Exogenous t-PA administration increases hippocampal mature BDNF levels. plasmin- or NMDA-dependent mechanism?
Authors: Claude Mossiat
Yannick Béjot
Anne Prigent-Tessier
Marion Rodier
Christine Marie
Philippe Garnier
Agnès Jacquin
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: Brain-derived neurotrophic factor (BDNF); TrkB activation; plasmin; tissue plasminogen activator (tPA); N-methyl-D-aspartate (NMDA) receptor
Affiliations: Unité INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Dijon, France; Université de Bourgogne, Dijon, France; Department of Neurology, University Hospital, Dijon, France., Unité INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Dijon, France; Université de Bourgogne, Dijon, France., Department of Neurology, University Hospital, Dijon, France; Centre d'Epidémiologie des Populations, EA4184, Dijon, France., Unité INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Dijon, France; Université de Bourgogne, Dijon, France; Département Génie Biologique, IUT, Dijon, France.

Abstract:  Brain-derived neurotrophic factor (BDNF) through TrkB activation is central for brain functioning. Since the demonstration that plasmin is able to process pro-BDNF to mature BDNF and that these two forms have opposite effects on neuronal survival and plasticity, a particular attention has been paid to the link between tissue plasminogen activator (tPA)/plasmin system and BDNF metabolism. However, t-PA via its action on different N-methyl-D-aspartate (NMDA) receptor subunits is also considered as a neuromodulator of glutamatergic transmission. In this context, the aim of our study was to investigate the effect of recombinant (r)t-PA administration on brain BDNF metabolism in rats. In the hippocampus, we found that rt-PA (10 mg/kg) administration induced a progressive increase in mature BDNF levels associated with TrkB activation. In order to delineate the mechanistic involved, plasmin activity was assessed and its inhibition was attempted using tranexamic acid (30 or 300 mg/kg, i.v.) while NMDA receptors were antagonized with MK801 (0.3 or 3 mg/kg, i.p.) in combination with rt-PA treatment. Our results showed that despite a rise in rt-PA activity, rt-PA administration failed to increase hippocampal plasmin activity suggesting that the plasminogen/plasmin system is not involved whereas MK801 abrogated the augmentation in mature BDNF levels observed after rt-PA administration. All together, our results show that rt-PA administration induces increase in hippocampal mature BDNF expression and suggests that rt-PA contributes to the control of brain BDNF synthesis through a plasmin-independent potentiation of NMDA receptors signaling. 

Retracted: Yes

PubPeer comments:
 Figures 2, 3, 5, and 6. * Some bands depicting different proteins or experimental conditions look more similar to each other than one would expect. Reported to the journal in October 2015, but no action taken as of today. ![file] , 
 2021 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0255763 After this article [1] was published, concerns were raised about the reported results. Specifically: Similarities were noted between western blot bands reported in Figs 2, 3, 5, and 6. These concerns involve most of the western blot image data shown. There appear to be differences in band sequences across panels (i.e. similar bands abut dissimilar bands in different panels), and when image levels are adjusted there appear to vertical discontinuities between some lanes of Figs 3A, 3B, 5A, and 6. These issues suggest that images may have been spliced in assembling the figures. The PLOS Publication Ethics team investigated these issues and asked the authors to comment on these concerns. The authors did not respond to our inquiries. However, after the retraction decision was communicated, the corresponding author acknowledged that identical western blot bands were used to represent protein expression in the articleu2019s figures, but noted that the blot images were presented only as representative of the results and that the statistical analyses reflect analysis of data from three separate experiments. The authors did not provide original image data needed to support the results or clarify the image data reporting concerns, stating they were unable to do so due to the passage of time. The concerns about the western blot data remain unresolved and call into question the reliability of the reported results. Therefore, the PLOS ONE Editors retract this article. We regret that the issues with the articleu2019s figures were not identified prior to publication. MR, APT, YB, CM, PG did not agree with retraction and stand by the articleu2019s findings. The other authors either could not be reached or did not respond directly. Reference 1.Rodier M, Prigent-Tessier A, Bu00e9jot Y, Jacquin A, Mossiat C, Marie C, et al. (2014) Exogenous t-PA Administration Increases Hippocampal Mature BDNF Levels. Plasmin- or NMDA-Dependent Mechanism? PLoS ONE 9(3): e92416. ,