Endothelium, inflammation and cognition : focus on BDNF

Le BDNF (brain-derived neurotrophic factor) a été découvert dans le cerveau et est largement impliqué dans la neuroplasticité, la mémoire et la cognition via l’activation des récepteurs TrkB (tropomyosin receptor kinase B) neuronaux. Nous avons récemment montré que le système cardiovasculaire contenait autant de BDNF que le cerveau et que le BDNF exogène était capable d’induire une relaxation vasculaire dépendante de l’endothélium. D’autres études ont suggéré que l’activation des récepteurs TrkB endothéliaux par le BDNF était impliquée dans les processus athérosclérotiques. Notre laboratoire soupçonne une interaction étroite entre NO et BDNF endothélial et a même envisagé la possibilité d’une implication du BDNF secrété par l’endothélium des microvaisseaux cérébraux dans la cognition. Les patients souffrant de polyarthrite rhumatoïde (PR), une maladie inflammatoire d’origine auto-immune, sont à risque cardiovasculaire et présentent une altération de la cognition avec notamment un risque plus élevé de dépression. Etonnamment, l’effet de la PR sur le BDNF est peu documenté. Les seules études disponibles rapportent une élévation du BDNF dans le sang et le liquide synovial en cas de PR. Notre hypothèse est qu’une réduction de l’expression endothéliale du BDNF pourrait contribuer au risque cardiovasculaire et au déficit cognitif associés à la PR. Ainsi, dans notre travail, nous avons étudié le BDNF vasculaire et cérébral et son récepteur TrkB sur le modèle rat d’arthrite induite à l’adjuvant.Nos principaux résultats montrent que l’arthrite conduit à 1) une réduction des taux aortiques de BDNF indépendamment de la sévérité des symptômes inflammatoires mais dépendante de la fonction endothéliale, 2) une diminution des taux cérébraux en BDNF indépendamment de la sévérité des symptômes inflammatoires mais en lien avec la fonction endothéliale, 3) une diminution de l’expression du BDNF et de son récepteur TrkB activé au niveau tant neuronal qu’endothélial dans les régions cérébrales impliquées dans la cognition, 4) une corrélation positive entre l’expression du BDNF par l’endothélium vasculaire et l’expression neuronale des TrkB activés, 5) une absence de corrélation entre les taux sériques de BDNF et ses taux cérébraux ou vasculaires mais en revanche l’existence d’une corrélation positive entre les taux sériques de BDNF et l’inflammation qu’elle soit clinique ou biologique.L’ensemble de ces données est en faveur de l’hypothèse selon laquelle le BDNF endothélial pourrait être impliqué dans le risque athérosclérotique et le déficit cognitif associé à l’arthrite. L’inflammation doit être considérée comme un facteur confondant lorsque les taux circulants de BDNF sont utilisés comme un reflet des taux présents dans le cerveau.BDNF (brain-derived neurotrophic factor) has been discovered in the brain and is widely implicated in neuroplasticity, memory and cognition through the activation of neuronal TrkB (tropomyosin receptor kinase B) receptors. We have recently shown that the cardiovascular system contained as much BDNF as the brain and that exogenous BDNF was able to induce endothelium-dependent vascular relaxation. Other studies have suggested that activation of endothelial TrkB receptors by BDNF is involved in atherosclerotic processes. Our laboratory suspects a close interaction between endothelial NO and BDNF and has even considered the possibility of involvement of BDNF secreted by cerebral microvessel endothelium in cognition. Patients suffering from rheumatoid arthritis (RA), an inflammatory disease of autoimmune origin, are at risk of cardiovascular disease and have an impairment of cognition, including a higher risk of depression. Surprisingly, the effect of RA on BDNF is poorly documented. The only available studies report an increase of BDNF in the blood and synovial fluid in RA. Our hypothesis is that a reduction in endothelial expression of BDNF may contribute to the cardiovascular risk and cognitive deficit associated with RA. Thus, in our work, we studied vascular and cerebral BDNF and its TrkB receptor on the rat model of adjuvant-induced arthritis.Our main findings show that arthritis leads to 1) a decrease in BDNF levels in aortas independently of the severity of inflammatory symptoms but dependent on endothelial function, 2) a decrease in brain BDNF levels independent of the severity of inflammatory symptoms, but link with endothelial function, 3) a decreased expression of BDNF and its activated TrkB receptor at both neuronal and endothelial levels in the brain regions involved in cognition, 4) a positive correlation between endothelial expression of BDNF and neuronal expression of activated TrkB, 5) a lack of correlation between serum BDNF levels and its cerebral or vascular levels, but on the other hand the existence of a positive correlation between serum BDNF levels and inflammation, whether clinical or biological.All of these data support the hypothesis that endothelial BDNF may be involved in atherosclerotic risk and cognitive impairment associated with arthritis. Inflammation should be considered as a confounding factor when circulating levels of BDNF are used as a reflection of levels present in the brain

