Cerebral Benefits Induced by Electrical Muscle Stimulation: Evidence from a Human and Rat Study.

Physical exercise (EX) is well established for its positive impact on brain health. However, conventional EX may not be feasible for certain individuals. In this regard, this study explores electromyostimulation (EMS) as a potential alternative for enhancing cognitive function. Conducted on both human participants and rats, the study involved two sessions of EMS applied to the quadriceps with a duration of 30 min at one-week intervals. The human subjects experienced assessments of cognition and mood, while the rats underwent histological and biochemical analyses on the prefrontal cortex, hippocampus, and quadriceps. Our findings indicated that EMS enhanced executive functions and reduced anxiety in humans. In parallel, our results from the animal studies revealed an elevation in brain-derived neurotrophic factor (BDNF), specifically in the hippocampus. Intriguingly, this increase was not associated with heightened neuronal activity or cerebral hemodynamics; instead, our data point towards a humoral interaction from muscle to brain. While no evidence of increased muscle and circulating BDNF or FNDC5/irisin pathways could be found, our data highlight lactate as a bridging signaling molecule of the muscle-brain crosstalk following EMS. In conclusion, our results suggest that EMS could be an effective alternative to conventional EX for enhancing both brain health and cognitive function.

Impact of Exercise Intensity on Cerebral BDNF Levels: Role of FNDC5/Irisin.

The positive effects of physical exercise (EX) are well known to be mediated by cerebral BDNF (brain-derived neurotrophic factor), a neurotrophin involved in learning and memory, the expression of which could be induced by circulating irisin, a peptide derived from Fibronectin type III domain-containing protein 5 (FNDC5) produced by skeletal muscle contraction. While the influence of EX modalities on cerebral BDNF expression was characterized, their effect on muscle FNDC5/Irisin expression and circulating irisin levels remains to be explored. The present study involved Wistar rats divided into four experimental groups: sedentary (SED), low- (40% of maximal aerobic speed, MAS), intermediate- (50% of MAS) and high- (70% of MAS) intensities of treadmill EX (30 min/day, 7 days). Soleus (SOL) versus gastrocnemius (GAS) FNDC5 and hippocampal BDNF expressions were evaluated by Western blotting. Additionally, muscular FNDC5/Irisin localization and serum/hippocampal irisin levels were studied by immunofluorescence and ELISA, respectively. Our findings revealed that (1) serum irisin and hippocampal BDNF levels vary with EX intensity, showing a threshold intensity at 50% of MAS; (2) hippocampal BDNF levels positively correlate with serum irisin but not with hippocampal FNDC5/Irisin; and (3) GAS, in response to EX intensity, overexpresses FNDC5/Irisin in type II muscle fibers. Altogether, peripheral FNDC5/Irisin levels likely explain EX-dependent hippocampal BDNF expression.

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.

Region-Dependent Increase of Cerebral Blood Flow During Electrically Induced Contraction of the Hindlimbs in Rats.

Elevation of cerebral blood flow (CBF) may contribute to the cerebral benefits of the regular practice of physical exercise. Surprisingly, while electrically induced contraction of a large muscular mass is a potential substitute for physical exercise to improve cognition, its effect on CBF remains to be investigated. Therefore, the present study investigated CBF in the cortical area representing the hindlimb, the hippocampus and the prefrontal cortex in the same anesthetized rats subjected to either acute (30 min) or chronic (30 min for 7 days) electrically induced bilateral hindlimb contraction. While CBF in the cortical area representing the hindlimb was assessed from both laser doppler flowmetry (LDFCBF) and changes in p-eNOSSer1177 levels (p-eNOSCBF), CBF was evaluated only from changes in p-eNOSSer1177 levels in the hippocampus and the prefrontal cortex. The contribution of increased cardiac output and increased neuronal activity to CBF changes were examined. Stimulation was associated with tachycardia and no change in arterial blood pressure. It increased LDFCBF with a time- and intensity-dependent manner as well as p-eNOSCBF in the area representing the hindlimb. By contrast, p-eNOSCBF was unchanged in the two other regions. The augmentation of LDFCBF was partially reduced by atenolol (a ß1 receptor antagonist) and not reproduced by the administration of dobutamine (a ß1 receptor agonist). Levels of c-fos as a marker of neuronal activation selectively increased in the area representing the hindlimb. In conclusion, electrically induced bilateral hindlimb contraction selectively increased CBF in the cortical area representing the stimulated muscles as a result of neuronal hyperactivity and increased cardiac output. The absence of CBF changes in cognition-related brain regions does not support flow-dependent neuroplasticity in the pro-cognitive effect of electrically induced contraction of a large muscular mass.

