Microglial Involvement in Neuroplastic Changes Following Focal Brain Ischemia in Rats

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

Physical training and hypertension have opposite effects on endothelial brain-derived neurotrophic factor expression

Aims Changes in circulating brain-derived neurotrophic factor (BDNF) levels were reported in patients with or at risk for cardiovascular diseases associated with endothelial dysfunction, suggesting a link between BDNF and endothelial functionality. However, little is known on cardiovascular BDNF. Our aim was to investigate levels/localization, function, and relevance of cardiovascular BDNF. Methods and results BDNF levels (western blotting) and localization (immunostaining) were assessed in the heart and aorta from rats with impaired (spontaneously hypertensive rats [SHR]), normal (Wistar Kyoto rats [WKY]), and improved (SHR and WKY subjected to physical training) endothelial function. BDNF levels were also measured in cultured endothelial cells (CECs) subjected to low and high shear stress. The cardiovascular effects of BDNF were investigated in isolated aortic rings and hearts. The results showed high BDNF levels in the heart and aorta, the expression being prominent in endothelial cells as compared with other cell types. Exogenous BDNF vasodilated aortic rings but changed neither coronary flow nor cardiac contractility. Hypertension was associated with decreased expression of BDNF in the endothelium, whereas physical training led to endothelial BDNF up-regulation not only in WKY but also in SHR. Exposure of CECs to high shear stress stimulated BDNF production and secretion. Conclusion Cardiovascular BDNF is mainly localized within endothelial cells in which its expression is dependent on endothelial function. These results open new perspectives on the role of endothelial BDNF in cardiovascular healt

''Mechanisms involved in the increase mBDNF after rt-PA infusion?''

Rodier, M. | Mossiat, C. | Marie, C. | Garnier, P.International audienc

''Role of rt-pa on bdnf metabolism in stroke''

Rodier, M. | Mossiat, C. | Marie, C. | Garnier, P.International audienc

Brain BDNF levels elevation induced by physical training is reduced after unilateral common carotid artery occlusion in rats

International audienceWe investigated the contribution of blood flow elevation in the cerebrovasculature to physical training-induced brain-derived neurotrophic factor (BDNF) levels elevation in the brain. Brain-derived neurotrophic factor protein levels were measured in the motor cortex 24 h after the last session of a forced treadmill walking (30 minutes a day, 18 m/minute for 7 consecutive days). Unilateral common carotid artery occlusion and modulation of exercise intensity (0 versus -10% inclination of the treadmill) were used as strategies to reduce the (normal) elevation of flow in the cerebrovasculature occurring during exercise. Administration of N-nitro-L-arginine methyl ester (L-NAME, 60 mg/kg before each exercise sessions) and genetic hypertension (spontaneously hypertensive rats) were used as approaches to reduce stimulation of nitric oxide production in response to shear stress elevation. Vascular occlusion totally and partially abolished the effect of physical training on BDNF levels in the hemisphere ipsilateral and contralateral to occlusion, respectively. BDNF levels were higher after high than low exercise intensity. In addition, both genetic hypertension and L-NAME treatment blunted the effects of physical training on BDNF. From these results, we propose that elevation of brain BDNF levels elicited by physical training involves changes in cerebral hemodynamics

''Role of cerebral blood flow in physical exercise-induced brain plasticity''

Banoujaafar, H. | Prigent-Tessier, A. | Mossiat, C. | Marie, C.International audienc

Bdnf and Chronic Cerebral Hypoperfusion in Rats. Effects of Exercise

International audienc

Diuretic and natriuretic responses in rats treated with enkephalinase inhibitors

International audienceRat atrial natriuretic factor (125I-rANF, 99-128) is hydrolysed by pure enkephalinase (EC 3.4.24.11) in vitro at a rate similar to that of 125I-hANF. Trichloroacetic precipitated radioactivity was significantly elevated in the kidneys of rats pretreated with acetorphan, an enkephalinase inhibitor, and receiving 125I-rANF, indicating that the exogenous hormone was protected against degradation. A single oral administration of acetorphan elicited diuretic and natriuretic effects in conscious normotensive rats and natriuretic effects in spontaneously hypertensive rats, effects which were not accompanied by significant changes in kaliuresis. The diuretic and natriuretic effects were still observed in conscious normotensive rats after three days of repeated administration of the drug. In conscious or anesthetized rats in which volume expansion was elicited by hydroelectrolytic loads, the initial rate of urinary elimination of water and sodium was nearly doubled by treatment with enkephalinase inhibitors. This effect was prevented by coadministration of an ANF antiserum, which suggests that the effect was mediated by endogenous ANF. These various observations suggest that enkephalinase inhibitors protect endogenous ANF from degradation and thereby enhance the typical renal effects of the hormone

Physical training restores brain-derived neurotrophic factor signaling in hypertensive rats

International audienceObjective: Hypertension is a major cause of cognitive decline even though the underlying mechanisms remain hypothetical. Supporting a contribution of deficient brain-derived neurotrophic factor (BDNF) signaling, animal studies recently reported low BDNF levels in the hippocampus of hypertensive rats as compared to their normotensive controls. Besides, physical training that is positively associated with cardiovascular health is also one of the most efficient strategies to increase brain BDNF levels and cognitive performance. These data led us to explore whether physical training may restore brain BDNF signaling in hypertensive rats and if right the mechanisms involved.Design and method: Experiments were performed on three groups of rats (n = 11 each). Sedentary spontaneously hypertensive rats (SHR), physically-trained SHR (SHR-T) and sedentary normotensive Wistar Kyoto rats (WKY). Physical training consisted in a daily (30-min) walking activity on a horizontal treadmill for 7 consecutive days. This protocol was previously shown to elevate hippocampal BDNF levels in normotensive rats. Systolic (SBP) and diastolic (DBP) blood pressures were measured by plethysmography. The hippocampus was collected 24 h after the last treadmill session in order to measure levels of BDNF, synaptophysin (SYN, as a marker of synaptogenesis), TrkB phosphorylated at tyrosine 816 (p-TrkB as a marker of TrkB activation by BDNF), eNOS phosphorylated at serine 1177 (as a marker of cerebrovascular eNOS activation by physical training) using Western blotting analysis.Results: SBP and DBP (mmHg) that were higher in SHR (180 +/- 8 and 150 +/- 12, respectively) than WKY (112 +/- 3 and 92 +/- 5, respectively) did not differ between SHR and SHR-T. By contrast, BDNF, SYN, p-TrkB and p-eNOS levels were significantly lower in SHR than WKY (p < 0.05), higher in SHR-T than SHR (p < 0.05) while no difference was observed between WKY and SHR-T. Of interest, a positive correlation was observed between BDNF and P-eNOS (r = 0,707, p < 0.001).Conclusions: Hypertension-induced deficient BDNF signaling in the hippocampus is fully restored by physical training through blood-pressure independent mechanisms. Further studies are needed to explore the role of cerebrovascular endothelium-derived NO in the control of brain BDNF signaling