Effect of Flupirtine on Bcl-2 and Glutathione Level in Neuronal Cells Treated in Vitro with the Prion Protein Fragment (PrP106-126)

Effect of Flupirtine on Bcl-2 and Glutathione Level in Neuronal Cells Treated in Vitro with the... Flupirtine, trade name Katadolon, is a centrally acting nonopioid analgesic that has recently been found to display cytoprotective activity in vitro and in vivo on neurons induced to undergo apoptosis. This report shows that the PrP106-126 fragment of the prion protein, which is the likely etiological agent for a series of encephalopathies, is toxic to cortical neurons in vitro. Simultaneously, PrP106–126 influences the molecular GSH content and the bcl-2 expression in neurons. Significant toxicity (32% reduction in cell viability) was observed at a concentration of 50 μ M of the peptide after 9 days of incubation, while at higher concentrations toxicity increased to 70%. Neurotoxicity was greatly reduced following coincubation with 1 to 3 μg/ml flupirtine. Concomitant with PrP106-126-mediated cytotoxicity, glutathione (GSH) content fell by >70% with respect to untreated controls. This decrease in GSH level was strongly blocked by flupirtine under incubation conditions that reduce cell toxicity. In addition to normalizing GSH content, flupirtine induced the expression of the anti-apoptotically acting proto-oncogene bcl-2. Based on these in vitro data and on the favorable pharmacokinetic profile of the drug, we strongly suggest that flupirtine may prove useful for treatment of patients with prion disease. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Experimental Neurology Elsevier

Effect of Flupirtine on Bcl-2 and Glutathione Level in Neuronal Cells Treated in Vitro with the Prion Protein Fragment (PrP106-126)

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Publisher
Elsevier
Copyright
Copyright © 1997 Academic Press
ISSN
0014-4886
DOI
10.1006/exnr.1997.6559
Publisher site
See Article on Publisher Site

Abstract

Flupirtine, trade name Katadolon, is a centrally acting nonopioid analgesic that has recently been found to display cytoprotective activity in vitro and in vivo on neurons induced to undergo apoptosis. This report shows that the PrP106-126 fragment of the prion protein, which is the likely etiological agent for a series of encephalopathies, is toxic to cortical neurons in vitro. Simultaneously, PrP106–126 influences the molecular GSH content and the bcl-2 expression in neurons. Significant toxicity (32% reduction in cell viability) was observed at a concentration of 50 μ M of the peptide after 9 days of incubation, while at higher concentrations toxicity increased to 70%. Neurotoxicity was greatly reduced following coincubation with 1 to 3 μg/ml flupirtine. Concomitant with PrP106-126-mediated cytotoxicity, glutathione (GSH) content fell by >70% with respect to untreated controls. This decrease in GSH level was strongly blocked by flupirtine under incubation conditions that reduce cell toxicity. In addition to normalizing GSH content, flupirtine induced the expression of the anti-apoptotically acting proto-oncogene bcl-2. Based on these in vitro data and on the favorable pharmacokinetic profile of the drug, we strongly suggest that flupirtine may prove useful for treatment of patients with prion disease.

Journal

Experimental NeurologyElsevier

Published: Oct 1, 1997

References

  • Neuronal cell death in scrapie-infected mice is due to apoptosis
    Giese, A.; Groschup, M.H.; Hess, B.; Kretzschmar, H.A.
  • Molecular biology of prion diseases
    Prusiner, S.B.
  • Biology and genetics of prion diseases
    Prusiner, S.B.
  • Flupirtine protects neurons against excitotoxic or ischemic damage and inhibits the increase in cytosolic Ca 2+
    Rupalla, K.; Cao, W.; Krieglstein, J.
  • Mode of antinociceptive action of Flupirtine in the rat
    Szelenyi, I.; Nickel, B.; Borbe, H.O.; Brune, K.
  • Exposure to gp120 of HIV-1 induces an increased release of arachidonic acid in rat primary neuronal cell culture followed by NMDA receptor mediated neurotoxicity
    Ushijima, H.; Nishio, O.; Klöcking, R.; Perovic, S.; Müller, W.E.G.

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