Relevance of Post-Stroke Circulating BDNF Levels as a Prognostic Biomarker of Stroke Outcome. Impact of rt-PA Treatment.

Marion Rodier,Philippe Garnier,Aurore Quirié,Agnès Jacquin,Yannick Béjot,Claude Mossiat,Christine Marie,Anne Prigent-Tessier,Thierry Amédée

doi:10.1371/journal.pone.0140668

Abstract

The recombinant form of tissue plasminogen activator (rt-PA) is the only curative treatment for ischemic stroke. Recently, t-PA has been linked to the metabolism of brain-derived neurotrophic factor (BDNF), a major neurotrophin involved in post-stroke neuroplasticity. Thus, the objective of our study was to investigate the impact of rt-PA treatment on post-stroke circulating BDNF levels in humans and in animals. Serum BDNF levels and t-PA/plasmin activity were measured at hospital admission and at up to 90 days in stroke patients receiving (n = 24) or not (n = 14) rt-PA perfusion. We investigated the relationships between serum BDNF with concurrent t-PA/plasmin activity, neurological outcomes and cardiovascular scores at admission. In parallel, serum BDNF levels and t-PA/plasmin activity were assessed before and after (1, 4 and 24h) the induction of ischemic stroke in rats. Our study revealed higher serum BDNF levels and better neurological outcome in rt-PA-treated than non-treated patients. However, serum BDNF levels did not predict stroke outcome when the whole cohort of stroke patients was analyzed. By contrast, serum BDNF levels when measured at admission and at day 90 correlated with cardiovascular scores, and those at day 1 correlated with serum t-PA/plasmin activity in the whole cohort of patients whereas no association could be found in the rt-PA-treated group. In rats devoid of cardiovascular risk, no difference in post-stroke serum BDNF levels was detected between rt-PA- and vehicle-treated animals and no correlation was found between serum BDNF levels and t-PA/plasmin activity. Overall, the data suggest that serum BDNF levels may not be useful as a prognostic biomarker of stroke outcome and that endothelial dysfunction could be a confounding factor when serum BDNF levels after stroke are used to reflect of brain BDNF levels.

Highlights

Despite intensive preclinical research that has led to a better characterization of the complex pathogenesis of stroke, the only available curative pharmacological treatment for stroke patients is the recombinant form of the tissue plasminogen activator
In order to verify whether or not these differences in serum brain-derived neurotrophic factor (BDNF) levels were due to changes in thrombocythemia, the platelet count was assessed from day 0 to day 7 (Table 3)
Our study revealed higher serum BDNF levels in the acute period following hospital admission and better neurological recovery in recombinant form of the tissue plasminogen activator (rt-PA)-treated than in non-treated stroke patients

Summary

Introduction

Despite intensive preclinical research that has led to a better characterization of the complex pathogenesis of stroke, the only available curative pharmacological treatment for stroke patients is the recombinant form of the tissue plasminogen activator (rt-PA). T-PA is involved in neuronal migration and synaptic outgrowth during development while in the adult brain, t-PA is implicated in neurotransmission, synaptic plasticity and cognitive function [2,3,4]. The pleiotropic effects of t-PA, which is able to cross blood brain barrier [6] can be explained by the activation of numerous receptors expressed by cells of the neurovascular unit [7] and by direct or indirect (plasmin) proteolytic action. It has been established that t-PA through plasmin activation is involved in the cleavage of proBDNF into its mature form [11,12] and that exogenous t-PA increases mature BDNF expression in the hippocampus through N-methyl-D-aspartate (NMDA) receptor activation [13]

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