We thank Dr. R. Milner from the Wellcome/CRC Institute of Cambridge (U.K.) for critical reading of the manuscript. We are also grateful to Dr. Y. Laperche from the Unité INSERM 99, Créteil (France), Dr. X. T. Do from the Laboratory of Biochemistry of the Faculty of Pharmacy of Angers (France), and Prof. P. Allain from the Laboratory of Toxicology-Pharmacology of the Centre Hospitalier Universitaire of Angers (France). Funds were provided by the Institut National de la Santé et de la Recherche Médicale (INSERM). E.G. was a postdoctoral fellow supported by the Association pour la Recherche sur la Sclérose en Plaques (ARSEP).

  • 1
    Ahmad S., Okine L., Wood R., Aljian J., Vistica D.T. (1987) Gamma-glutamyl transpeptidase (gamma-GT) and maintenance of thiol pools in tumor cells resistant to alkylating agents.J. Cell. Physiol. 131,240246.
  • 2
    Alexianu M.E., Robbins E., Carswell S., Appel S.H. (1998) 1α,25-Dihydroxyvitamin D3-dependent up-regulation of calcium-binding proteins in motoneuron cells. J. Neurosci. Res. 51,5866.
  • 3
    Auffray C. & Rougeon F. (1980) Purification of mouse immunoglobulin heavy chain messenger RNAs for total myeloma tumor RNA.Eur. J. Biochem. 107,303314.
  • 4
    Back S.E., Gan X., Li Y., Rosenberg P.A., Volpe J.J. (1998) Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion.J. Neurosci. 18,62416253.
  • 5
    Bains J.S. & Shaw C.A. (1997) Neurodegenerative disorders in humans : the role of glutathione in oxidative stress-mediated neuronal death.Brain Res. Rev. 25,335358.
  • 6
    Bidmon H.J., Mayerhofer A., Heiss C., Bartke A., Stumpf W.E. (1991) Vitamin D (soltriol) receptors in the choroid plexus and ependyma : their species-specific presence.Mol. Cell. Neurosci. 2,145156.
  • 7
    Black K.L., Baba T., Pardridge W.M. (1994) Enzymatic barrier protects brain capillaries from leukotriene C4.J. Neurosurg. 81,745751.
  • 8
    Cai J., Huang Z.Z., Lu S.C. (1997) Differential regulation of gamma-glutamylcysteine synthetase heavy and light subunit gene expression.Biochem. J. 326,167172.
  • 9
    Cantorna M.T., Woodward W.D., Hayes C.E., DeLuca H.F. (1998) 1,25-Dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4.J. Immunol. 160,53145319.
  • 10
    Cooper A.J. & Kristal B.S. (1997) Multiple roles of glutathione in the central nervous system.Biol. Chem. 378,793802.
  • 11
    Damier P., Hirsch E.C., Zhang P., Agid Y., Javoy-Agid F. (1993) Glutathione peroxidase, glial cells and Parkinson's disease.Neuroscience 52,16.
  • 12
    Dawson V.L. & Dawson T.M. (1996) Nitric oxide neurotoxicity.J. Chem. Neuroanat. 10,179190.
  • 13
    Dehouck M., Méresse S., Delorme P., Fruchart J., Cecchelli R. (1990) An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro.J. Neurochem. 54,17981801.
  • 14
    Devesa A., O'Connor J.E., Garcia C., Puertes I.R., Vina J.R. (1993) Glutathione metabolism in primary astrocyte cultures : flow cytometric evidence of heterogeneous distribution of GSH content.Brain Res. 618,181189.
  • 15
    Ding A.H., Nathan C.F., Stuehr D. (1988) Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages.J. Immunol. 141,24072412.
  • 16
    Do K.Q., Benz B., Grima G., Gutteck-Amsler U., Kluge I., Salt T.E. (1996) Nitric oxide precursor arginine and S-nitrosoglutathione in synaptic and glial function. Neurochem. Int. 29,213224.
