Advances in Neuroprotection Research for Neurodegenerative Diseases

  • Mario E. Götz
  • Peter Riederer
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 541)


Recent advances in science enable new and closer insights into brain structure and function. The extent of CNS damage due to ischemia, or neurodegeneration can be followed by the use of modern brain imaging technology such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) and radiolabeled tracers. Ex vivo the systematic use of gene expression arrays is becoming more and more important to select sensitive genes as targets for neuroprotection. And gene therapy is considered as an alternative approach to trigger neuroprotection in experimental models of neurodegeneration. At the same time as these modern technologies pave their way, new promising pharmacological intervention concepts to halt disease progression of Parkinson’s and Alzheimer’s disease, and to diminish ischemia reperfusion injury, have emerged.


NMDA Receptor Dopamine Agonist NMDA Receptor Antagonist Lipoic Acid Parkinsonian Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    M. Gerlach, P. Riederer, M. B. Youdim, Neuroprotective therapeutic strategies, comparison of experimental and clinical results, Biochem. Pharmacol. 50(1), 1–16 (1995).PubMedCrossRefGoogle Scholar
  2. E. Grün blatt, R. Schlö ßer, M. Gerlach, and P. Riederer, Preclinical versus clinical neuroprotection, in Parkinson’s disease: Advances in Neurology 91, edited by A. Gordin, S. Kaakkola, and H. Teräväinen (Lippincott Williams & Wilkins, Philadelphia, 2003), pp. 309–328.Google Scholar
  3. 3.
    C. E. Clarke, and M. Guttman, Dopamine agonist monotherapy in Parkinson’s disease, Lancet 360(9347), 1767–1769 (2002).PubMedCrossRefGoogle Scholar
  4. 4.
    W. Birkmayer, P. Riederer, L. Ambrozi, and M. H. Youdim, Implications of combined treatment with “Madopar“ and L-deprenyl in Parkinson’s disease; A long-term study, Lancet 1(8009), 439–443 (1977).PubMedCrossRefGoogle Scholar
  5. 5.
    J. Knoll, J. Dallo, and, T.T. Yen, Striatal dopamine, sexual activity and lifespan, Longevity of rats treated with (-) deprenyl, Life Sci. 45(6), 525–531 (1989).PubMedCrossRefGoogle Scholar
  6. 6.
    M. C. Carrillo, K. Kitani, S. Kanai, Y. Sato, K. Miyasaka, and G. O. Ivy, (-)Deprenyl increases activities of Superoxide dismutase and catalase in certain brain regions in old mice, Life Sci. 54(14), 975–981 (1994).PubMedCrossRefGoogle Scholar
  7. 7.
    I. Mizuta, M. Ohta, K. Ohta, M. Nishimura, E. Mizuta, K. Hayashi, and S. Kuno, Selegiline and desmethylselegiline stimulate NGF, BDNF, and GDNF synthesis in cultured mouse astrocytes, Biochem. Biophys. Res. Commun. 279(3), 751–755 (2000).PubMedCrossRefGoogle Scholar
  8. 8.
    W. Maruyama, and M. Naoi, Neuroprotection by (-)deprenyl and related compounds, Mech. Aging Dev. 111(2-3), 189–200 (1999).PubMedCrossRefGoogle Scholar
  9. 9.
    Parkinson Study Group, DATATOP: a multicenter controlled clinical trial in early Parkinson’s disease, Arch. Neurol. 46(10), 1052–1060 (1989).CrossRefGoogle Scholar
  10. 10.
    Parkinson Study Group, Effect of deprenyl on the progression of disabilityy in early Parkinson’s disease, N. Engl. J. Med. 321(20), 1364–1371 (1989).CrossRefGoogle Scholar
  11. 11.
    Parkinson Study Group, Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease, N. Engl. J. Med. 328(3), 176–183 (1993).CrossRefGoogle Scholar
  12. 12.
    Parkinson Study Group, Mortality in DATATOP: a multicenter trial in early Parkinson’s disease, Ann. Neurol. 43(3), 318–325 (1998).CrossRefGoogle Scholar
  13. 13.
    J. W. Tetrud, and J. W. Langston, The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease, Science 245(4917), 519–522 (1989).PubMedCrossRefGoogle Scholar
  14. 14.
    H. Przuntek, B. Conrad, J. Dichgans, P. H. Kraus, P. Krauseneck, G. Pergande, U. Rinne, K. Schimrigk, J. Schnitker, and H. P. Vogel, SELEDO: a 5-year long-term trial on the effect of selegiline in early parkinsonian patients treated with levodopa. Eur. J. Neurol. 6(2), 141–150 (1999).PubMedCrossRefGoogle Scholar
  15. 15.
    J. Birks, and L. Flicker, Selegiline for Alzheimer’s disease (Cochrane Review), Cochrane Database Syst. Rev. 1, CD000442 (2003).PubMedGoogle Scholar
  16. 16.
    M. Gerlach, M. B. Youdim, and P. Riederer, Pharmacology of selegiline, Neurology 47(6 Suppl 3), S137–145 (1996).PubMedCrossRefGoogle Scholar
  17. 17.
    K. Magyar, and D. Haberle, Neuroprotective and neuronal rescue effects of selegiline: review, Neurobiology (BP) 7(2), 175–190(1999).Google Scholar
  18. 18.
    P. C. Waldmeier, A. A. Boulton, A. R. Cools, A. C. Kato, and W. G. Tatton, Neurorescuing effects of the GAPDH ligand CGP 3466B, J. Neural Transm. 60(Suppl.), 197–214 (2000).Google Scholar
  19. 19.
    G. Andringa, and A. R. Cools, The neuroprotective effects of CGP 3466B in the best in vivo model of Parkinson’s disease, the bilaterally MPTP-treated rhesus monkey, J. Neural Transm. 60(Suppl.), 215–225 (2000).Google Scholar
  20. 20.
    E. Kragten, I. Lalande, K. Zimmermann, S. Roggo, P. Schindler, D. Muller, J. van Oostrum, P. Waldmeier, and P. Furst, Glyceraldehyd-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(-)-deprenyl, J. Biol. Chem. 273(10), 5821–5828 (1998).PubMedCrossRefGoogle Scholar
  21. 21.
    K. J. Huebscher, J. Lee, G. Rovelli, B. Ludin, A. Matus, D. Stauffer, and P. Furst, Protein isoaspartyl methyltransferase protects from Bax-induced apoptosis, Gene 240(2), 333–341 (1999).PubMedCrossRefGoogle Scholar
  22. 22.
