''Circulating and Brain BDNF Levels in Stroke Rats. Relevance to Clinical Studies''
International audience; ''Background: Whereas brain-derived neurotrophic factor (BDNF) levels are measured in the brain in animal models of stroke, neurotrophin levels in stroke patients are measured in plasma or serum samples. The present study was designed to investigate the meaning of circulating BDNF levels in stroke patients. Methods and Results: Unilateral ischemic stroke was induced in rats by the injection of various numbers of microspheres into the carotid circulation in order to mimic the different degrees of stroke severity observed in stroke patients. Blood was serially collected from the jugular vein before and after (4 h, 24 h and 8 d) embolization and the whole brains were co…
Bdnf and Chronic Cerebral Hypoperfusion in Rats. Effects of Exercise
International audience
Brain BDNF Levels Elevation Induced by Physical Training is Reduced after Unilateral Common Carotid Artery Occlusion in Rats
International audience; We 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 (…
Exogenous t-PA Administration Increases Hippocampal Mature BDNF Levels. Plasmin- or NMDA-Dependent Mechanism?
International audience; Brain-derived neurotrophic factor (BDNF) through TrkB activation is central for brain functioning. Since the demonstration that plasmin is able to process pro-BDNF to mature BDNF and that these two forms have opposite effects on neuronal survival and plasticity, a particular attention has been paid to the link between tissue plasminogen activator (tPA)/plasmin system and BDNF metabolism. However, t-PA via its action on different N-methyl-D-aspartate (NMDA) receptor subunits is also considered as a neuromodulator of glutamatergic transmission. In this context, the aim of our study was to investigate the effect of recombinant (r)t-PA administration on brain BDNF metabo…
Temporal changes in free iron levels after brain ischemia
Whereas iron chelators have been proposed as therapeutic agents in stroke, changes in free iron levels have never been explored after focal brain ischemia. Therefore, free and total iron levels in cortical tissue and free iron levels in plasma were measured before and after (1, 4 and 24h) photothrombotic occlusion of cortical vessels in rats. Brain ferritin expression and localization were also investigated before and after (24, 72 and 192 h) occlusion. The results showed that free iron remained below detectable levels in plasma and that the lesion exhibited high levels of free and total iron. As compared to contralateral values, free iron levels in ischemic core and penumbra increased (+50…
Quantitative assessment of stereotyped and challenged locomotion after lesion of the striatum: a 3D kinematic study in rats.
Background Although the striatum is in position to regulate motor function, the role of the structure in locomotor behaviour is poorly understood. Therefore, a detailed analysis of locomotion- and obstacle avoidance-related parameters was performed after unilateral lesion of the striatum in rats. Methods and Results Using the three dimensional motion capture technology, kinematics of walking and clearing obstacles, head and body orientation were analyzed before and up to 60 days after the lesion. Recordings were performed in treadmill running rats with or without obstacles attached to the treadmill belt. The lesion, which was induced by the direct injection of the mitochondrial toxin malona…
''Deferoxamine blocks death induced by glutathione depletion in PC 12 cells''
Chouraqui, E. | Leon, A. | Repesse, Y. | Prigent-Tessier, A. | Bouhallab, S. | Bougle, D. | Marie, C. | Duval, D.; International audience; ''The purpose of the present work was to investigate the mechanisms by which glutathione depletion induced by treatment with buthionine sulfoximine (BSO) led within 24-30 h to PC 12 cells apoptosis. Our results showed that treatment by relatively low concentrations (10-30 mu M) of deferoxamine (DFx), a natural iron-specific chelator, almost completely shielded the cells from BSO-induced toxicity and that DFx still remained protective when added up to 9-12 h after BSO treatment. On the other hand, phosphopeptides derived from milk casein and known to carr…
Vasorelaxing effect of a TrkB receptor agonist on mesenteric arteries
International audience; Introduction: Brain-derived neurotrophic factor (BDNF) is a neurotrophin unanimously recognized for its promoting effect on neuroplasticity and cognition, through activation of tropomyosin receptor kinase B (TrkB). In opposition with the traditional thinking that neurons are the main source of BDNF, endothelial cells were found to express large amounts of BDNF. Exogenous BDNF was reported to exert vasodilating properties on isolated pulmonary artery and aorta. However, whether peripheral vascular resistances are controlled by endothelial BDNF is not known. To address this question, we investigated the vasorelaxant properties and the underlying signaling pathways of a…
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. BD…
''Plasma Phospholipid Transfer Protein (pltp) Is A Procoagulant Factor In Vivo''
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Ipsilateral versus contralateral spontaneous post-stroke neuroplastic changes: involvement of BDNF?
