title: Exogenous t-PA administration increases hippocampal mature BDNF levels. plasmin- or NMDA-dependent mechanism?
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.
authors.affiliation: Unité INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Dijon, France; Université de Bourgogne, Dijon, France; Department of Neurology, University Hospital, Dijon, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Rodier
authors.affiliation: Unité INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Dijon, France; Université de Bourgogne, Dijon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Prigent-Tessier
authors.affiliation: Department of Neurology, University Hospital, Dijon, France; Centre d'Epidémiologie des Populations, EA4184, Dijon, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Béjot
authors.affiliation: Department of Neurology, University Hospital, Dijon, France; Centre d'Epidémiologie des Populations, EA4184, Dijon, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Jacquin
authors.affiliation: Unité INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Dijon, France; Université de Bourgogne, Dijon, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Mossiat
authors.affiliation: Unité INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Dijon, France; Université de Bourgogne, Dijon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Marie
authors.affiliation: Unité INSERM U1093 Cognition, Action et Plasticité Sensorimotrice, Dijon, France; Université de Bourgogne, Dijon, France; Département Génie Biologique, IUT, Dijon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Garnier
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005341:Fibrinolysin / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000494:pharmacology*; D014148:Tranexamic Acid / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; C426674:brain-derived neurotrophic factor precursor; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D014148:Tranexamic Acid; D020813:Receptor, trkB; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin