S. Perovic et al., EFFECT OF FLUPIRTINE ON BCL-2 AND GLUTATHIONE LEVEL IN NEURONAL CELLSTREATED IN-VITRO WITH THE PRION PROTEIN-FRAGMENT (PRP-106-126), Experimental neurology, 147(2), 1997, pp. 518-524
Flupirtine, trade name Katadolon, is a centrally acting nonopioid anal
gesic that has recently been found to display cytoprotective activity
in vitro and in vivo on neurons induced to undergo apoptosis, This rep
ort shows that the PrP106-126 fragment of the prion protein, which is
the likely etiological agent for a series of encephalopathies, is toxi
c to cortical neurons in vitro. Simultaneously, PrP106-126 influences
the molecular GSM content and the bcl-2 expression in neurons. Signifi
cant toxicity (32% reduction in cell viability) was observed at a conc
entration of 50 mu 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 mu g/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 cond
itions that reduce cell toxicity. Hn addition to normalizing GSH conte
nt, flupirtine induced the expression of the anti-apoptotically acting
proto-oncogene bcl-2. Based on these in vitro data and on the favorab
le pharmacokinetic profile of the drug, we strongly suggest that flupi
rtine may prove useful far treatment of patients with prion disease. (
C) 1997 Academic Press.