Endothélium, inflammation et cognition : focus sur le BDNF

BDNF (brain-derived neurotrophic factor) has been discovered in the brain and is widely implicated in neuroplasticity, memory and cognition through the activation of neuronal TrkB (tropomyosin receptor kinase B) receptors. We have recently shown that the cardiovascular system contained as much BDNF as the brain and that exogenous BDNF was able to induce endothelium-dependent vascular relaxation. Other studies have suggested that activation of endothelial TrkB receptors by BDNF is involved in atherosclerotic processes. Our laboratory suspects a close interaction between endothelial NO and BDNF and has even considered the possibility of involvement of BDNF secreted by cerebral microvessel endothelium in cognition. Patients suffering from rheumatoid arthritis (RA), an inflammatory disease of autoimmune origin, are at risk of cardiovascular disease and have an impairment of cognition, including a higher risk of depression. Surprisingly, the effect of RA on BDNF is poorly documented. The only available studies report an increase of BDNF in the blood and synovial fluid in RA. Our hypothesis is that a reduction in endothelial expression of BDNF may contribute to the cardiovascular risk and cognitive deficit associated with RA. Thus, in our work, we studied vascular and cerebral BDNF and its TrkB receptor on the rat model of adjuvant-induced arthritis.Our main findings show that arthritis leads to 1) a decrease in BDNF levels in aortas independently of the severity of inflammatory symptoms but dependent on endothelial function, 2) a decrease in brain BDNF levels independent of the severity of inflammatory symptoms, but link with endothelial function, 3) a decreased expression of BDNF and its activated TrkB receptor at both neuronal and endothelial levels in the brain regions involved in cognition, 4) a positive correlation between endothelial expression of BDNF and neuronal expression of activated TrkB, 5) a lack of correlation between serum BDNF levels and its cerebral or vascular levels, but on the other hand the existence of a positive correlation between serum BDNF levels and inflammation, whether clinical or biological.All of these data support the hypothesis that endothelial BDNF may be involved in atherosclerotic risk and cognitive impairment associated with arthritis. Inflammation should be considered as a confounding factor when circulating levels of BDNF are used as a reflection of levels present in the brain.Le BDNF (brain-derived neurotrophic factor) a été découvert dans le cerveau et est largement impliqué dans la neuroplasticité, la mémoire et la cognition via l’activation des récepteurs TrkB (tropomyosin receptor kinase B) neuronaux. Nous avons récemment montré que le système cardiovasculaire contenait autant de BDNF que le cerveau et que le BDNF exogène était capable d’induire une relaxation vasculaire dépendante de l’endothélium. D’autres études ont suggéré que l’activation des récepteurs TrkB endothéliaux par le BDNF était impliquée dans les processus athérosclérotiques. Notre laboratoire soupçonne une interaction étroite entre NO et BDNF endothélial et a même envisagé la possibilité d’une implication du BDNF secrété par l’endothélium des microvaisseaux cérébraux dans la cognition. Les patients souffrant de polyarthrite rhumatoïde (PR), une maladie inflammatoire d’origine auto-immune, sont à risque cardiovasculaire et présentent une altération de la cognition avec notamment un risque plus élevé de dépression. Etonnamment, l’effet de la PR sur le BDNF est peu documenté. Les seules études disponibles rapportent une élévation du BDNF dans le sang et le liquide synovial en cas de PR. Notre hypothèse est qu’une réduction de l’expression endothéliale du BDNF pourrait contribuer au risque cardiovasculaire et au déficit cognitif associés à la PR. Ainsi, dans notre travail, nous avons étudié le BDNF vasculaire et cérébral et son récepteur TrkB sur le modèle rat d’arthrite induite à l’adjuvant.Nos principaux résultats montrent que l’arthrite conduit à 1) une réduction des taux aortiques de BDNF indépendamment de la sévérité des symptômes inflammatoires mais dépendante de la fonction endothéliale, 2) une diminution des taux cérébraux en BDNF indépendamment de la sévérité des symptômes inflammatoires mais en lien avec la fonction endothéliale, 3) une diminution de l’expression du BDNF et de son récepteur TrkB activé au niveau tant neuronal qu’endothélial dans les régions cérébrales impliquées dans la cognition, 4) une corrélation positive entre l’expression du BDNF par l’endothélium vasculaire et l’expression neuronale des TrkB activés, 5) une absence de corrélation entre les taux sériques de BDNF et ses taux cérébraux ou vasculaires mais en revanche l’existence d’une corrélation positive entre les taux sériques de BDNF et l’inflammation qu’elle soit clinique ou biologique.L’ensemble de ces données est en faveur de l’hypothèse selon laquelle le BDNF endothélial pourrait être impliqué dans le risque athérosclérotique et le déficit cognitif associé à l’arthrite. L’inflammation doit être considérée comme un facteur confondant lorsque les taux circulants de BDNF sont utilisés comme un reflet des taux présents dans le cerveau