    M. B. Youdim, A. Gross, and J. P. Finberg, Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B, Br. J. Pharmacol. 132(2), 500–506 (2001).PubMedCrossRefGoogle Scholar
  23. 23.
    D. Haberle, K. Magyar, and E. Szoko, Determination of the norepinephrine level by high-performance liquid chromatography to assess the protective effect of MAO-B inhibitors against DSP-4 toxicity, J. Chromatogr. Sci. 40(9), 495–499 (2002).PubMedGoogle Scholar
  24. 24.
    W. Maruyama, T. Yamamoto, K. Kitani, M. C. Carrillo, M. B. Youdim and M. Naoi, Mechanism underlying anti-apoptotic activity of a (-)deprenyl-related propargylamine, rasagiline, Mech. Aging Dev. 116(2-3), 181–191 (2000).PubMedCrossRefGoogle Scholar
  25. 25.
    W. Maruyama, Y. Akao, M. B. Youdim, and M. Naoi, Neurotoxins induce apoptosis in dopamine neurons; protection by N-propargylamine-l-(R)-and (S)-aminoindan, rasagiline and TV1022, J. Neural Transm. 60(Suppl), 171–186 (2000).Google Scholar
  26. 26.
    W. Maruyama, Y. Akao, M. C. Carrillo, K. Kitani, M. B. Youdim, and M. Naoi, Neuroprotection by propargylamines in Parkinson’s disease: suppression of apoptosis and induction of prosurvival genes, Neurotoxicol. Teratol. 24(5), 675–682 (2002).PubMedCrossRefGoogle Scholar
  27. 27.
    W. Maruyama, T. Takahashi, M. B. Youdim, and M. Naoi, The anti-Parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells, J. Neural Transm. 109(4), 467–481 (2002).PubMedCrossRefGoogle Scholar
  28. 28.
    Y. Akao, W. Maruyama, S. Shimizu, H. Yi, Y. Nakagawa, M. Shamoto-Nagai, M. B. Youdim, Y. Tsujimoto, and M. Naoi, Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan, J. Neurochem. 82(4), 913–923 (2002).PubMedCrossRefGoogle Scholar
  29. 29.
    J. P. Finberg, and M. B. Youdim, Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours, Neuropharmacology 43(7), 1110–1118 (2002).PubMedCrossRefGoogle Scholar
  30. 30.
    J. M. Rabey, I. Sagi, M. Huberman, E. Melamed, A. Korczyn, N. Giladi, R. Inzelberg, R. Djaldetti, C. Klein, and G. Berecz, The Rasagiline Study Group, Rasagiline mesylate, a new MAO-B inhibitor, for the treatment of Parkinson’s disease: a double blind study as adjunctive therapy to levodopa, Clin. Neuropharmacol. 23(6), 324–330 (2000).PubMedCrossRefGoogle Scholar
  31. 31.
    Parkinson Study Group, A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study, Arch. Neurol. 59(12), 1937–1943 (2002).CrossRefGoogle Scholar
  32. 32.
    J. Sterling, Y. Herzig, T. Goren, N. Finkelstein, D. Lerner, W. Goldenberg, I. Miskolczi, S. Molnar, F. Rantal, T. Tamas, G. Toth, A. Zagyva, A. Zekany, G. Lavian, A. Gross, R. Friedman, M. Razin, W. Huang, B. Krais, M. Chorev, M. B. Youdim, and M. Weinstock, Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer’s disease. J. Med. Chem. 45(24), 5260–5279 (2002).PubMedCrossRefGoogle Scholar
  33. 33.
    M. Weinstock, N. Kirschbaum-Slager, P. Lazarovici, C. Bejar, M. B. Youdim and S. Shoham, Neuroprotective effects of novel cholinesterase inhibitors derived from rasagiline as potential anti-Alzheimer drug, in: Neuroprotective Agents, Ann. N. Y. Acad. Sci. U. S. A. vol. 939, edited by W. Slikker Jr., and B. Trembly (N. Y. Acad. Sci., New York, 2001) pp. 148–161.Google Scholar
  34. 34.
    M. B. Youdim, and M. Weinstock, Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3)aminoindan-5-yl)-ethyl methyl carbamate], Cell. Mol. Neurobiol. 21(6), 555–573 (2001).PubMedCrossRefGoogle Scholar
  35. 35.
    M. B. Youdim, and M. Weinstock, Novel neuroprotective anti-Alzheimer drugs with anti-depressant activity derived from the anti-Parkinson drug, rasagiline, Mech. Ageing Dev. 123(8), 1081–1086 (2002).PubMedCrossRefGoogle Scholar
  36. 36.
    M. Yogev-Falach, T. Amit, O. Bar-Am, M. Weinstock, and M. B. Youdim, Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline, FASEB J. 16(12), 1674–1676 (2002).PubMedGoogle Scholar
  37. 37.
    Parkinson Study Group, Pramipexole vs L-DOPA as initial treatment for Parkinson disease: a randomized controlled trial, JAMA 284(15), 1931–1938 (2000).CrossRefGoogle Scholar
  38. 38.
    A. Lieberman, A. Ranhosky, and D. Korts, Clinical evaluation of pramipexole in advanced Parkinson’s disease: results of a double-blind, placebo-controlled, parallel-group study, Neurology 49(1), 162–168 (1997).PubMedCrossRefGoogle Scholar
  39. 39.
    H. Allain, A. Destee, H. Petit, M. Patay, S. Schuck, D. Bentue-Ferrer, and P. Le Cavorzin, Five-year follow-up of early lisuride and L-DOPA combination therapy versus L-DOPA monotherapy in de novo Parkinson’s disease, The French Lisuride Study Group, Eur. Neurol. 44(1), 22–30 (2000).PubMedCrossRefGoogle Scholar
  40. 40.
    P. Barone, D. Bravi, F. Bermejo-Pareja, R. Marconi, J. Kulisevsky, S. Malagu, R. Weiser, and N. Rost, Pergolide monotherapy in the treatment of early PD: a randomized, controlled study, Neurology 53, 573–579(1999).PubMedCrossRefGoogle Scholar
  41. 41.
    B. Bergamasco, L. Frattola, A. Muratorio, F. Piccoli, F. Mailland, and L. Parnetti, α-Dihydroergocryptine in the treatment of de novo parkinsonian patients: results of a multicentre, randomized, double-blind, placebo-controlled study, Acta Neurol. Scand. 101(6), 372–380 (2000).PubMedCrossRefGoogle Scholar
  42. 42.