International audience; Stroke is a leading cause of death and disability in industrialized countries. Although surviving patients exhibit a certain degree of restoration of function attributable to brain plasticity, the majority of stroke survivors has to struggle with persisting deficits. In order to potentiate post-stroke recovery, several rehabilitation therapies have been undertaken and many experimental studies have reported that brain-derived neurotrophic factor (BDNF) is central to many facets of neuroplastic processes. However, although BDNF role in brain plasticity is well characterized through strategies that manipulate its content, the involvement of this neurotrophin in spontan…
''Role of rt-pa on bdnf metabolism in stroke''
Rodier, M. | Mossiat, C. | Marie, C. | Garnier, P.; International audience
Time-dependent contribution of non neuronal cells to BDNF production after ischemic stroke in rats.
International audience; Although brain-derived neurotrophic factor (BDNF) plays a central role in recovery after cerebral ischemia, little is known about cells involved in BDNF production after stroke. The present study testes the hypothesis that neurons are not the unique source of neosynthesized BDNF after stroke and that non neuronal-BDNF producing cells differ according to the delay after stroke induction. For this purpose, cellular localization of BDNF and BDNF content of each hemisphere were analysed in parallel before and after (4h, 24h and 8d) ischemic stroke in rats. Stroke of different severities was induced by embolization of the brain with variable number of calibrated microsphe…
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…
Effet neuroprotecteur de l’accident ischémique transitoire
Transient ischemic attack (TIA) is a well-recognized risk factor of ischemic stroke. Hence, 7 to 25% of ischemic stroke patients have a history of TIA, and the risk of ischemic stroke after TIA is about 15% at 3 months. However, epidemiological studies have demonstrated that among patients with ischemic stroke, those with a history of TIA have better functional and vital prognoses. This protective effect is particularly found in case of recent and short TIA, and in case of non-lacunar ischemic stroke. Hence, TIA can induce endogenous neuroprotection by the ischemic tolerance phenomenon that decreases the neurodegeneration usually caused by a severe cerebral ischemia in a non-preconditioned …
''Comparative Effect of Treadmill Exercise on Mature BDNF Production in Control versus Stroke Rats''
Quirie, Aurore | Hervieu, Marie | Garnier, Philippe | Demougeot, Celine | Mossiat, Claude | Bertrand, Nathalie | Martin, Alain | Marie, Christine | Prigent-Tessier, Anne; International audience; ''Physical exercise constitutes an innovative strategy to treat deficits associated with stroke through the promotion of BDNF-dependent neuroplasticity. However, there is no consensus on the optimal intensity/duration of exercise. In addition, whether previous stroke changes the effect of exercise on the brain is not known. Therefore, the present study compared the effects of a clinically-relevant form of exercise on cerebral BDNF levels and localization in control versus stroke rats. For this purpo…
Brain BDNF levels are dependent on cerebrovascular endothelium-derived nitric oxide
International audience; Scientific evidence continues to demonstrate a link between endothelial function and cognition. Besides, several studies have identified a complex interplay between nitric oxide (NO) and brain-derived neurotrophic factor (BDNF), a neurotrophin largely involved in cognition. Therefore, this study investigated the link between cerebral endothelium-derived NO and BDNF signaling. For this purpose, levels of BDNF and the phosphorylated form of endothelial NO synthase at serine 1177 (p-eNOS) were simultaneously measured in the cortex and hippocampus of rats subjected to either bilateral common carotid occlusion (n=6), physical exercise (n=6) or a combination of both (n=6) …
Opposite effects of hypertension and physical exercise on cerebrovascular BDNF levels
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Protective action of 1,3-butanediol in cerebral ischemia. A neurologic, histologic, and metabolic study.
