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Neuroscience 2009 Conference Paper on Glutathione


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Title: Liposomal glutathione for replenishment and maintenance of intracellular glutathione in mesencephalic cultures

 Presentation: Oct 18, 2009 @ Society for Neuroscience Annual Meeting

 Authors: *G. ZEEVALK1, F. T. GUILFORD2, L. P. BERNARD1;
1UMDNJ RW Johnson Med. School, Piscataway, NJ; 2Your Energy Systems, LLC, Palo Alto, CA

 Abstract: Glutathione (GSH) is the major small molecule thiol antioxidant in all cells including the brain. Alterations in GSH are implicated in a number of neuropathological and neurodegenerative conditions including Parkinson’s disease, autism, schizophrenia and HIV. Maintenance and/or repletion of intracellular GSH in neuronal cells may, therefore, be of neuroprotective benefit for a variety of pathological conditions. Here we studied a liposomal formulation of GSH consisting of reduced GSH encapsulated in lipid vesicles consisting of hydroxylated lecithin, glycerin and potassium sorbate for its ability to replenish intracellular levels of GSH in mixed neuronal and glial mesencephalic cultures. Mesencephalic cultures contain presumptive midbrain dopamine neurons which are the neurons that degenerate in Parkinson’s disease. Cultures were transiently depleted of GSH by 60% with a 30min pretreatment with diethyl maleate. Repletion of intracellular GSH was followed over 4 hr in a Krebs Ringer containing either no additives, GSH amino acid substrates glutamine, cysteine and glycine (for optimal repletion) or various concentrations of non-liposomal GSH (non-L-GSH) or liposomal-GSH (L-GSH). No repletion of GSH was observed in the absence of additives, whereas precursor amino acids, L-GSH and non-L-GSH fully restored intracellular GSH to control levels by 4 hr. L-GSH was 100-fold more potent than non-L-GSH in replenishing intracellular GSH (4.75uM vs 533uM for L-GSH and non-L-GSH, respectively). Blockade of GSH biosynthesis with buthionine sulfoximine (10uM) completely prevented replenishment by L-GSH indicating that hydrolysis and resynthesis was required for utilization. Preliminary studies with acivicin, an inhibitor of the ecto-enzyme γ-glutamyl transpeptidase, which metabolizes GSH in the extracellular milleiu, did not prevent repletion, whereas, 3-methyladenine, an inhibitor of autophagy showed partial inhibition of repletion by L-GSH. These findings suggest that L-GSH is not metabolized extracellularly and may be taken up by the endosomal system for hydrolysis and intracellular supply of precursor amino acids. Additional studies are being conducted to determine if L-GSH replenishes GSH specifically in neurons and if it can provide protection from oxidative challenge. While it remains to be investigated whether L-GSH can gain entry to the CNS, studies in neuronal cultures in vitro demonstrate its utility for maintenance and/or repletion of GSH in neuronal cells with high potency. L-GSH may thus offer promise as a means for brain maintenance of GSH in conditions where perturbation of GSH has been implicated in disease etiology.