    L. Battistin, P. G. Bardin, F. Ferro-Milone, C. Ravenna, V. Toso, and G. Reboldi, a-Dihydroergocryptine in Parkinson’s disease: a multicentre randomized double blind parallel group study, Acta Neurol. Scand. 99(1), 36–42 (1999).PubMedCrossRefGoogle Scholar
  43. 43.
    U. K. Rinne, F. Bracco, C. Chouza, E. Dupont, O. Gershanik, J. F. Marti-Masso, J. L. Montastruc, and C. D. Marsden, Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications, Results of a double-blind L-DOPA controlled trial, The PKDS009 Study Group, Drugs 55(Suppl 1), 23–30 (1998).PubMedCrossRefGoogle Scholar
  44. 44.
    A. Lledo, Dopamine agonists: the treatment for Parkinson’s disease in the XXI century? Parkinsonism Relat. Disord. 7(1), 51–58 (2000).PubMedCrossRefGoogle Scholar
  45. 45.
    J. P. Bennett, and M. F. Piercey, Pramipexole-a new dopamine agonist for the treatment of Parkinson’s disease, J. Neurol. Sci. 163(1), 25–31 (1999).PubMedCrossRefGoogle Scholar
  46. 46.
    P. M. Carvey, S. O. McGuire, and Z. D. Ling, Neuroprotective effects of D3 dopamine receptor agonists, Parkinsonism & Related Disorders 7(3), 213–223 (2001).CrossRefGoogle Scholar
  47. 47.
    N. Ogawa, K. Tanaka, M. Asanuma, M. Kawai, T. Masumizu, M. Kohno, and A. Mori, Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro, Brain Res. 657(1-2), 207–213 (1994).PubMedCrossRefGoogle Scholar
  48. 48.
    T. Yoshikawa, Y. Minamiyama, Y. Naito, and M. Kondo, Antioxidant properties of bromocriptine, a dopamine agonist, J. Neurochem. 62(3), 1034–1038 (1994).PubMedCrossRefGoogle Scholar
  49. 49.
    A. Ubeda, C. Montesino, M. Paya, and M. J. Alcaraz, Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines. Free Radie. Biol. Med. 15(2), 159–167 (1993).CrossRefGoogle Scholar
  50. 50.
    E. E. Sam, and N. Verbeke, Free radical scavenging properties of apomorphine enantiomers and dopamine: possible implication in their mechanism of action in parkinsonism, J. Neural Transtn. Park Dis. Dement. Sect. 10(2-3), 115–127 (1995).CrossRefGoogle Scholar
  51. 51.
    M. Gassen, Y. Glinka, B. Pinchasi, and M. B. Youdim, Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction, Eur. J. Pharmacol. 308(2), 219–225 (1996).PubMedCrossRefGoogle Scholar
  52. 52.
    M. Iida, I. Miyazaki, K.-I. Tanaka, H. Kabuto, E. Iwata-Ichikawa, and N. Ogawa, Dopamine D2 receptormediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist, Brain Res. 838(1-2), 51–59 (1999).PubMedCrossRefGoogle Scholar
  53. 53.
    T. Kihara, S. Shimohama, H. Sawada, K. Honda, T. Nakamizo, R. Kanki, H. Yamashita, and A. Akaike, Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade, J. Neurosci. Res. 70(3), 274–282 (2002).PubMedCrossRefGoogle Scholar
  54. 54.
    W. D. Le, and J. Jankovic, Are dopamine receptor agonists neuroprotective in Parkinson’s disease?, Drugs Aging 18(6), 389–396 (2001).PubMedCrossRefGoogle Scholar
  55. 55.
    S. Thobois, S. Guillouet, and E. Broussolle, Contributions of PET and SPECT to the understanding of the pathophysiology of Parkinson’s disease, Neuophysiol. Clin. 31(5), 321–340 (2001).CrossRefGoogle Scholar
  56. 56.
    K. Marek, β-CIT/SPECT assessments of progression of Parkinson’s disease in subjects participating in the CALM PD study, Neurology 54(Suppl 3), A90 (2000).Google Scholar
  57. 57.
    J. S. Rakshi, N. Pavese, T. Uema, K. Ito, P. K. Morrish, D. L. Bailey, and D. J. Brooks, A comparison of the progression of early Parkinson’s disease in patients started on ropinirole or L-dopa: an (18)F-DOPA PET study, J. Neural Transm. 109(12), 1433–1443 (2002).PubMedCrossRefGoogle Scholar
  58. 58.
    M. E. Götz, G. Künig, P. Riederer, and M. B. Youdim, Oxidative stress: Free radical production in neural degeneration, Pharmac. Ther. 63(1), 37–122 (1994).CrossRefGoogle Scholar
  59. 59.
    A. D. Mooradian, Antioxidant properties of steroids, J. Steroid Biochem. Mol. Biol. 45(6), 509–511 (1993).PubMedCrossRefGoogle Scholar
  60. 60.
    B. Ruiz-Larrea, A. Leal, C. Martin, R. Martinez, and M. Lacort, Effects of estrogens on the redox chemistry of iron: A possible mechanism of the antioxidant action of estrogens, Steroids 60(11), 780–783 (1995).PubMedCrossRefGoogle Scholar
  61. 61.
    C. Behl, M. Widmann, T. Trapp, and F. Holsboer, 17β-estradiol protects neurons from oxidative stressinduced cell death in vitro, Biochem. Biophys. Res. Commun. 216(2), 473–482 (1995).CrossRefGoogle Scholar
  62. 62.
    C. Behl, T. Skutella, F. Lezoualc’h, A. Post, M. Widmann, C. J. Newton, and F. Holsboer, Neuroprotection against oxidative stress by estrogens: Structure-activity relationship, Mol. Pharm. 51(4), 535–541 (1997).Google Scholar
  63. 63.
    C. P. Miller, I. Jirkovsky, D. A. Hayhurst, and S. J. Adelman, In vitro antioxidant effects of estrogens with a hindered 3-OH function on the copper-induced oxidation of low density lipoprotein, Steroids 61(5), 305–308 (1996).PubMedCrossRefGoogle Scholar
  64. 64.
    J. N. Keller, A. Germeyer, J. G. Begley, and M. P. Mattson, 17β-estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid β-peptide and iron, J. Neurosci. Res. 50(4), 522–530 (1997).PubMedCrossRefGoogle Scholar
  65. 65.