Endothelial cells are an important source of BDNF in rat skeletal muscle.

BDNF (brain-derived neurotrophic factor) is present in skeletal muscle, controlling muscular metabolism, strength and regeneration processes. However, there is no consensus on BDNF cellular source. Furthermore, while endothelial tissue expresses BDNF in large amount, whether endothelial cells inside muscle expressed BDNF has never been explored. The aim of the present study was to provide a comprehensive analysis of BDNF localization in rat skeletal muscle. Cellular localization of BDNF and activated Tropomyosin-related kinase B (TrkB) receptors was studied by immunohistochemical analysis on soleus (SOL) and gastrocnemius (GAS). BDNF and activated TrkB levels were also measured in muscle homogenates using Western blot analysis and/or Elisa tests. The results revealed BDNF immunostaining in all cell types examined with a prominent staining in endothelial cells and a stronger staining in type II than type I muscular fibers. Endothelial cells but not other cells displayed easily detectable activated TrkB receptor expression. Levels of BDNF and activated TrkB receptors were higher in SOL than GAS. In conclusion, endothelial cells are an important and still unexplored source of BDNF present in skeletal muscle. Endothelial BDNF expression likely explains why oxidative muscle exhibits higher BDNF levels than glycolytic muscle despite higher the BDNF expression by type II fibers.

Tofacitinib improved peripheral endothelial dysfunction and brain-derived neurotrophic factor levels in the rat adjuvant-induced arthritis model.

This study aimed to explore the effect of Tofacitinib on endothelial dysfunction and cerebral levels of brain-derived neurotrophic factor (BDNF) in the adjuvant-induced arthritis (AIA) rat model. Tofacitinib (10 mg/kg twice a day) or vehicle was administered from the first signs of inflammation. Arthritis scores were daily monitored while other parameters including endothelial function assessed from aortic rings, radiographic scores, blood pressure, heart rate, circulating levels of triglycerides, cholesterol, and interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), IL-17A, and cerebral BDNF levels were determined after 3 weeks of treatment. A group of non-AIA rats served as controls. In AIA rats, as compared with vehicle, Tofacitinib significantly reduced arthritis and radiographic scores, decreased total cholesterol and low-density lipoprotein cholesterol (LDL-C), but changed neither blood pressure nor heart rate and proinflammatory cytokines levels. It also fully restored acetylcholine (Ach)-induced relaxation (p < 0.05) through increased nitric oxide (NO) synthase activity, reduced BH4 deficiency and O2 -° production, decreased cyclo-oxygenase-2 (COX-2)/arginase activities, and enhanced endothelium-derived hyperpolarizing factor (EDHF) production. These effects translated into a decrease in atherogenic index and an elevation of BDNF levels in the prefrontal cortex (p < 0.05) and hippocampus (p < 0.001). The present study identified Tofacitinib as an efficient therapeutic option to reduce cardiovascular risk and improve BDNF-dependent cognition in arthritis.

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

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.

Brain-derived neurotrophic factor is a full endothelium-derived factor in rats.

Most of what is known on vascular brain-derived neurotrophic factor (BDNF) derived from experiments on cultured endothelial cells. Therefore, the present study compared BDNF levels/localization in artery (aorta) vs vein (vena cava) from a same territory in rats either sedentary (SED) or exposed to treadmill exercise (EX) as a mean to stimulate endogenous endothelial nitric oxide (NO) production. In SED rats, for both artery and vein, BDNF was strongly expressed by endothelial cells, while only a faint and scattered expression was observed throughout the media. Endothelial and muscular BDNF staining as vascular BDNF protein levels were however higher in artery than in vein, while BDNF mRNA levels did not differ between vessels. Irrespective of the vessels, EX resulted in an increase (+50%) in BDNF protein levels with no change in BDNF mRNA levels, a selective endothelial BDNF overexpression (x4) and an increase in vascular levels of tropomyosin related kinase B receptors (TrkB) phosphorylated at tyrosine 816 (p-TrkBTyr816). Endothelial expressions of BDNF and p-TrkBTyr816 were positively associated when SED and EX rats were simultaneously examined. The results incite to consider endothelial BDNF as a full and NO-dependent endothelium-derived factor that exerts autocrine effects.

Vascular Arginase Is a Relevant Target to Improve Cerebrovascular Endothelial Dysfunction in Rheumatoid Arthritis: Evidence from the Model of Adjuvant-Induced Arthritis.

