Microglial Involvement in Neuroplastic Changes Following Focal Brain Ischemia in Rats

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.

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

“…PARP-1 was inhibited to dampen the microglial response to hypoxia-ischemia, but it resulted in a dampened response of BDNF in the infarct zone. They also showed decreased expression of the intracellular neuronal growth protein GAP-43 and synaptophysin, an integral membrane protein of synaptic vesicles and a marker of Articles synaptogenesis (31). Similarly, the increased microglia in our model may be a source for neurotrophic factors.…”

“…In an ischemic stroke rat model, Madinier et al demonstrated that decreased microglial activation was associated with decreased tissue brain derived neurotrophic factor (BDNF) expression (31). PARP-1 was inhibited to dampen the microglial response to hypoxia-ischemia, but it resulted in a dampened response of BDNF in the infarct zone.…”

Thinning, movement, and volume loss of residual cortical tissue occurs after stroke in the adult rat as identified by histological and magnetic resonance imaging analysis

“…Both basic fibroblast growth factor (bFGF) and brain derived neurotrophic factor (BDNF) are known to be upregulated in distal astrocytes and neurons between 1 and 3 days post-stroke (Lippoldt et al, 1993;Madinier et al, 2009;Speliotes et al, 1996;Wei et al, 2000). Increased neurotrophic factor expression is thought to promote dendritic and axonal sprouting in residual cortical tissue in order to support compensatory recovery.…”

Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats

“…Available studies support increased BDNF production after stroke as suggested by increased BDNF levels in areas collected either at the lesion site or around the lesion for at least one week following stroke (Kokaia et al, 1998;Madinier et al, 2009;Sulejczak et al, 2007). Because increased levels of BDNF mRNA were observed in degenerating and surviving neurons in the acute post-stroke period (Comelli et al, 1992;Kokaia et al, 1995;Rickhag et al, 2007;Zhao et al, 2000), it has been generally accepted that neurons are the predominant source of neosynthesized BDNF in the ischemic brain.…”

“…Interventions that improve recovery of function are most often associated with increased BDNF levels in perilesional areas (Chen et al, 2005b;Kim et al, 2005;Vaynman et al, 2004). Conversely, attenuating BDNF levels or its effects following cerebral ischemia reduces neuroplastic changes or recovery of function either spontaneous or induced by rehabilitation (Chen et al, 2005a;Madinier et al, 2009;Ploughman et al, 2009). From these data, pharmacological strategies aimed at increasing post-ischemic cerebral BDNF production appear to be a promising option in the treatment of stroke.…”