    W. Röm er, M. Oettel, P. Droescher, and S. Schwarz, Novel “scavestrogens“ and their radical scavenging effects, iron-chelating, and total antioxidative activities: Δ8,9-dehydro derivatives of 17α-estradiol and 17β-estradiol, Steroids 62(3), 304–310 (1997).PubMedCrossRefGoogle Scholar
  66. 66.
    D. Blum-Degen, M. Haas, S. Pohli, R. Harth, W. Röm er, M. Oettel, P. Riederer, M. E. Götz, Scavestrogens protect IMR 32 cells from oxidative stress — induced cell death, Toxicol. Appl. Pharmacol. 152(1), 49–55 (1998).PubMedCrossRefGoogle Scholar
  67. 67.
    W. Röm er, M. Oettel, B. Menzenbach, P. Droescher, S. Schwarz, Novel estrogens and their radical scavenging effects, iron-chelating, and total antioxidative activities: 17α-substituted analogs of Δ9(11)-dehydro-17ß-estradiol, Steroids 62(11), 688–694 (1997).PubMedCrossRefGoogle Scholar
  68. 68.
    C. Behl, Vitamin E protects neurons against oxidative cell death in vitro more effectively than 17β-estradiol and induces the activity of the transcription factor NF-kappaB, J. Neural Transm. 107(4), 393–407 (2000).PubMedCrossRefGoogle Scholar
  69. 69.
    G.A. Fritsma, Vitamin E and autoxidation, Am. J. Med. Tech. 49(6) 453–456 (1983).Google Scholar
  70. 70.
    J.A. Lucy, Functional and structural aspects of biological membranes: a suggested role for vitamin E in the control of membrane permeability and stability. Ann. N. Y. Acad. Sci. 203, 4–11 (1972).PubMedCrossRefGoogle Scholar
  71. 71.
    J. R. Burton, and K. U. Ingold, Autoxidation of biological molecules. The antioxidant activity of vitamin E and related chain-breaking phenolic antioxidants in vitro, J. Am. Chem. Soc. 103, 6472–6477 (1981).CrossRefGoogle Scholar
  72. 72.
    C. K. Chow, Vitamin E and oxidative stress, Free Radic. Biol. Med. 11(2), 215–232 (1991).PubMedCrossRefGoogle Scholar
  73. 73.
    A. Bjorneboe, G.-E. Bjorneboe, and C. A. Drevon, Absorption, transport and distribution of vitamin E, J. Nutr. 120(3), 233–242 (1989).Google Scholar
  74. 74.
    C. A. Drevon, Absorption, transport and metabolism of vitamin E, Free Radic. Res. Commun. 14(4), 229–246 (1991).PubMedCrossRefGoogle Scholar
  75. 75.
    R. J. Sokol, Vitamin E and neurologic function in man, Free Radic. Biol. Med. 6(2), 189–207 (1989).PubMedCrossRefGoogle Scholar
  76. 76.
    G. T. Vatassery, C. K. Angerhofer, and C. A. Knox, Effect of age on vitamin E concentrations in various regions of the brain and a few selected peripheral tissues of the rat, and on the uptake of radioactive vitamin E by various regions of the rat brain, J. Neurochem. 43(2), 409–412 (1984).PubMedCrossRefGoogle Scholar
  77. 77.
    G. T. Vatassery, Selected aspects of the neurochemistry of vitamin E, in: Clinical and nutritional aspects of vitamin E, edited by, O. Hayaishi, and M. Mino, (Elsevier, Amsterdam, 1987), pp. 147–155.Google Scholar
  78. 78.
    M. A. Goss-Sampson, C. J. McEvilly, and D. P. R. Muller, Longitudinal studies of the neurobiology of vitamin E and other antioxidant systems, and neurological function in the vitamin E deficient rat, J. Neurol. Sci. 87(1), 25–35 (1988).PubMedCrossRefGoogle Scholar
  79. 79.
    E. Southam, P. K. Thomas, R. H. M. King, M. A. Goss-Sampson, and D. P. R. Muller, (1991) Experimental vitamin E deficiency in rats, morphological and functional evidence of abnormal axonal transport secondary to free radical damage, Brain 114(Pt 2), 915–936 (1991).PubMedCrossRefGoogle Scholar
  80. 80.
    G. T. Vatassery, C. K. Angerhofer, C. A. Knox, and D. S. Deshmukh, Concentrations of vitamin E in various neuroanatomical regions and subcellular fractions, and the uptake of vitamin E by specific areas, of rat brain, Biochim. Biophys. Acta 792(2), 118–122 (1984).PubMedCrossRefGoogle Scholar
  81. 81.
    D.A. Butterfield, T. Koppal, R. Subramaniam, and S. Yatin, Vitamin E as an antioxidant/free radical scavenger against amyloid β-peptide-induced oxidative stress in neocortical synaptosomal membranes and hippocampal neurons in culture: insights into Alzheimer’s disease, Rev.Neurosci. 10(2), 141–149 (1999).PubMedCrossRefGoogle Scholar
  82. 82.
    S. M. Yatin, S., Varadaryjan, and D. A. Butterfield, Vitamin E prevents Alzheimer’s amyloid β-peptide (1-42)-induced neuronal protein oxidation and reactive oxygen species production, J. Alzheimers Dis. 2(2), 123–131 (2000).PubMedGoogle Scholar
  83. 83.
    Y. Li, L. Liu, S. W. Barger, R. E. Mrak, and W. S. Griffin, Vitamin E suppression of microglial activation is neuroprotective, J. Neurosci. Res. 66(2), 163–170 (2001).PubMedCrossRefGoogle Scholar
  84. 84.
    C. Behl, and B. Moosmann, Oxidative nerve cell death in Alzheimer’s disease and stroke: antioxidants as neuroprotective compounds, Biol. Chem. 383(3-4), 521–536 (2002).PubMedCrossRefGoogle Scholar
  85. 85.
    M. Grundman, Vitamin E and Alzheimer disease: the basis for additional clinical trials, Am. J. Clin. Nutr. 71(2), 630S–636S (2000).PubMedGoogle Scholar
  86. 86.
    D. Offen, I. Ziv, H. Sternin, E. Melamed, and A. Hochman, Prevention of dopamine-induced cell death by thiol antioxidant: possible implications for treatment of Parkinson’s disease, Exp. Neurol. 141(1), 32–39 (1996).PubMedCrossRefGoogle Scholar
  87. 87.
