Rodier Marion, Prigent-Tessier Anne, Béjot Yannick, Jacquin Agnès, Mossiat Claude, Marie Christine, Garnier Philippe
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.
PLoS One. 2014 Mar 26;9(3):e92416. doi: 10.1371/journal.pone.0092416. eCollection 2014.
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.
脑源性神经营养因子（BDNF）通过激活TrkB对大脑功能至关重要。自从有研究表明纤溶酶能够将前体BDNF加工成成熟BDNF，且这两种形式对神经元存活和可塑性具有相反作用以来，人们对组织纤溶酶原激活物（tPA）/纤溶酶系统与BDNF代谢之间的联系给予了特别关注。然而，t-PA通过对不同的N-甲基-D-天冬氨酸（NMDA）受体亚基起作用，也被认为是谷氨酸能传递的神经调节剂。在此背景下，我们研究的目的是探讨重组（r）t-PA给药对大鼠脑内BDNF代谢的影响。在海马体中，我们发现给予rt-PA（10mg/kg）会导致与TrkB激活相关的成熟BDNF水平逐渐升高。为了阐明其中涉及的机制，我们评估了纤溶酶活性，并尝试用氨甲环酸（30或300mg/kg，静脉注射）抑制其活性，同时在rt-PA治疗的基础上，用MK801（0.3或3mg/kg，腹腔注射）拮抗NMDA受体。我们的结果表明，尽管rt-PA活性有所升高，但给予rt-PA未能增加海马体纤溶酶活性，这表明纤溶酶原/纤溶酶系统未参与其中，而MK801消除了rt-PA给药后观察到的成熟BDNF水平的升高。总之，我们的结果表明，给予rt-PA可诱导海马体成熟BDNF表达增加，并表明rt-PA通过对NMDA受体信号的纤溶酶非依赖性增强作用，有助于控制脑内BDNF的合成。
