Flupirtine Partially Prevents Neuronal Injury Induced by Prion Protein Fragment and Lead Acetate |
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| Institution: | 1. Douglas Stephens Surgical Research Group, Murdoch Children''s Research Institute, Melbourne, Australia;2. Department of Paediatrics, University of Melbourne, Australia;3. Department of Paediatric Surgery, Rigshospitalet, Copenhagen, Denmark;4. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;5. Department of Pathology, Rigshospitalet, Copenhagen, Denmark;6. Department of Pediatrics, Hvidovre University Hospital and University of Copenhagen, Denmark;7. Department of Urology, The Royal Children''s Hospital, Melbourne, Australia;1. Division of Endocrinology and Metabolism, Indiana University, Indianapolis, Indiana.;2. Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana.;3. Section of Pediatric Endocrinology, Riley Hospital for Children, Indiana University, Indianapolis, Indiana. |
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| Abstract: | Flupirtine belongs to the class of triaminopyridines and is successfully applied clinically as a non-opiate analgesic drug with additional muscle relaxant properties. Recently it was reported that flupirtine acts like an antagonist of the N-methyl-D-aspartate (NMDA) receptor complex in neuronal cells bothin vitroandin vivo. Here we have used primary cortical cells from rat embryos to demonstrate that this compound is also neuroprotective against the toxic effects caused by the prion agent PrPScand lead acetate (Pb). These two agents display pleiotropic effects on neurons, which include activation of the NMDA receptor complex. At concentrations above 30 μM the toxic-peptide fragment of PrPSccauses apoptotic fragmentation of DNA and is consequently neurotoxic. Pb is neurotoxic at concentrations above 10 μM. Co-administration of flupirtine (10 μM) with either of these agents resulted in reduced neurotoxicity. These data indicate that the cytoprotective effect of flupirtine is measurablein vitroagainst these noxious agents which show their effects, including modulation of the NMDA receptor complex, pleiotropically. |
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