    A. Roth, W. Schaffner, and C. Hertel, Phytoestrogen kaempferol (3,4’,5,7-tetrahydroxyflavone) protects PC12 and T47D cells from β-amyloid-induced toxicity, J. Neurosci. Res. 57(3), 399–404 (1999).PubMedCrossRefGoogle Scholar
  88. 88.
    M. S. Kobayashi, D. Han, and L. Packer, Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity, Free Radic. Res. 32(2), 115–124 (2000).PubMedCrossRefGoogle Scholar
  89. 89.
    L. Iacovitti, N. D. Stull, and A. Mishizen, Neurotransmitters, KC1 and antioxidants rescue striatal neurons from apoptotic cell death in culture, Brain Res. 816(2), 276–285 (1999).PubMedCrossRefGoogle Scholar
  90. 90.
    E. J. Lien, S. Ren, H.-H. Bui, and R. Wang, Quantitative structure-activity relationship analysis of phenolic antioxidants, Free Radic. Biol. Med. 26(3/4), 285–294 (1999).PubMedCrossRefGoogle Scholar
  91. 91.
    H. Padh, Vitamin C: Newer insights into its biochemical functions, Nutr. Rev. 49(3), 65–70 (1991).PubMedCrossRefGoogle Scholar
  92. 92.
    B. H. J. Bielski, and H. W. Richter, Some properties of the ascorbate free radical. Ann. N.Y. Acad. Sci. 258, 231–237 (1975).PubMedCrossRefGoogle Scholar
  93. 93.
    R. L. Levine, Oxidative modification of glutamine synthetase: characterization of the ascorbate model system, J. Biol. Chem. 258(19), 11828–11833 (1983).PubMedGoogle Scholar
  94. 94.
    D. W. Choi, Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemie damage, Trends Neurosci. 11(10), 465–469 (1988).PubMedCrossRefGoogle Scholar
  95. 95.
    D. W. Choi, Glutamate neurotoxicity and diseases of the nervous system, Neuron 1(8), 623–634 (1988).PubMedCrossRefGoogle Scholar
  96. 96.
    P. B. McCay, Vitamin E: nteractions with free radicals and ascorbate, Ann. Rev. Nutr. 5, 323–340 (1985).CrossRefGoogle Scholar
  97. 97.
    E. Niki, Antioxidants in relation to lipid peroxidation, Chem. Phys. Lipids 44(2-4), 227–253 (1987).PubMedCrossRefGoogle Scholar
  98. 98.
    E. Niki, Interaction of ascorbate and a-tocopherol, Ann. N.Y. Acad. Sci. 498, 186–199 (1987).PubMedCrossRefGoogle Scholar
  99. 99.
    J. E. Packer, T. F. Slater, and R. L. Willson, Direct observation of a free radical interaction between vitamin E and vitamin C, Nature. Lond. 278(5706), 737–738 (1979).PubMedCrossRefGoogle Scholar
  100. 100.
    M. Scarpa, A. Rigo, M. Maiorino, F. Ursini, and C. Gregolin, Formation of α-tocopherol radical and recycling of a-tocopherol by ascorbate during peroxidation of phosphatidylcholine liposomes. An electron paramagnetic resonance study, Biochim. Biophys. Acta 801(2), 215–219 (1984).PubMedCrossRefGoogle Scholar
  101. 101.
    F. Hruba, V. Novakova, and E. Ginter, The effect of chronic marginal vitamin C deficiency on the α-tocopherol content of the organs and plasma of guinea pigs, Experientia 38(12), 1454–1455 (1982).PubMedCrossRefGoogle Scholar
  102. 102.
    A. Bendich, L. J. Machlin, O. Scandurra, G. W. Burton, and D. N. Wayner, The antioxidant role of vitamin C, Adv. Free Radic. Biol. Med. 2, 419–444 (1986).CrossRefGoogle Scholar
  103. 103.
    J. Huang, D. B. Agus, C. J. Winfree, S. Kiss, W. J. Mack, R. A. McTaggart, T. F. Choudhri, L. J. Kim, J. Mocco, D. J. Pinsky, W. D. Fox, R. J. Israel, T. A. Boyd, D. W. Golde, and E. S. Connolly Jr., Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke, Proc. Natl. Acad. Sci. U. S. A. 98(20), 11720–11724 (2001).PubMedCrossRefGoogle Scholar
  104. 104.
    F. Fornai, S. Piaggi, M. Gesi, M. Saviozzi, P. Lenzi, A. Paparelli, and A. F. Casini, Subcellular localization of a glutathione-dependent dehydroascorbate reductase within specific rat brain regions, Neuroscience 104(1), 15–31 (2001).PubMedCrossRefGoogle Scholar
  105. 105.
    M. Maden, Heads or tails? Retinoic acid will decide, Bioessays 21(10), 809–812 (1999).PubMedCrossRefGoogle Scholar
  106. 106.
    G. Begemann, and A. Meyer, Hindbrain patterning revisited: timing and effects of retinoic acid signalling, Bioessays 23(11), 981–986 (2001).PubMedCrossRefGoogle Scholar
  107. 107.
    G. Wolf, Vitamin A functions in the regulation of the dopaminergic system in the brain and pituitary gland, Nutr. Rev. 56(12), 354–355 (1998).PubMedCrossRefGoogle Scholar
  108. 108.
    B. Ahlemeyer, R. Huhne, and J. Krieglstein, Retinoic acid potentiated the protective effect of NGF against staurosporine-induced apoptosis in cultured chick neurons by increasing the trk A protein expression, J. Neurosci. Res. 60(6), 767–778 (2000).PubMedCrossRefGoogle Scholar
  109. 109.
    S. T. Omaye, Safety of megavitamin therapy, Adv. Exp. Med. Biol. 177, 169–203 (1984).PubMedGoogle Scholar
  110. 110.
    M. R. McCall, and B. Frei, Can antioxidant vitamins materially reduce damage in humans? Free Radic. Biol. Med. 26(7/8), 1034–1053 (1999).PubMedCrossRefGoogle Scholar
  111. 111.
    R. E. Beyer, The participation of CoQ10 in free radical production and antioxidation, Free Radic. Biol. Med. 8(6), 545–565 (1990).PubMedCrossRefGoogle Scholar
  112. 112.
