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

Cytoprotective Efficacy and Mechanisms of the Liposoluble Iron Chelator 2,2Ј-Dipyridyl in the Rat Photothrombotic Ischemic Stroke Model

ABSTRACT We examined the efficacy of the liposoluble iron chelator 2,2Ј-dipyridyl (DP) in reducing histological damage in rats submitted to cerebral ischemia and the mechanisms involved in the potential cytoprotection. For this purpose, DP (20 mg/kg, i.p.) was administered 15 min before and 1 h after induction of cortical photothrombotic vascular occlusion in rat. Histological studies were performed to assess infarct volume (at days 1 and 3 postischemia) and astromicroglial activation (at day 3 postischemia). Damage to endothelial and neuronal cells was evaluated at day 1 postischemia by quantitative measurements of Evans Blue extravasation and N-acetylaspartate levels, respectively. Cerebral blood flow was recorded in the ischemic core by laser-Doppler flowmetry within the 15 min to 2 h period after photothrombosis. At 4-h postischemia, radical oxygen species (ROS) production was evaluated by measuring brain glutathione concentrations. The cortical expression of the proteins heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1␣ (HIF-1␣) was analyzed by Western blotting at day 1 postischemia. Infarct volume and ischemic damage to endothelial and neuronal cells were significantly reduced by DP treatment. This cytoprotection was associated with a reduction in ROS production, perfusion deficits, and astrocytic activation. DP treatment also resulted in significant changes in HO-1 (ϩ100%) and HIF-1␣ (Ϫ50%) protein expression at the level of the ischemic core. These results report the efficacy of the liposoluble iron chelator DP in reducing histological damage induced by permanent focal ischemia

Molecular mechanisms underlying physical exercise-induced brain BDNF overproduction

Accumulating evidence supports that physical exercise (EX) is the most effective non-pharmacological strategy to improve brain health. EX prevents cognitive decline associated with age and decreases the risk of developing neurodegenerative diseases and psychiatric disorders. These positive effects of EX can be attributed to an increase in neurogenesis and neuroplastic processes, leading to learning and memory improvement. At the molecular level, there is a solid consensus to involve the neurotrophin brain-derived neurotrophic factor (BDNF) as the crucial molecule for positive EX effects on the brain. However, even though EX incontestably leads to beneficial processes through BDNF expression, cellular sources and molecular mechanisms underlying EX-induced cerebral BDNF overproduction are still being elucidated. In this context, the present review offers a summary of the different molecular mechanisms involved in brain’s response to EX, with a specific focus on BDNF. It aims to provide a cohesive overview of the three main mechanisms leading to EX-induced brain BDNF production: the neuronal-dependent overexpression, the elevation of cerebral blood flow (hemodynamic hypothesis), and the exerkine signaling emanating from peripheral tissues (humoral response). By shedding light on these intricate pathways, this review seeks to contribute to the ongoing elucidation of the relationship between EX and cerebral BDNF expression, offering valuable insights into the potential therapeutic implications for brain health enhancement

Hyperthymic affective temperament and hypertension are independent determinants of serum brain-derived neurotrophic factor level

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has neuroprotective, proangiogenic and myogenic effects and, therefore, possibly acts as a psychosomatic mediator. Here, we measured serum BDNF (seBDNF) level in hypertensive patients (HT) and healthy controls (CONT) and its relation to affective temperaments, depression and anxiety scales, and arterial stiffness parameters. METHODS: In this cross-sectional study, affective temperaments, anxiety, and depression were studied with questionnaires (TEMPS-A, HAM-A, and BDI, respectively). SeBDNF level and routine laboratory parameters were measured as well. Arterial stiffness was evaluated with a tonometric method. RESULTS: Allover, 151 HT, and 32 CONT subjects were involved in the study. SeBDNF level was significantly higher in HT compared to CONT (24880 +/- 8279 vs 21202.6 +/- 6045.5 pg/mL, p < 0.05). In the final model of regression analysis, hyperthymic temperament score (Beta = 405.8, p = 0.004) and the presence of hypertension (Beta = 6121.2, p = 0.001) were independent determinants of seBDNF. In interaction analysis, it was found that in HT, a unit increase in hyperthymic score was associated with a 533.3 (95 %CI 241.3-825.3) pg/mL higher seBDNF. This interaction was missing in CONT. CONCLUSIONS: Our results suggest a complex psychosomatic involvement of BDNF in the pathophysiology of hypertension, where hyperthymic affective temperament may have a protective role. BDNF is not likely to have an effect on large arteries

La sclérose latérale amyotrophique (aspects physiopathologiques, thérapeutiques, rôle du pharmacien d officine, conseils aux patients, et réalisation d une fiche d information)

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Importance de la composante apoptotique dans la mort neuronale chez le rat soumis à une ischémie cérébrale par thrombose photochimique