  • 17
    Dringen R., Kranich O., Löschmann P.A., Hamprecht B. (1997) Use of dipeptides for the synthesis of glutathione by astroglia-rich primary cultures.J. Neurochem. 69,868874.
  • 18
    Dringen R., Hamprecht B., Bröer S. (1998) The peptide transporter PepT2 mediates the uptake of the glutathione precursor CysGly in astroglia-rich primary cultures.J. Neurochem. 71,388393.
  • 19
    Dringen R., Pfeiffer B., Hamprecht B. (1999) Synthesis of the antioxidant glutathione in neurons : supply by astrocytes of Cys-Gly as precursor for neuronal glutathione.J. Neurosci. 19,562569.
  • 20
    Favilli F., Marraccini P., Iantomasi T., Vincenzini M.T. (1997) Effect of orally administered glutathione on glutathione levels in some organs of rats : role of specific transporters.Br. J. Nutr. 78,293300.
  • 21
    Fort P., Marty L., Piechaczyk M., Sabrouty S., Dani C., Jeanteur P., Blanchard J.M. (1985) Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family.Nucleic Acids Res. 13,14311442.
  • 22
    Furman I., Baudet C., Brachet P. (1996) Differential expression of M-CSF, LIF, and TNF-alpha genes in normal and malignant rat glial cells : regulation by lipopolysaccharide and vitamin D.J. Neurosci. Res. 46,360366.
  • 23
    Galea E., Reis D.J., Feinstein D.L. (1994) Cloning and expression of inducible nitric oxide synthase from rat astrocytes.J. Neurosci. Res. 37,406414.
  • 24
    Garcion E., Do Thanh X., Bled F., Teissier E., Dehouck M.P., Rigault F., Brachet P., Girault A., Torpier G., Darcy F. (1996) 1,25-Dihydroxyvitamin D3 regulates gamma glutamyl transpeptidase activity in rat brain.Neurosci. Lett. 216,183186.
  • 25
    Garcion E., Nataf S., Bérod A., Darcy F., Brachet P. (1997) 1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis.Mol. Brain Res. 45,255267.
  • 26
    Garcion E., Sindji L., Montero-Menei C., André C., Brachet P., Darcy F. (1998) Expression of inducible nitric oxide synthase during rat brain inflammation : regulation by 1,25-dihydroxyvitamin D3.Glia 22,282294.
  • 27
    Gascon-Barré M. & Huet P.M. (1983) Apparent [3H]1,25-dihydroxyvitamin D3 uptake by canine and rodent brain.Am. J. Physiol. 244,E266E271.
  • 28
    Halliwell B. (1992) Reactive oxygen species and the central nervous system.J. Neurochem. 59,16091623.
  • 29
    Hogg N., Singh R.J., Kalyanaraman B. (1996) The role of glutathione in the transport and catabolism of nitric oxide.FEBS Lett. 382,223228.
  • 30
    Huang J. & Philbert M.A. (1995) Distribution of glutathione and glutathione-related enzyme systems in mitrochondria and cytosol of cultured cerebellar astrocytes and granule cells.Brain Res. 680,1622.
  • 31
    Jain A., Martensson J., Stole E., Auld P.A., Meister A. (1991) Glutathione deficiency leads to mitochondrial damage in brain.Proc. Natl. Acad. Sci. USA 88,19131917.
  • 32
    Kang Y., Oiao X., Jurma O., Knusel B., Andersen J.K. (1997) Cloning/brain localization of mouse glutamylcysteine synthetase heavy chain mRNA.Neuroreport 8,20532060.
  • 33
    Kannan R., Yi J.R., Tang D., Li Y., Zlokovic B.V., Kaplowitz N. (1996) Evidence for the existence of a sodium-dependent glutathione (GSH) transporter. Expression of bovine brain capillary mRNA and size fractions in Xenopus laevis oocytes and dissociation from gamma-glutamyltranspeptidase and facilitative GSH transporters.J. Biol. Chem. 271,97549758.