    F. L. Crane, Development of concepts for the role of ubiquinones in biological membranes, in: Highlights in Ubiquinone Research, edited by G. Lenaz, O. Barnabei, A. Rabbi, M. Battino (Taylor & Francis, London, 1990) pp. 3–17.Google Scholar
  113. 113.
    T. Takahashi, T. Okamoto, K. Mori, H. Sayo, and T. Kishi, Distribution of ubiquinone and ubiquinol homologues in rat tissues and subcellular fractions, Lipids 28(9), 803–809 (1993).PubMedCrossRefGoogle Scholar
  114. 114.
    L. Ernster, P. Forsmark, and K. Nordenbrand, The mode of action of lipid-soluble antioxidants in biological membranes: Relationship between the effects of ubiquinol and vitamin E as inhibitors of lipid peroxidation in submitochondrial particles, BioFactors 3(4), 241–248 (1992).PubMedGoogle Scholar
  115. 115.
    F. Aberg, E. L. Appelkvist, G. Dallner, and L. Ernster, Distribution and redox state of ubiquinones in rat and human tissues, Arch. Biochem. Biophys. 295(2), 230–234 (1992).PubMedCrossRefGoogle Scholar
  116. 116.
    M. E. Götz, A. Dirr, W. Gsell, R. Burger, B. Janetzky, A. Freyberger, H. Reichmann, W.-D. Rausch, and P. Riederer, Influence of N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, lipoic acid, and L-deprenyl on the interplay between cellular redox systems, J. Neural Transm. 43 (Suppl.), 145–162 (1994).Google Scholar
  117. 117.
    C. W. Shults, R.H. Haas, D. Passov, and F. Beal, Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects, Ann. Neurol. 42(2), 261–264 (1997).PubMedCrossRefGoogle Scholar
  118. 118.
    J. P. Sheehan, R.H. Swerdlow, W.D. Parker, S.W. Miller, R.E. Davis, and J. B. Tuttle, Altered calcium homeostasis in cells transformed by mitochondria from individuals with Parkinson’s disease, J. Neurochem. 68(3), 1221–1233 (1997).PubMedCrossRefGoogle Scholar
  119. 119.
    M. E. Götz, A. Dirr, R. Burger, B. Janetzky, M. Weinmül ler, W. W. Chan, S. C. Chen, H. Reichmann, W.-D. Rausch, and P. Riederer, Effect of lipoic acid on redox state of coenzyme Q in mice treated with 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine and diethyldithiocarbamate, Eur. J. Pharmacol. Mol. Pharmacol. Sect. 266(3), 291–300 (1994).CrossRefGoogle Scholar
  120. 120.
    M. F. Beal, D. R. Henshaw, B. G. Jenkins, B. R. Rosen, and J. B. Schulz, Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate, Ann. Neurol. 36(6), 882–888 (1994).PubMedCrossRefGoogle Scholar
  121. 121.
    J. B. Schulz, D. R. Henshaw, R. T. Matthews, and M. F. Beal, Coenzyme Q10 and nicotinamide and a free radical spin trap protect against MPTP neurotoxicity, Exp. Neurol. 132(2), 279–283 (1995).PubMedCrossRefGoogle Scholar
  122. 122.
    R. T. Matthews, L. Yang, S. Browne, M. Baik, and M. F Beal, Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects, Proc. Natl. Acad. Sci. U.S.A. 95(15), 8892–8897 (1998).PubMedCrossRefGoogle Scholar
  123. 123.
    J. Fallon, R. T. Matthews, B. T. Hyman, and M. F. Beal, MPP+ produces progressive neuronal degeneration which is mediated by oxidative stress, Exp. Neurol. 144(1), 193–198 (1997).PubMedCrossRefGoogle Scholar
  124. 124.
    S. E. Stephans, T. S. Whittingham, A. J. Douglas, W. D. Lust, and B. K. Yamamoto, Substrates of energy metabolism attenuate methamphetamine-induced neurotoxicity in striatum, J. Neuochem. 71(2), 613–621 (1998).CrossRefGoogle Scholar
  125. 125.
    M. F. Beal, Coenzyme Q10 as a possible treatment for neurodegenerative diseases, Free Radic. Res. 36(4), 455–60 (2002).PubMedCrossRefGoogle Scholar
  126. 126.
    R. J. Ferrante, O. A. Andreassen, A. Dedeoglu, K. L. Ferrante, B. G. Jenkins, S. M. Hersch, and M. F. Beal, Therapeutic effects of coenzyme Q10 and remacide in transgenic mouse models of Huntington’s disease, J. Neurosci. 22(5), 1592–1599 (2002).PubMedGoogle Scholar
  127. 127.
    R. P. Ostrowski, Effect of coenzyme Q(10) on biochemical and morphological changes in experimental ischemia in the rat brain, Brain Res. Bull. 53(4), 399–407 (2000).PubMedCrossRefGoogle Scholar
  128. 128.
    H. Li, G. Klein, P. Sun, and A. M. Buchan, CoQ10 fails to protect brain against focal and global ischemia in rats, Brain Res. 877(1), 7–11 (2000).PubMedCrossRefGoogle Scholar
  129. 129.
    M. E. Götz, A. Gerstner, R. Harth, A. Dirr, B. Janetzky, W. Kuhn, P. Riederer, and M. Gerlach, Altered redox state of platelet coenzyme Q10 in Parkinson’s disease, J. Neural Transm. 107, 41–48 (2000).PubMedCrossRefGoogle Scholar
  130. 130.
    E. Strijks, H. P. Kremer, and M. W. Horstink, Q10 therapy in patients with idiopathic Parkinson’s disease, Mol. Aspects Med. 18(Suppl), S237–240 (1997).PubMedCrossRefGoogle Scholar
  131. 131.
    K. Lonnrot, T. Metsa-Ketela, G. Molnar, J. P. Ahonen, M. Latvala, J. Peltola, T. Pietila, and H. Alho, The effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity, Free Radic. Biol. Med. 21(2), 211–217 (1996).PubMedCrossRefGoogle Scholar
  132. 132.
    L. Packer, H. J. Tritschler, and K. Wessel, Neuroprotection by the metabolic antioxidant α-lipoic acid, Free Radic. Biol. Med. 22(1-2), 359–378 (1997).CrossRefGoogle Scholar
  133. 133.
    A. Bast, and G. R. M. M. Haenen, Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation, Biochem. Biophys. Acta 963(3), 558–561 (1988).PubMedCrossRefGoogle Scholar
  134. 134.
