EFFECT OF FLUPIRTINE ON BCL-2 AND GLUTATHIONE LEVEL IN NEURONAL CELLSTREATED IN-VITRO WITH THE PRION PROTEIN-FRAGMENT (PRP-106-126)

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.