Emerging data revealed that rheumatoid arthritis (RA) is associated with higher risk of cerebrovascular diseases. Whereas cerebral endothelial dysfunction is acknowledged as a critical aspect of cerebrovascular diseases, its presence in RA and the mechanisms involved are currently unknown. By using the model of rat adjuvant-induced arthritis (AIA), the present study investigated cerebrovascular reactivity in pressurized middle cerebral arteries (MCA) on day 33 post-immunization. The results revealed that arthritis induced a dramatic decrease in the vasodilatory response to acetylcholine (ACh), ADP, and bradykinin (n = 7-9 arteries, p < 0.0001). By using nor-NOHA, L-NAME, BH4, and Tempol, the results showed that the reduced response to ACh relied on arginase overactivation (n = 8), low NOS activity (n = 8), BH4 deficiency (n = 9), and excessive superoxide production (n = 9). Immunohistological analysis revealed an endothelial upregulation of arginase 2 (p < 0.05, n = 5-6) and NADPH oxidase (p < 0.05, n = 5-7) while eNOS expression was unchanged in AIA (n = 6). To assess whether arginase inhibition may be a relevant therapeutic, AIA rats were treated with an arginase inhibitor (nor-NOHA, 40 mg/kg/day, i.p., n = 20 rats) daily from day 10 to day 33 post-immunization. The treatment alleviated the impaired response of MCA to endothelium-dependent agonists, through an increase in NOS signaling and a suppression of BH4 deficiency and superoxide overproduction. By contrast, it did not change the course of arthritis. In conclusion, arthritis induced a cerebrovascular endothelial dysfunction involving an imbalance in the arginase/NOS pathway. Arginase inhibition appears as a promising therapy beyond anti-rheumatic drugs for reducing the risk of cerebrovascular diseases in RA.

The effect of exercise on memory and BDNF signaling is dependent on intensity.

The aims of the present study were to investigate in brain of adult rats (1) whether exercise-induced activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway is dependent on exercise intensity modality and (2) whether exercise-induced improvement of memory is proportional to this pathway activation. Wistar rats were subjected to low (12 m/min) or high (18 m/min) exercise intensity on horizontal treadmill (30 min/day, 7 consecutive days) that corresponds to ~ 40 and 70% of maximal aerobic speed, respectively. Animals treated with scopolamine to induce memory impairment were subjected to novel object recognition test to assess potential improvement in cognitive function. Expressions of BDNF, phosphorylated TrkB receptors, synaptophysin (a marker of synaptogenesis), c-fos (a neuronal activity marker) and phosphorylated endothelial nitric oxide synthase (a cerebral blood flow marker) were measured in prefrontal cortex and hippocampus of different groups of rats. In terms of cognition, our data reported that only the most intense exercise improves memory performance. Our data also revealed that BDNF pathway is dependent on intensity modality of exercise with a gradual effect in hippocampus whereas only the highest intensity leads to this pathway activation in prefrontal cortex. Our study revealed that memory improvement through BDNF pathway activation is dependent on exercise intensity. While reporting that our protocol is sufficient to improve cognition in animals with impaired memory, our data suggest that prefrontal cortex is possibly a more suitable structure than hippocampus when neuroplastic markers are used to mirror potential improvement in memory performance.

Brain-derived Neurotrophic Factor Pathway after Downhill and Uphill Training in Rats.

INTRODUCTION: The elevation of brain-derived neurotrophic factor (BDNF) levels in the brain and the subsequent phosphorylation of its cognate tropomyosin-related kinase B (TrkB) receptors at tyrosine 816 (pTrkB) are largely involved in the positive effect of aerobic exercise on brain functioning. Although BDNF levels were reported to increase in proportion with exercise intensity, the effect of the type of contraction is unknown. Therefore, the cerebral BDNF/TrkB pathway was investigated after uphill and downhill treadmill activities at equivalent intensity to preferentially induce eccentric and concentric contractions, respectively. METHODS: A treadmill activity (30 min·d for seven consecutive days) either in a horizontal position at two different speeds to modulate intensity (experiment 1) or at three different inclinations (null, -10%, and +5%) but at equivalent intensity to modulate the type of contraction (experiment 2) was induced in rats. Both experiments included sedentary rats. Levels of BDNF, pTrkB, synaptophysin (marker of synaptogenesis), endothelial nitric oxide synthase phosphorylated at serine 1177 (peNOS), and c-fos levels (indicators of elevation in blood flow in the cerebrovasculature and neuronal activity, respectively) were measured in motor- and cognition-related brain regions using Western blotting analysis. RESULTS: Experiment 1 indicated that treadmill activity induces an intensity-dependent increase in peNOS, c-fos, and BDNF levels. Experiment 2 showed that intensity of exercise as well as activation of the cerebral BDNF pathway, and synaptogenesis did not differ among horizontal, uphill, and downhill treadmill activities. CONCLUSION: The cerebral response of the BDNF pathway to a treadmill activity is dependent on exercise intensity, but not on the type of contraction (eccentric vs concentric).

