of multiple mechanisms of drug transport through the BBB. Molecular identification and functional analysis of influx transport proteins (from blood to brain) and efflux transport proteins (from brain to blood) have progressed rapidly. Therefore, the BBB is now considered to be a dynamic interface that controls the influx and efflux of a wide variety of substances, including endogenous nutrients and exogenous compounds such as drugs, to maintain a favorable environment for the CNS. This review focuses on the role of transport systems in the uptake of xenobiotics, including organic anionic/cationic and neutral drugs, across the BBB into the brain, as well as on strategies to increase drug delivery into the brain by blocking efflux transport protein function, or to reduce CNS side effects by modulating BBB transport processes.

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“…There is a carrier mediated transport of GSH across the BBB (Kannan et al 1990), but it is found to be of low capacity (Cornford et al 1978). Indeed, brain extraction of radiolabeled GSH after intracarotid injection was only 0.5% (Cornford et al 1978).…”

Section: Discussionmentioning

confidence: 99%

Characterization of intracellular elevation of glutathione (GSH) with glutathione monoethyl ester and GSH in brain and neuronal cultures: Relevance to Parkinson's disease

Zeevalk

Manzino

Sonsalla

et al. 2007

Experimental Neurology

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Parkinson's disease (PD) is associated with loss of total glutathione (GSH) which may contribute to progressive cell death. Peripheral GSH administration has been used clinically with reported benefits. Despite this, there is little specific information to characterize its cellular uptake or clearance, brain elevation with peripheral delivery or neuroprotective efficacy in PD models. The current study was carried out to provide this information using in vitro and in vivo approaches. In rat mesencephalic culture, the monoethyl-ester of GSH (GEE), but not GSH (1-10mM, 24hr) produced a dosedependent elevation in GSH. The half-life for clearance was 10.14hr and was not different in cells depleted of GSH prior to loading. Elevation of GSH with GEE protected neurons from oxidative stress with H 2 O 2 or metabolic stress with the complex I and II inhibitors, MPP + and malonate, respectively. To determine if peripheral administration of GEE could elevate brain GSH levels, rats were administered 0.1-50mg/kg/d GEE via osmotic minipump either subcutaneously (sc) or via a cannula placed into the left cerebral ventricle (icv) for 28d. Only central delivery of GEE resulted in significant elevations of brain GSH. Elevation of brain GSH by icv infusion of GEE was examined for its neuroprotective effects against chronic central delivery of MPP + . Infusion of 0.142mg/kg/d MPP + for 28d caused a selective ipsilateral loss of striatal dopamine. Co-infusion of MPP + with 10mg/kg/d GEE significantly protected against striatal dopamine loss. These findings show that the ethyl ester of GSH but not GSH per se can elevate intracellular GSH, that brain elevation of GSH requires central delivery of the ethyl-ester and that this elevation provides neuroprotection against oxidative stress or chronic mitochondrial impairment. Keywords oxidative stress; glutathione ethyl ester; neurodegeneration; neuroprotectionThe underlying etiology of sporadic Parkinson's disease (PD) remains elusive, although much evidence implicates oxidative stress in the process. The substantia nigra (SN) from autopsied brain material has been shown to contain increased levels of protein carbonyls (Alam et al. 1997), malondialdehyde or 4-hydroxynonenol (Dexter et al. 1994a;Yoritaka et al. 1996) and 8-hydroxy-2-deoxyguanosine (Sanchez-Ramos et al. 1994), indicative of oxidative damage to proteins, lipids and DNA, respectively. One of the earliest biochemical derangements observed in the SN of patients with PD is loss of total glutathione levels (Perry & Yong 1986; Corresponding Author: Gail D. Zeevalk, zeevalgd@umdnj.edu, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, Building UBHC, Rm 405D, 675, Hoes Lane, Piscataway, N.J. 08854, Phone: 732 235-3494, Fax: 732 235-5295 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting p...

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Evidence for carrier-mediated transport of glutathione across the blood-brain barrier in the rat.

Cited by 148 publications

References 35 publications

Impairment in Consolidation of Learned Place Preference Following Dopaminergic Neurotoxicity in Mice is Ameliorated by N-acetylcysteine but not D1 and D2 Dopamine Receptor Agonists

Impairment in Consolidation of Learned Place Preference Following Dopaminergic Neurotoxicity in Mice is Ameliorated by N-acetylcysteine but not D1 and D2 Dopamine Receptor Agonists

Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems

Characterization of intracellular elevation of glutathione (GSH) with glutathione monoethyl ester and GSH in brain and neuronal cultures: Relevance to Parkinson's disease

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