This work was funded by the Brain Research Trust and the Worshipful Company of Pewterers. The authors would like to thank Miss June Smalley for her assistance with the manuscript.

  • 1
    Bagasra O., Michaels F.H., Zheng Y.M., Bobroski L.E., Spitsin S.V., Fu Z.F., Tawadros R. & Koprowski H. (1995) Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis.Proc. Natl. Acad. Sci. USA 92,1204112045.
  • 2
    Bates T.E., Strangward M., Keelan J., Davey G.P., Munro P.M.G. & Clark J.B. (1996) Inhibition of N-acetylaspartate production : implications for 1H-MRS studies in vivo. Neuroreport 7,13971400.
  • 3
    Beal M.F., Hyman B.T. & Koroshetz W. (1993) Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases ?Trends Neurosci. 16,125131.
  • 4
    Beckman J.S., Beckman T.W., Chen J., Marshall P.A. & Freeman B.A. (1990) Apparent hydroxyl radical production by peroxynitrite : implications for endothelial injury from nitric oxide and superoxide.Proc. Natl. Acad. Sci. USA 87,16201624.
  • 5
    Bo L., Dawson T.M., Wesselingh S., Mork S., Choi S., Kong P.A., Hanley D. & Trapp B.D. (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis.Ann. Neurol. 36,778786.
  • 6
    Bolaños J.P., Peuchen S., Heales S.J.R., Land J.M. & Clark J.B. (1994) Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes.J. Neurochem. 63,910916.
  • 7
    Bolaños J.P., Heales S.J.R., Land J.M. & Clark J.B. (1995) Effect of peroxynitrite on the mitochondrial respiratory chain : differential susceptibility of neurones and astrocytes in primary cultures.J. Neurochem. 64,19651972.
  • 8
    Bolaños J.P., Heales S.J.R., Peuchen S., Barker J.E., Land J.M. & Clark J.B. (1996) Nitric oxide-mediated mitochondrial damage : a potential neuroprotective role for glutathione.Free Radic. Biol. Med. 21,9951001.
  • 9
    Brookes P.S., Land J.M., Clark J.B. & Heales S.J.R. (1998) Peroxynitrite and brain mitochondria : evidence for increased proton leak.J. Neurochem. 70,21952202.
  • 10
    Brown G.C., Bolaños J.P., Heales S.J.R. & Clark J.P. (1995) Nitric oxide produced by activated astrocytes rapidly and reversibly inhibits cellular respiration.Neurosci. Lett. 193,201204.
  • 11
    Chao C.C., Hu S., Sheng W.S., Bu D., Bikrinsky M.I. & Peterson P. (1996) Cytokine-stimulated astrocytes damage human neurons via a nitric oxide mechanism.Glia 16,276284.
  • 12
    Davie C.A., Hawkins C.P., Barker G.J., Brennan A., Tofts P.A., Miller D.H. & McDonald W.I. (1994) Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions.Brain 117,4958.
  • 13
    Dawson V.L., Brahmbatt H.P., Mong J.A. & Dawson T.M. (1994) Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures.Neuropharmacology 33,14251430.
  • 14
    Dobson J.V. & Taylor M.J. (1986) The permeability of gases through PTFE membranes at 25°C. Electrochim. Acta 31,231233.
  • 15
    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.
  • 16
    Green L.C., Wagner D.A., Glogowski J., Skipper P.L., Wishnock J.S. & Tannenbaum S.R. (1982) Analysis of nitrate, nitrite, and [N-15N]-labelled nitrate in biological effects. Anal. Biochem. 126,131138.
  • 17
    Heales S.J.R., Davies S.E.C., Bates T.E. & Clark J.B. (1995) Depletion of brain glutathione is accompanied by impaired mitochondrial function and decreased N-acetyl aspartate concentration. Neurochem. Res. 20,3138.
  • 18
    Heales S.J.R., Bolaños J.P., Stewart V.C., Brookes P.S., Land J.M. & Clark J.B. (1999) Nitric oxide, mitochondria and neurological disease.Biochim. Biophys. Acta 1410,215228.
  • 19
    Johnson A.W., Land J.M., Thompson E.J., Bolanos J.P., Clark J.B. & Heales S.J.R. (1995) Evidence for increased nitric oxide production in multiple sclerosis.J. Neurol. Neurosurg. Psychiatry 58,107.
  • 20
    Keilhoff G. & Wolf G. (1993) Comparison of double fluorescence staining and LDH-test for monitoring cell viability in vitro.Neuroreport 5,129132.
  • 21
    Koh J.Y. & Choi D.W. (1987) Quantitative determination of glutamate mediated cortical neuron injury in cell culture by lactate dehydrogenase efflux assay.Neurosci. Methods 20,8390.
  • 22
    Koh J.Y. & Choi D.W. (1988) Vulnerability of cultured cortical neurons to damage by excitotoxins : differential susceptibility of neurons containing NADPH-diaphorase.J. Neurosci. 8,21532163.
  • 23
    Lowry O.H., Rosebrough N.J., Farr A.L. & Randall R.J. (1951) Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193,265275.
  • 24
    Magistretti P.J., Bittar P., Pellegri G., Martin J.L. & Pellerin L. (1997) Activity-dependent astrocyte-neuron lactate shuttle. (Abstr.)J. Neurochem. 69 (Suppl.) , S263A.
  • 25
    Mitrovic B., Ignarro L.J., Montestruque S., Smoll A. & Merrill J.E. (1994) Nitric oxide as a potential pathological mechanism in demyelination : its differential effects on primary glial cells in vitro.Neuroscience 61,575585.
  • 26
    Moffet J.R., Namboodiri M.A.A., Cangro C.B. & Neale J.H. (1991) Immunohistochemical localisation of N-acetylaspartate in rat brain. Neuroreport 2,131134.
  • 27
    Paradies G., Petrosillo G., Pistolese M. & Ruggiero F.M. (2000) The effect of reactive oxygen species generated from mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles.FEBS Lett. 466,323326.
  • 28
    Poderoso J.J., Carreras M.C., Shopfer F., Lisdero C., Riobo N., Giuliviv C., Boveris A. & Cadenas E. (1999) The reaction of nitric oxide with ubiquinol : kinetic properties and biological significance.Free Radic. Biol. Med. 26,925935.
  • 29
    Redford E.J., Kapoor R. & Smith K.J. (1997) Nitric oxide donors reversibly block axonal conduction : demyelinated axons are especially susceptible.Brain 120,21492157.
  • 30
    Rustin P., Chretien D., Bourgeron T., Gerard B., Rotig A., Saudubray J.M. & Munnich A. (1994) Biochemical and molecular investigations in respiratory chain deficiencies.Clin. Chim. Acta 228,3551.
  • 31
    Stewart V.C., Giovannoni G., Land J.M., McDonald W.I., Clark J.B. & Heales S.J.R. (1997) Pretreatment of astrocytes with interferon-α/β impairs interferon-γ induction of nitric oxide synthase.J. Neurochem. 68,25472551.
  • 32
    Stewart V.C., Land J.M., Clark J.B. & Heales S.J.R. (1998) Pretreatment of astrocytes with interferon-α/β prevents neuronal mitochondrial respiratory chain damage.J. Neurochem. 70,432434.
  • 33
    Tabernero A., Bolaños J.P. & Medina J.M. (1993) Lipogenesis from lactate in rat neurons and astrocytes in primary culture.Biochem. J. 294,635638.
  • 34
    Turrens J.F. (1997) Superoxide production by mitochondrial respiratory chain.Biosci. Rep. 17,38.
  • 35
    Uppu R.M. & Pryor W.A. (1996) Biphasic synthesis of high concentrations of peroxynitrite using water-insoluble alkyl nitrite and hydrogen peroxide.Methods Enzymol. 269,322329.
  • 36
    Vassault A. (1983) Lactate dehydrogenase. UV method with pyruvate and NADH, inMethods of Enzymatic Analysis, Vol. 3 (Bergmeyer J. and Grassl M., eds), pp. 118126. Verlag Chemie GmbH, Weinheim.
  • 37
    Wolff S.P. & Dean R.T. (1987) Glucose autooxidation and protein modification.Biochem. J. 245,243250.