Vascular brain-derived neurotrophic factor pathway in rats with adjuvant-induced arthritis: Effect of anti-rheumatic drugs.

BACKGROUND AND AIMS: In rheumatoid arthritis, the control of both disease activity and standard cardiovascular (CV) risk factors is expected to attenuate the increased CV risk. Evidence that brain-derived neurotrophic factor (BDNF) plays a role in vascular biology led us to investigate the vascular BDNF pathway in arthritis rats as well as the interaction between endothelial nitric oxide (NO) and BDNF production. METHODS: The aortic BDNF pathway was studied in rats with adjuvant-induced arthritis, (AIA) using Western blot and immunohistochemical analysis. Control of arthritis score was achieved by administration (for 3 weeks) of an equipotent dosage of etanercept, prednisolone, methotrexate, celecoxib or diclofenac. Aortas were exposed to an NO donor or an NO synthase inhibitor and vasoreactivity experiments were performed using LM22A-4 as a TrkB agonist. RESULTS: Vascular BDNF and full length tropomyosin-related kinase B receptor (TrkB-FL) were higher in AIA than in control rats. These changes coincided with decreased endothelial immunoreactivity in BDNF and pTrkBtyr816 and were disconnected from arthritis score. Among anti-rheumatic drugs, only prednisolone and methotrexate prevented AIA-induced vascular BDNF loss. The effect of AIA on aortic BDNF levels was reversed by an NO donor and reproduced by an NOS inhibitor. Finally, LM22A-4 induced both NO-dependent vasodilation and phosphorylation of endothelial NO synthase at serine 1177. CONCLUSIONS: Our study identified changes in the BDNF/TrkB pathway as a disease activity-independent component of AIA-associated changes in endothelial phenotype. It provides new perspectives in the understanding and management of the high CV risk reported in rheumatoid arthritis.

Brain-derived neurotrophic factor secreted by the cerebral endothelium: A new actor of brain function?

Low cerebral levels of brain-derived neurotrophic factor (BDNF), which plays a critical role in many brain functions, have been implicated in neurodegenerative, neurological and psychiatric diseases. Thus, increasing BDNF levels in the brain is considered an attractive possibility for the prevention/treatment of various brain diseases. To date, BDNF-based therapies have largely focused on neurons. However, given the cross-talk between endothelial cells and neurons and recent evidence that BDNF expressed by the cerebral endothelium largely accounts for BDNF levels present in the brain, it is likely that BDNF-based therapies would be most effective if they also targeted the cerebral endothelium. In this review, we summarize the available knowledge about the biology and actions of BDNF derived from endothelial cells of the cerebral microvasculature and we emphasize the remaining gaps and shortcomings.

Effect of short-term exercise training on brain-derived neurotrophic factor signaling in spontaneously hypertensive rats.

OBJECTIVE: Decreased brain-derived neurotrophic factor (BDNF) level has been reported in the hippocampus of hypertensive rats. The present study explored whether brain neurons and/or endothelial cells are targeted by hypertension with respect to BDNF expression and the potential of physical exercise to cope with hypertension. METHODS: Physical exercise was induced in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. The hippocampus of sedentary and exercised rats (n = 6 for each group) were used for western blots to assess proBDNF, mature BDNF (mBDNF), tropomyosin-related kinase B (TrkB), P-TrkB (TrkB phosphorylated at tyrosine 816), synaptophysin, endothelial nitric oxide synthase (eNOS) and eNOS phosphorylated at serine 1177 protein levels. BDNF and proBDNF localization in the hippocampus was studied in WKY rats, SHR and exercised SHR (n = 5 each). mBDNF and proBDNF protein levels were also assessed in hippocampal slices prepared from SHR (n = 10) that were incubated for 24 h with the nitric oxide (NO) donor glyceryl trinitrate. SBP was measured by the tail-cuff method. RESULTS: Exercise modified blood pressure neither in SHR nor WKY. As compared with WKY rats, SHR displayed decreased levels of mBDNF, P-TrkB, synaptophysin, eNOS and eNOS phosphorylated at serine 1177 but no change in proBDNF and TrkB levels. These effects coincided with low BDNF staining in both endothelial cells and neurons. Exercise improved the endothelium-derived NO system and the BDNF pathway in both strains. The NO donor increased mBDNF but decreased proBDNF levels. CONCLUSION: Our results revealed that endothelial and neuronal BDNF expressions were both impaired in hypertension and that physical exercise improved hippocampal mBDNF levels and signaling through blood pressure-independent mechanisms.