    H. Scholich, M. E. Murphy, and H. Sies, Antioxidant activity of dihydrolipoate against microsomal lipid peroxidation and its dependence on α-tocopherol, Biochem. Biophys. Acta 1001(3), 256–261 (1989).PubMedCrossRefGoogle Scholar
  135. 135.
    M. Panigrahi, Y. Sadguna, B. R. Shivakumar, S. V. Kolluri, S. Roy, L. Packer, and V. Ravindranath, α-Lipoic acid protects against reperfusion injury following cerebral ischemia in rats, Brain Res. 717(1-2), 184–188 (1996).PubMedCrossRefGoogle Scholar
  136. 136.
    P. Wolz, and J. Krieglstein, Neuroprotective effects of α-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia. Neuropharmacology 35(3), 369–375 (1996).PubMedCrossRefGoogle Scholar
  137. 137.
    N. Aguirre, M. Barrionuevo, M. J. Ramirez, J. Del Rio, and B. Lasheras, a-Lipoic acid prevents 3,4-methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity, Neuroreport 10(17), 3675–3680 (1999).PubMedCrossRefGoogle Scholar
  138. 138.
    O. A. Andreassen, R. J. Ferrante, A. Dedeoglu, and M. F. Beal, Lipoic acid improves survival in transgenic mouse models of Huntington’s disease, Neuroreport 12(15), 3371–3373 (2001).PubMedCrossRefGoogle Scholar
  139. 139.
    O. A. Andreassen, A. Dedeoglu, A. Friedlich, K. L. Ferrante, D. Hughes, C. Szabo, and M.F. Beal, Effects of an inhibitor of poly(ADP-ribose)polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice, Exp. Neurol. 168(2), 419–424 (2001).PubMedCrossRefGoogle Scholar
  140. 140.
    M. F. McCarty, Versatile cytoprotective activity of lipoic acid may reflect its ability to activate signalling intermediates that trigger the heat-shock and phase II responses, Med. Hypotheses 57(3), 313–317 (2001).PubMedCrossRefGoogle Scholar
  141. 141.
    L. Zhang, G. Q. Xing, J. L. Barker, Y. Chang, D. Maric, W. Ma, B. S. Li, and Rubinow, α-Lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway, Neurosci. Lett. 312(3), 125–128 (2001).PubMedCrossRefGoogle Scholar
  142. 142.
    B. Drukarch, and F. L. van Muiswinkel, Neuroprotection for Parkinson’s disease: a new approach for a new millennium, Expert Opinion on Investigational Drugs 10(10), 1855–1868 (2001).PubMedCrossRefGoogle Scholar
  143. 143.
    J. Flier, F. L. Van Muiswinkel, C. A. Jongenelen, and B. Drukarch, The neuroprotective antioxidant α-lipoic acid induces detoxication enzymes in cultured astroglial cells, Free Radic. Res. 36(6), 695–699 (2002).PubMedCrossRefGoogle Scholar
  144. 144.
    K. Hager, A. Marahrens, M. Kenklies, P. Riederer, and G. Münch, α-Lipoic acid as a new treatment option for Alzheimer type dementia, Arch. Geronlol. Geriatr. 32(3), 275–282 (2001).CrossRefGoogle Scholar
  145. 145.
    J. C. Watkins, P. Krogsgaard-Larsen, and T. Honore’, Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists, in: Trends in Pharmacological Sciences, The Pharmacology of Excitatory Amino Acids, Special Report, edited by D. Lodge, and G. L. Collingridge, (Elsevier, Amsterdam, 1991). pp. 4–12.Google Scholar
  146. 146.
    D.T. Monaghan, R. J. Bridges, and C. W. Cotman, The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system, Ann. Rev. Pharmacol. Toxicol. 29, 365–402 (1989).CrossRefGoogle Scholar
  147. 147.
    M. DiFiglia, M. Excitotoxic injury of the neostriatum: a model for Huntington’s disease, Trends Neurosci. 13(7), 286–289 (1990).CrossRefGoogle Scholar
  148. 148.
    M. H. M. Bakker, and A. C. Foster, An investigation of the mechanism of delayed neurodegeneration caused by direct injection of quinolinate into the rat striatum in vivo. Neuroscience 42(2), 387–395 (1991).PubMedCrossRefGoogle Scholar
  149. 149.
    H. S. Chen, J. W. Pellegrini, S. K. Aggarwal, S. Z. Lei, S. Warach, F. E. Jensen, and S. A. Upton, Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J. Neurosci. 12(11), 4427–4436 (1992).PubMedGoogle Scholar
  150. 150.
    H. S. Lustig, K. V. Ahem and D. A. Greenberg, Antiparkinsonian drugs and in vitro excitotoxicity, Brain Res. 597(1), 148–150 (1992).PubMedCrossRefGoogle Scholar
  151. 151.
    D. L. Small, and A. M. Buchan, NMDA antagonists: their role in neuroprotection, Int. Rev. Neurobiol. 40, 137–171 (1997).PubMedCrossRefGoogle Scholar
  152. 152.
    W. Danielczyk, Therapy of akinetic crises, Med. Welt 24, 1278–1282 (1973).PubMedGoogle Scholar
  153. 153.
    R. J. Uitti, A. H. Rajput, J. E. Ahlskog, K. P. Offord, D. R. Schroeder, M. M. Ho, M. Prasad, A. Rajput, and P. Basran, Amantadine treatment is an independent predictor of improved survival in Parkinson’s disease, Neurology 46(6), 1551–1556 (1996).PubMedCrossRefGoogle Scholar
  154. 154.
    R. J. Uitti, More recent lessons from amantadine, Neurology 52(3), 676 (1999).PubMedCrossRefGoogle Scholar
  155. 155.
    K. L. R. Jansen, R. L. M. Faull, M. Dragunow, and B. L. Synek, Alzheimer’s disease: changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensine, adenosine, benzodiazepine, serotonin and opioid receptors, an autoradiographic study. Neuroscience 39(3), 613–627 (1990).PubMedCrossRefGoogle Scholar
  156. 156.
    J. W. Newcomer, and J. H. Krystal, NMDA receptor regulation of memory and behavior in humans, Hippocampus 11(5), 529–542 (2001).PubMedCrossRefGoogle Scholar
  157. 157.