Effect of arthritis on brain BDNF levels

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The Cerebral Brain-Derived Neurotrophic Factor Pathway, Either Neuronal or Endothelial, Is Impaired in Rats with Adjuvant-Induced Arthritis. Connection with Endothelial Dysfunction

Cognitive abilities are largely dependent on activation of cerebral tropomyosin-related kinase B receptors (TrkB) by brain-derived neurotrophic factor (BDNF) that is secreted under a bioactive form by both neurons and endothelial cells. In addition, there is mounting evidence for a link between endothelial function and cognition even though the underlying mechanisms are not well known. Therefore, we investigated the cerebral BDNF pathway, either neuronal or endothelial, in rheumatoid arthritis (RA) that combines both endothelial dysfunction (ED) and impaired cognition. Adjuvant-induced arthritis (AIA) in rats was used as a model of RA. Clinical inflammatory symptoms were evaluated from an arthritis score and brains were collected at day 31 ± 2 post-immunization. Neuronal expression of BDNF and TrkB phosphorylated at tyrosine 816 (p-TrkB) was examined in brain slices. Endothelial BDNF and p-TrkB expression was examined on both brain slices (hippocampal arterioles) and isolated cerebral microvessels-enriched fractions (vessels downstream to arterioles). The connection between endothelial nitric oxide (NO) and BDNF production was explored on the cerebrovascular fractions using endothelial NO synthase (eNOS) levels as a marker of NO production, Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) as a NOS inhibitor and glyceryl-trinitrate as a slow releasing NO donor. Brain slices displayed lower BDNF and p-TrkB staining in both neurons and arteriolar endothelial cells in AIA than in control rats. For endothelial cells but not neurons, a strong correlation was observed between BDNF and p-TrkB staining. Of note, a strong correlation was also observed between neuronal p-TrkB and endothelial BDNF staining. In cerebral microvessels-enriched fractions, AIA led to decreased BDNF and eNOS levels with a positive association between the 2 parameters. These effects coincided with decreased BDNF and p-TrkB staining in endothelial cells. The exposure of AIA cerebrovascular fractions to GTN increased BDNF levels while the exposure of control fractions to L-NAME decreased BDNF levels. Changes in the cerebral BDNF pathway were not associated with arthritis score. The present study reveals that AIA impairs the endothelial and neuronal BDNF/TrkB pathway, irrespective of the severity of inflammatory symptoms but dependent on endothelial NO production. These results open new perspectives for the understanding of the link between ED and impaired cognition

Effects of eccentric and concentric trainings on brain-derived neurotrophic factor (BDNF) signaling in cognition-related brain regions

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Association between endothelial dysfunction and brain BDNF levels in a rat model of arthritis

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Brain-derived neurotrophic factor in adjuvant-induced arthritis in rats. Relationship with inflammation and endothelial dysfunction

International audienceOBJECTIVES: Both peripheral and central brain-derived neurotrophic factor (BDNF) levels are decreased in depression and normalized by efficient anti-depressive therapies. While depression symptoms are frequent in rheumatoid arthritis, BDNF has been poorly investigated in this pathology. Therefore, the present study explored cerebral and peripheral BDNF in arthritis rats as well as the link between brain BDNF and the two factors recently involved in the pathogenesis of depression and present in rheumatoid arthritis namely inflammation and endothelial dysfunction.METHODS: The brain (hippocampus and frontal cortex) and blood (serum) were collected in rats subjected to adjuvant-induced arthritis (AIA) when inflammatory symptoms and endothelial dysfunction are fully developed. Anhedonia as a core symptom of depression symptom was assessed from preference for a saccharin drinking solution. Inflammation was assessed from the arthritis score and serum levels of TNFalpha and IL-1beta. Treatment with the arginase inhibitor N(w)-hydroxy-nor-l-arginine (nor-NOHA) was used as a strategy to prevent endothelial dysfunction without improving inflammatory symptoms.RESULTS: As compared to controls, AIA rats displayed decreased brain BDNF levels that coexisted with anhedonia but contrasted with increased BDNF levels in serum. Brain BDNF deficiency correlated neither with arthritis score nor with pro-inflammatory cytokines levels, while it was mitigated by nor-NOHA treatment. A positive correlation was observed between serum BDNF and TNFalpha levels.CONCLUSIONS: Our study reveals that arthritis decreases BDNF levels in the brain and that endothelial dysfunction rather than inflammation contributes to the decrease. It also identifies a disconnection between serum and brain BDNF levels in arthritis