  • 34
    Laperche Y., Guellaen G., Barouki R., Hanoune J. (1990) Biosynthesis and regulation of γ-glutamyl transpeptidase, in Handbook of Glutathione, Metabolism and Physiological Functions, Vol. 1 (Visa J., ed), pp. 7990. CRC Press, Boca Raton, Florida.
  • 35
    Lucas J.H., Debra G., Wheeler B.S., Dennis G., Mallery S.R. (1998) The endogenous antioxidant glutathione as a factor in the survival of physically injured mammalian spinal cord neurons.J. Neuropathol. Exp. Neurol. 57,937954.
  • 36
    Makar T.K., Nedergaard M., Preuss A., Gelbard A.S., Perumal A.S., Cooper A.J. (1994) Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons : evidence that astrocytes play an important role in antioxidative processes in the brain.J. Neurochem. 62,4553.
  • 37
    Maniatis T., Fritsch E.F., Sambrook J. (1982) Molecular Cloning : A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
  • 38
    Martin J. & White I.N. (1991) Fluorometric determination of oxidised and reduced glutathione in cells and tissues by high-performance liquid chromatography following derivatization with dansyl chloride.J. Chromatogr. 568,219225.
  • 39
    Matsumoto Y., Ohmori K., Fujiwara M. (1992) Microglial and astroglial reactions to inflammatory lesions of experimental autoimmune encephalomyelitis in the rat central nervous system.J. Neuroimmunol. 37,2333.
  • 40
    McKhann G.M.II, D'Ambrosio R., Janigro D. (1997) Heterogeneity of astrocyte resting membrane potentials and intercellular coupling revealed by whole-cell and gramicidin-perforated patch recordings from cultured neocortical and hippocampal slice astrocytes.J. Neurosci. 17,68506863.
  • 41
    Meister A. (1988) Glutathione metabolism and its selective modification.J. Biol. Chem. 263,1720517208.
  • 42
    Mercier T., Chaumontet C., Gaillard-Sanchez I., Martel P., Heberden C. (1996) Calcitriol and Lexicalcitol (KH1060) inhibit the growth of human breast adenocarcinoma cells by enhancing transforming growth factor-β production.Biochem. Pharmacol. 52,505510.
  • 43
    Merrill J.E., Ignarro L.J., Sherman M.P., Melinek J., Lane T.E. (1993) Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide.J. Immunol. 151,21322141.
  • 44
    Mitrovic B., Ignarro L.J., Vinters H.V., Akers M.A., Schmid I., Uittenbogaart C., Merrill J.E. , (1995) Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes.Neuroscience 65,531539.
  • 45
    Morgenstern K., Hanson-Painton O., Wang B.L., De Bault L. (1992) Density-dependent regulation of cell surface gamma-glutamyl transpeptidase in cultured glial cells.J. Cell. Physiol. 150,104115.
  • 46
    Nataf S., Garcion E., Darcy F., Chabannes D., Muller J.Y., Brachet P. (1996) 1,25-Dihydroxyvitamin D3 exerts regional effects in the central nervous system during experimental allergic encephalomyelitis.J. Neuropathol. Exp. Neurol. 55,904914.
  • 47
    Naveilhan P., Neveu I., Baudet C., Ohyama K.Y., Brachet P., Wion D. (1993) Expression of 25(OH) vitamin D3 24-hydroxylase gene in glial cells.Neuroreport 5,255257.
  • 48
    Neveu I., Jehan F., Houlgatte R., Wion D., Brachet P. (1992) Activation of nerve growth factor synthesis in primary glial cells by phorbol 12-myristate 13-acetate : role of protein kinase C.Brain Res. 570,316322.
  • 49
    Neveu I., Naveilhan P., Menaa C., Wion D., Brachet P., Garabedian M. (1994a) Synthesis of 1,25-dihydroxyvitamin D3 by rat brain macrophages in vitro.J. Neurosci. Res. 38,214220.
  • 50
    Neveu I., Naveilhan P., Jehan F., Baudet C., Wion D., De Luca H.F., Brachet P. (1994b) 1,25-Dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells. Mol. Brain Res. 24,7076.