1,3-Butanediol (BD) is converted in the body to β-hydroxybutyrate, and previous studies have shown that hyperketonemia had beneficial effects in experimental models of generalized hypoxia. The aim of this study was to determine if BD would reduce brain damage following cerebral ischemia. A transient forebrain ischemia of 30-min duration was induced by the four-vessel occlusion technique in control and BD-treated rats (25 mmol/kg, i.p.; 30 min prior to ischemia). BD treatment led to significant improvement of neurologic deficit during the 72-h recovery period and reduced neuronal damage in the striatum and cortex but not in the CA1 sector of the hippocampus. Evaluation of cerebral energy me…
''Expression of endothelial brain-derived neurotrophic factor is dependent on endothelial function''
Quirie, A. | Prigent-Tessier, A. | Mossiat, C. | Nappey, M. | Marie, C. | Demougeot, C.; International audience
Effects of eccentric and concentric trainings on brain-derived neurotrophic factor (BDNF) signaling in cognition-related brain regions
International audience
''Effect of stroke on arginase expression and localization in the rat brain''
Quirie, Aurore | Demougeot, C. Eline | Bertrand, Nathalie | Mossiat, Claude | Garnier, Philippe | Marie, Christine | Prigent-Tessier, Anne; International audience; ''Because arginase and nitric oxide (NO) synthases (NOS) compete to degrade l-arginine, arginase plays a crucial role in the modulation of NO production. Moreover, the arginase 1 isoform is a marker of M2 phenotype macrophages that play a key role in tissue remodeling and resolution of inflammation. While NO has been extensively investigated in ischemic stroke, the effect of stroke on the arginase pathway is unknown. The present study focuses on arginase expression/activity and localization before and after (1, 8, 15 and 30days) …
''Ipsilateral vs. contralateral post-stroke neuroplastic changes: involvement of BDNF?''
Madinier, A. | Rodier, M. | Quirie, A. | Bertrand, N. | Mossiat, C. | Marie, C. | Garnier, P.; International audience
Intérêt du growth differentiation factor 15 (GDF15) comme biomarqueur pronostique après la survenue d'un Accident Vasculaire Cérébral ischémique (AVC)
Introduction Le GDF15 est un biomarqueur de mauvais pronostic dans certaines pathologies cardiovasculaires comme le syndrome coronarien aigu. Son interet dans le domaine de AVC n’a ete que peu etudie a ce jour. Objectifs Notre travail consistait a l’evaluation des taux de GDF15 chez des patients hospitalises a la phase aigue d’un AVC ischemique traites par fibrinolyse et/ou thrombectomie. L’objectif principal etait d’evaluer l’association entre les taux de GDF15 et la recuperation fonctionnelle a 3 mois. Methodes Au total, 174 patients ont ete inclus entre le 16/01 et le 30/09/2017. Le consentement etait recueilli oralement. Des prelevements biologiques ont ete realises a l’admission du pat…
Beneficial effect of dipyridyl, a liposoluble iron chelator against focal cerebral ischemia: In vivo and in vitro evidence of protection of cerebral endothelial cells
Whereas iron chelators were shown to induce neuroprotection against brain injury, the effect of iron chelators on ischemia-induced damage of cerebral endothelium is largely unknown. Our objective was to explore the endothelioprotective effect of the lipophilic iron chelator dipyridyl (DP) (i) in vitro on the death of cerebral endothelial cells (CECs) subjected to intracellular iron loading and (ii) in vivo on the ischemia-induced blood-brain barrier (BBB) disruption. When given shortly after iron exposure or brain ischemia, DP prevented the death of CECs and diminished BBB disruption, respectively, whereas a delayed administration of DP was associated with a lower CECs protection. Interesti…
BDNF signaling and endothelial no production in rats subjected to physical training
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Association between endothelial dysfunction and brain BDNF levels in a rat model of arthritis
International audience
Kinematics of obstacle clearance in the rat
Although the rat has become the favourite animal model in preclinical research on locomotion, studies designed to assess the strategy used by rats to avoid obstacle are lacking. Using an optoelectronic 3D motion analysis system, we therefore, compared the step pattern, timing and length variables of locomotor cycles, trajectories and joint angles of limbs when rats step between and over obstacles (3 cm-high) fixed on a treadmill belt (25 cm/s). Motion in all four limbs of adult animals with an initial age of 11 weeks was serially recorded for a period of 10 weeks. The results showed that obstacle clearance is associated with the reorganization of the basic step pattern resulting in increase…
Fasting prior to transient cerebral ischemia reduces delayed neuronal necrosis.
A transient brain ischemia of 30-min duration was induced by the four-vessel occlusion technique in normally fed and in 48-hr-fasted rats. Evaluation of brain damage 72 hr after ischemia showed that fasting reduced neuronal necrosis in the striatum, the neocortex, and the lateral part of the CA1 sector of hippocampus. Signs of status spongiosis in the pars reticulata of the substantia nigra were seen in 75% of fed rats and in only 19% of fasted rats. The protective effect was associated with reduction in mortality and in postischemic seizure incidence. The metabolic changes induced by fasting were evaluated before and during ischemia. After 30 min of four-vessel occlusion, fasted rats showe…