Activation of endothelial TrkB receptors induces relaxation of resistance arteries

International audienceWhile brain-derived neurotrophic factor (BDNF) was previously reported to induce relaxation of conduit artery, whether the BDNF/TrkB (tropomyosin-related kinase) pathway is involved in the tone control of resistance arteries is not known. This study investigated TrkB receptors levels/localization and the vasomotor effect of the TrkB receptor agonist LM22A-4 in isolated third-order mesenteric arteries from rats.Immunostaining revealed the presence of both full-length and truncated TrkB receptors, especially at the endothelial level. By using wire myography, LM22A-4 induced vascular relaxation that was significantly decreased by cyclotraxin B as a non-competitive TrkB antagonist and fully prevented by endothelium removal. Inhibitors of NO, EDHF, PGI2 production and the PI3K/Akt pathways separately reduced LM22A-4 inducedrelaxation. By contrast, inhibition of Raf/MEK, PLC gamma and CaM/CaMKII pathways did not change the relaxant effect of LM22A-4. Interestingly, BDNF also induced an endothelium and TrkB-dependent relaxation.These results indicate that endothelial TrkB activation results in the relaxation of resistance vessels via PI3K/ Akt-induced eNOS phosphorylation and production of EDHF and PGI(2). These data are consistent with the contribution of the endothelial BDNF/TrkB pathway to the regulation of peripheral vascular tone. They also validate the use of LM22A-4 as a reliable pharmacological agent for studying the vascular effect of BDNF

Brain-derived neurotrophic factor in peripheral blood mononuclear cells and stroke outcome

International audienceStroke outcome is dependent on brain-derived neurotrophic factor (BDNF)-dependent neuroplasticity. As peripheral blood mononuclear cells (PBMC) contain BDNF, diapedesis of these cells might be followed by BDNF delivery to the ischemic brain. To test this hypothesis, we investigated the association between BDNF levels in PBMC and functional outcome in patients with ischemic stroke. BDNF was measured in PBMC that were isolated from ischemic stroke patients (n ¼ 40) just before (day 0) and after (days 1 and 3) fibrinolysis. Three months after stroke, patients were stratified using the modified Rankin Scale (mRS) according to the unfavorable (mRS scores 3-6) and favorable (mRS scores 0-2) functional outcome. We used univariate and multivariate logistic regressions to assess the relationship between BDNF levels in PBMC and functional outcome. BDNF levels in PBMC decreased from day 0 to day 3 in patients with unfavorable outcome, while they remained stable in patients with favorable outcome. Patients with favorable outcome exhibited at day 3 higher PBMC-BDNF levels than patients with unfavorable outcome and the levels were associated with good outcome (odd ratio: 12.0; 95% confidence interval, 1.4-106.2, P ¼ 0.023). PBMC-BDNF levels remained a predictor of stroke outcome after adjusting from cardiovascular risk, interval between admission and fibrinolysis, stroke severity from hospital admission to discharge, lymphocytes count, neutrophils/lymphocytes ratio at admission. Favorable functional outcome in ischemic stroke patients that benefited from fibrinolysis was predicted by a high BDNF level in PBMC, suggesting that PBMC might serve as a cellular vector to deliver BDNF to the ischemic brain

A reconciling hypothesis centred on brain-derived neurotrophic factor to explain neuropsychiatric manifestations in rheumatoid arthritis

International audienceAbstract Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease characterized by synovitis leading to joint destruction, pain and disability. Despite efficient antirheumatic drugs, neuropsychiatric troubles including depression and cognitive dysfunction are common in RA but the underlying mechanisms are unclear. However, converging evidence strongly suggests that deficit in brain-derived neurotrophic factor (BDNF) signalling contributes to impaired cognition and depression. Therefore, this review summarizes the current knowledge on BDNF in RA, proposes possible mechanisms linking RA and brain BDNF deficiency including neuroinflammation, cerebral endothelial dysfunction and sedentary behaviour, and discusses neuromuscular electrical stimulation as an attractive therapeutic option