  • 51
    Neveu I., Naveilhan P., Baudet C., Brachet P., Metsis M. (1994c) 1,25-Dihydroxyvitamin D3 regulates NT-3, NT-4 but not BDNF mRNA in astrocytes.Neuroreport 6,124126.
  • 52
    O'Connor J.E., Devesa A., Garcia C., Puertes I.R., Vina J.R. (1995) Biosynthesis and maintenance of GSH in primary astrocyte cultures : role of l-cystine and ascorbate. Brain Res. 680,157163.
  • 53
    Okonkwo P.O., Orlowski M., Green J.P. (1974) Enzymes of the gamma-glutamyl cycle in the choroid plexus and brain.J. Neurochem. 22,10531058.
  • 54
    Pardridge W.M., Sakiyama R., Coty W.A. (1985) Restricted transport of vitamin D and A derivatives through the rat blood-brain barrier.J. Neurochem. 44,11381141.
  • 55
    Pellmar T.C., Roney D., Lepinski D.L. (1992) Role of glutathione in repair of free radical damage in hippocampus in vitro.Brain Res. 583,194200.
  • 56
    Perry T.L. & Wee Yong V. (1986) Idiopathic Parkinson's disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients.Neurosci. Lett. 67,269274.
  • 57
    Peuchen S., Bolanos J.P., Heales S.J., Almeida A., Duchen M.R., Clark J.B. (1997) Interrelationships between astrocyte function, oxidative stress and antioxidant status within the central nervous system.Prog. Neurobiol. 52,261281.
  • 58
    Prezioso J.A., Shields D., Wang N., Rosenstein M. (1994) Role of gamma-glutamyltranspeptidase-mediated glutathione transport on the radiosensitivity of B16 melanoma variant cell lines.Int. J. Radiat. Oncol. Biol. Phys. 30,373381.
  • 59
    Saporito M.S., Brown E.R., Hartpence K.C., Wilcox H.M., Vaught J.L., Carswell S. (1994) Chronic 1,25-dihydroxyvitamin D3-mediated induction of nerve growth factor mRNA and protein in L929 fibroblasts and in adult rat brain. Brain Res. 633,189196.
  • 60
    Schmidlin A. & Wiesinger H. (1995) Stimulation of arginine transport and nitric oxide production by lipopolysaccharide is mediated by different signaling pathways in astrocytes.J. Neurochem. 65,590594.
  • 61
    Shine H.D., Hertz L., De Vellis J., Haber B. (1981) A fluorometric assay fro gamma-glutamyl transpeptidase : demonstration of enzymatic activity in cultured cells of neural origin.Neurochem. Res. 6,453463.
  • 62
    Sian J., Dexter D.T., Lees A.J., Daniel S., Jenner P., Marsden C.D. (1994) Glutathione-related enzymes in brain in Parkinson's disease.Ann. Neurol. 36,356361.
  • 63
    Sonnenberg J., Luine V.N., Krey L.C., Christakos S. (1986) 1,25-Dihydroxyvitamin D3 treatment results in increased choline acetyltransferase activity in specific brain nuclei.Endocrinology 118,14331439.
  • 64
    Stumpf W.E. & O'Brien L.P. (1987) 1,25-(OH)2 vitamin D3 sites of action in the brain. An autoradiographic study.Histochemistry 87,393406.
  • 65
    Tietze F. (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione : applications to mammalian blood and other tissues.Anal. Biochem. 27,502522.
  • 66
    Virgin C.E.J, Ha T.P., Packan D.R., Tombaugh G.C., Yang S.H., Horner H.C., Sapolsky R.M. (1991) Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes : implications for glucocorticoid neurotoxicity.J. Neurochem. 57,14221428.
  • 67
    Wilson J.X. (1997) Antioxidant defense of the brain : a role for astrocytes.Can. J. Physiol. Pharmacol. 75,11491163.
  • 68
    Wolff J.E., Munstermann G., Grebenkamper K., Erben M. (1998) Gamma-glutamyl transpeptidase does not act as a cystine transporter in brain microvessels.Neurochem. Res. 23,11751178.