Date Published: December 1, 2009
Publisher: Public Library of Science
Author(s): Alexandre Madinier, Nathalie Bertrand, Claude Mossiat, Anne Prigent-Tessier, Alain Beley, Christine Marie, Philippe Garnier, Colin Combs. http://doi.org/10.1371/journal.pone.0008101
Abstract: The pathogenesis of ischemic stroke is a complex sequence of events including inflammatory reaction, for which the microglia appears to be a major cellular contributor. However, whether post-ischemic activation of microglial cells has beneficial or detrimental effects remains to be elucidated, in particular on long term brain plasticity events. The objective of our study was to determine, through modulation of post-stroke inflammatory response, to what extent microglial cells are involved in some specific events of neuronal plasticity, neurite outgrowth and synaptogenesis. Since microglia is a source of neurotrophic factors, the identification of the brain-derived neurophic factor (BDNF) as possible molecular actor involved in these events was also attempted. As a means of down-regulating the microglial response induced by ischemia, 3-aminobenzamide (3-AB, 90 mg/kg, i.p.) was used to inhibit the poly(ADP-ribose) polymerase-1 (PARP-1). Indeed, PARP-1 contributes to the activation of the transcription factor NF-kB, which is essential to the upregulation of proinflammatory genes, in particular responsible for microglial activation/proliferation. Experiments were conducted in rats subjected to photothrombotic ischemia which leads to a strong and early microglial cells activation/proliferation followed by an infiltration of macrophages within the cortical lesion, events evaluated at serial time points up to 1 month post-ictus by immunostaining for OX-42 and ED-1. Our most striking finding was that the decrease in acute microglial activation induced by 3-AB was associated with a long term down-regulation of two neuronal plasticity proteins expression, synaptophysin (marker of synaptogenesis) and GAP-43 (marker of neuritogenesis) as well as to a significant decrease in tissue BDNF production. Thus, our data argue in favour of a supportive role for microglia in brain neuroplasticity stimulation possibly through BDNF production, suggesting that a targeted protection of microglial cells could represent an innovative approach to potentiate post-stroke neuroregeneration.
Partial Text: The pathogenesis of ischemic stroke is a complex sequence of events including inflammatory reaction. Extensively studied over the last decade, this phenomenon is characterized by the involvement of several central and peripheral cell types as well as a large number of inflammatory molecules –. Post-ischemic inflammation includes the infiltration of polymorphonuclear granulocytes, monocytes/macrophages into the injured brain and the activation of astrocytes and microglia. Among these cells, it is now well admitted that microglia appears to be a major cellular contributor of post-ischemic inflammation . After focal ischemia, reactive microgliosis is characterized by a specific chronology which includes a rapid microglial activation followed by a massive expansion and migration of the resident microglial cells. Several studies have shown that this initial intrinsic response is followed by the recruitment of blood-born macrophages which migrate after a delay of several days into the neuronal parenchyma –.
Our study reveals that the decrease in acute microglial activation was associated with a long term down regulation of synaptophysin and GAP-43 expression and to a significant decrease in BDNF production. Taken together, our data argue in favour of an important role for microglia in brain neuroplasticity stimulation possibly through BDNF production.