    K. A. Habemy, M. G. Paule, A. C. Scallet, F. D. Sistare, D. S. Lester, J. P. Hanig, and W. Slikker Jr., Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity, Toxicol. Sci. 68(1), 9–17 (2002).CrossRefGoogle Scholar
  158. 158.
    B. K. Siesjö, H. Memezawa, and M. L. Smith, Neurotoxicity: pharmacological implications, Fundam. Clin. Pharmacol. 5(9), 755–767 (1991).PubMedCrossRefGoogle Scholar
  159. 159.
    G. G. C. Hwa, and M. Avoli, The involvement of excitatory amino acids in neocortical epileptogenesis: NMDA and non-NMDA receptors. Exp. Brain Res. 86(2), 248–256 (1991).PubMedCrossRefGoogle Scholar
  160. 160.
    B. K. Kohl, and G. Dannhardt, The NMDA receptor complex: a promising target for novel antiepileptic strategies, Curr. Med Chem. 8(11), 1275–1289 (2001).PubMedGoogle Scholar
  161. 161.
    K. Williams, Ifenprodil, a novel NMDA receptor antagonist: site and mechanism of action, Curr. Drug Targets 2(3), 285–298 (2001).PubMedCrossRefGoogle Scholar
  162. 162.
    J. Ruel, M. J. Guitton, and J. L. Puell, Negative allosteric modulation of AMPA-preferring receptors by the selective isomer GYK1 53784 (LY303070), a specific non-competitive AMPA antagonist, CNS Drug Rev. 8(3), 235–254 (2002).PubMedCrossRefGoogle Scholar
  163. 163.
    D. M. Turetsky, L. M. T. Canzoniero, and D. W. Choi, Kainate-induced toxicity in cultured neocortical neurons is reduced by the AMPA receptor selective antagonist SYM2206, Soc. Neurosci. Abstr. 24, 578 (1998).Google Scholar
  164. 164.
    J. Cartmell, and D. D. Schoepp, Regulation of neurotransmitter release by metabotropic glutamate receptors, J. Neurochem. 75(3), 889–907 (2000).PubMedCrossRefGoogle Scholar
  165. 165.
    A. Stefani, A. Pisani, N. B. Mercuri, and P. Calabresi, The modulation of calcium currents by the activation of mGluRs, functional implications, Mol. Neurobiol. 13(1), 81–95 (1996).PubMedCrossRefGoogle Scholar
  166. 166.
    V. Bruno, G. Battaglia, I. Ksiazek, H. van der Putten, M. V. Catania, R. Giuffrida, S. Lukic, T. Leonhardt, W. Inderbitzin, F. Gasparini, R. Kuhn, D. R. Hampson, F. Nicoletti, and P. J. Flor, Selective activation of mGlu4 metabotropic glutamate receptors is protective against excitotoxic neuronal death. J. Neurosci. 20(17), 6413–6420 (2000).PubMedGoogle Scholar
  167. 167.
    J. R. Brorson, P. A. Manzolillo, and R. J. Miller, Calcium entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells, J. Neurosci. 14(1), 187–197 (1994).PubMedGoogle Scholar
  168. 168.
    K. S. Lee, S. Frank, P. Vanderklish, A. Arai, and G. Lynch, Inhibition of proteolysis protects hippocampal neurons from ischemia, Proc. Natl. Acad. Sci. U. S. A. 88(16), 7233–7237 (1991).PubMedCrossRefGoogle Scholar
  169. 169.
    C. G. Markgraf, N. L. Velajo, M. P. Johnson, D. R. McCarty, S. Medhi, J. R. Koehl, P. A. Chmielewski, and M. D. Linnik, Six-hour window of opportunity for calpain inhibition in focal cerebral ischemia in rats. Stroke 29(1), 152–158 (1998).PubMedCrossRefGoogle Scholar
  170. 170.
    M. Miyamoto, and J. T. Coyle, Idebenone atttenuates neuronal degeneration induced by intrastriatal injection of excitotoxins, Exp. Neurol. 108(1), 38–45 (1990).PubMedCrossRefGoogle Scholar
  171. 171.
    H. Monyer, D. M. Hartley, and D. W. Choi, 21-Aminosteroids attenuate excitotoxic neuronal injury in cortical cell cultures, Neuron 5(2), 121–126 (1990).PubMedCrossRefGoogle Scholar
  172. 172.
    J. S. Beckman, and W. H. Koppenol, Nitric oxide, Superoxide, and peroxynitrite: the good, the bad, and ugly. Am. J. Physiol. 271(5 Pt 1), C1424–1437 (1996).PubMedGoogle Scholar
  173. 173.
    L. L. Dugan, S. L. Sensi, L. M. Canzoniero, S. D. Handran, S. M. Rothman, T. S. Lin, M. P.Goldberg, and D. W. Choi, Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate, J. Neurosci. 15(10), 6377–6388 (1995).PubMedGoogle Scholar
  174. 174.
    A. F. Schinder, E. C. Olson, N. C. Spitzer, and M. Montai, Mitochondrial dysfunction is a primary event in glutamate neurotoxicity, J. Neurosci. 16(19), 6125–6133 (1996).PubMedGoogle Scholar
  175. 175.
    E. P. Wei, M. D. Ellison, H. A. Kontos, and J. T. Povlishock, O2 radicals in arachidonate-induced increased blood-brain barrier permeability to proteins, Am. J. Physiol. 251(4 Pt 2), H693–699 (1986).PubMedGoogle Scholar
  176. 176.
    S. J. Hewett, T. F. Uliasz, A. S. Vidwans, and J. A. Hewett, Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture, J. Pharmacol. Exp. Ther. 293(3), 417–425 (2000).PubMedGoogle Scholar
  177. 177.
    M. P. Mattson, Stabilizing calcium homeostasis, in: Handbook of Experimental Pharmacology, CNS Neuroprotection, edited by F. W. Marcoux, and D. W. Choi (Springer-Verlag, Berlin, New York, 2002), pp. 115–153.Google Scholar
  178. 178.
    J. W. Phillis, Neuroprotection by free radical scavengers and other antioxidants, in: Handbook of Experimental Pharmacology, CNS Neuroprotection, edited by F. W. Marcoux, and D. W. Choi (Springer-Verlag, Berlin, New York, 2002), pp. 245–280.Google Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Mario E. Götz
    • 1
  • Peter Riederer
    • 2
  1. 1.Institute of Pharmacology and ToxicologyWürzburgGermany
  2. 2.Department of Psychiatry, Head Division of Clinical NeurochemistryWürzburgGermany

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