Notre étude a été réalisée sur un modèle d'ischémie focale permanente induite par photothrombose chez le Rat, au cours des 24 premières heures suivant l'induction de l'ischémie. Nos résultats permettent de distinguer deux vagues de dommages neuronaux à forte composante apoptotique. La première correspond à la maturation du cœur de l'infarctus, la deuxième, décalée dans le temps, à l'extension de la lésion. Le dipyridyl, un chélateur liposoluble de fer, diminue d'environ 40% la taille de l'infarctus après 24h d'ischémie. Son action neuroprotectrice s'exerce dans une large mesure par une limitation des mécanismes apoptotiques : diminution de la fragmentation internucléosomale de l'ADN, une réduction du nombre de corps apoptotiques et réduction du clivage des caspases-9 et -3 et de la PARP-1. Nos résultats montrent également une corrélation entre l'expression nucléaire de HIF-1a et celle de la procaspase-3. Ces 2 protéines, ainsi que le fragment clivé de la caspase-3, sont exprimés par les mêmes cellules. Nos résultats indiquent l'existence d'une liaison de HIF-1 sur le promoteur du gène de la caspase-3, suggérant que ce facteur de transcription puisse être un des facteurs déclencheurs de l'apoptose dans le cerveau ischémique.The aim of our study was to investigate the contribution of apoptosis to neuronal death following focal ischemia. Rats were subjected to chemical photothrombosis and analyses were performed over a period of 24h. Our results showed two waves of neuronal death. The first wave corresponded to morphological changes in the infarct core while the second wave coincided with the extension of the lesion. Neurons displayed progressive time dependent evidence of both apoptosis and necrosis. The effects of lipophilic antioxidant iron chelator dipyridyl were evaluated 24h after photothrombosis. Dipyridyl treatment markedly blocked the enlargement of the lesion. Moreover, a large decrease in apoptotic bodies and DNA internucleosomal fragmentation was associated with a significant drop of caspase and PARP-1 cleavages, suggesting that the protective effect of dipyridyl correlates with a limitation of apoptosis expansion. Our results also indicate that HIF-1a and procaspase-3 expressions increased with a similar pattern. Furthermore, caspase-3 activation was observed in the same cells that express HIF-1a. Finally, in agreement with a causal transcriptional relationship between HIF-1a and procaspase-3 expression, EMSA revealed a HIF-1 activity to caspase-3 gene promoter.DIJON-BU Sciences Economie (212312102) / SudocSudocFranceF

Importance de la composante apoptotique dans la mort neuronale chez le rat soumis à une ischémie cérébrale par thrombose photochimique

Notre étude a été réalisée sur un modèle d'ischémie focale permanente induite par photothrombose chez le Rat, au cours des 24 premières heures suivant l'induction de l'ischémie. Nos résultats permettent de distinguer deux vagues de dommages neuronaux à forte composante apoptotique. La première correspond à la maturation du cœur de l'infarctus, la deuxième, décalée dans le temps, à l'extension de la lésion. Le dipyridyl, un chélateur liposoluble de fer, diminue d'environ 40% la taille de l'infarctus après 24h d'ischémie. Son action neuroprotectrice s'exerce dans une large mesure par une limitation des mécanismes apoptotiques : diminution de la fragmentation internucléosomale de l'ADN, une réduction du nombre de corps apoptotiques et réduction du clivage des caspases-9 et -3 et de la PARP-1. Nos résultats montrent également une corrélation entre l'expression nucléaire de HIF-1a et celle de la procaspase-3. Ces 2 protéines, ainsi que le fragment clivé de la caspase-3, sont exprimés par les mêmes cellules. Nos résultats indiquent l'existence d'une liaison de HIF-1 sur le promoteur du gène de la caspase-3, suggérant que ce facteur de transcription puisse être un des facteurs déclencheurs de l'apoptose dans le cerveau ischémique.The aim of our study was to investigate the contribution of apoptosis to neuronal death following focal ischemia. Rats were subjected to chemical photothrombosis and analyses were performed over a period of 24h. Our results showed two waves of neuronal death. The first wave corresponded to morphological changes in the infarct core while the second wave coincided with the extension of the lesion. Neurons displayed progressive time dependent evidence of both apoptosis and necrosis. The effects of lipophilic antioxidant iron chelator dipyridyl were evaluated 24h after photothrombosis. Dipyridyl treatment markedly blocked the enlargement of the lesion. Moreover, a large decrease in apoptotic bodies and DNA internucleosomal fragmentation was associated with a significant drop of caspase and PARP-1 cleavages, suggesting that the protective effect of dipyridyl correlates with a limitation of apoptosis expansion. Our results also indicate that HIF-1a and procaspase-3 expressions increased with a similar pattern. Furthermore, caspase-3 activation was observed in the same cells that express HIF-1a. Finally, in agreement with a causal transcriptional relationship between HIF-1a and procaspase-3 expression, EMSA revealed a HIF-1 activity to caspase-3 gene promoter.DIJON-BU Sciences Economie (212312102) / SudocSudocFranceF