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.

Brain BDNF levels are dependent on cerebrovascular endothelium-derived nitric oxide.

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) as experimental approaches to modulate flow-induced NO production by the cerebrovasculature. Tropomyosin-related kinase type B (TrkB) receptors and its phosphorylated form at tyrosine 816 (p-TrkB) were also measured. Moreover, we investigated BDNF synthesis in brain slices exposed to the NO donor glyceryl trinitrate. Our results showed increased p-eNOS and BDNF levels after exercise and decreased levels after vascular occlusion as compared to corresponding controls, with a positive correlation between changes in p-eNOS and BDNF (r = 0.679). Exercise after vascular occlusion did not change levels of these proteins. Gyceryl trinitrate increased proBDNF and BDNF levels in brain slices, thus suggesting a possible causal relationship between NO and BDNF. Moreover, vascular occlusion, like exercise, resulted in increased TrkB and p-TrkB levels, whereas no change was observed with the combination of both. These results suggest that brain BDNF signaling may be dependent on cerebral endothelium-derived NO production.

Relevance of Post-Stroke Circulating BDNF Levels as a Prognostic Biomarker of Stroke Outcome. Impact of rt-PA Treatment.

The recombinant form of tissue plasminogen activator (rt-PA) is the only curative treatment for ischemic stroke. Recently, t-PA has been linked to the metabolism of brain-derived neurotrophic factor (BDNF), a major neurotrophin involved in post-stroke neuroplasticity. Thus, the objective of our study was to investigate the impact of rt-PA treatment on post-stroke circulating BDNF levels in humans and in animals. Serum BDNF levels and t-PA/plasmin activity were measured at hospital admission and at up to 90 days in stroke patients receiving (n = 24) or not (n = 14) rt-PA perfusion. We investigated the relationships between serum BDNF with concurrent t-PA/plasmin activity, neurological outcomes and cardiovascular scores at admission. In parallel, serum BDNF levels and t-PA/plasmin activity were assessed before and after (1, 4 and 24h) the induction of ischemic stroke in rats. Our study revealed higher serum BDNF levels and better neurological outcome in rt-PA-treated than non-treated patients. However, serum BDNF levels did not predict stroke outcome when the whole cohort of stroke patients was analyzed. By contrast, serum BDNF levels when measured at admission and at day 90 correlated with cardiovascular scores, and those at day 1 correlated with serum t-PA/plasmin activity in the whole cohort of patients whereas no association could be found in the rt-PA-treated group. In rats devoid of cardiovascular risk, no difference in post-stroke serum BDNF levels was detected between rt-PA- and vehicle-treated animals and no correlation was found between serum BDNF levels and t-PA/plasmin activity. Overall, the data suggest that serum BDNF levels may not be useful as a prognostic biomarker of stroke outcome and that endothelial dysfunction could be a confounding factor when serum BDNF levels after stroke are used to reflect of brain BDNF levels.

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 health.

Effect of stroke on arginase expression and localization in the rat brain.

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 30 days) the photothrombotic ischemic stroke model. This model results in a cortical lesion that reaches maximal volume at day 1 post-stroke and then decreases as a result of astrocytic scar formation. Before stroke, arginase 1 and 2 expressions were restricted to neurons. Stroke resulted in up-regulation of arginase 1 and increased arginase activity in the region centered on the lesion where inflammatory cells are present. These changes were associated with an early and long-lasting arginase 1 up-regulation in activated macrophages and astrocytes and a delayed arginase 1 down-regulation in neurons at the vicinity of the lesion. A linear positive correlation was observed between expressions of arginase 1 and glial fibrillary acidic protein as a marker of activated astrocytes. Moreover, the pattern of arginase 1 and brain-derived neurotrophic factor (BDNF) expressions in activated astrocytes was similar. Unlike arginase 1, arginase 2 expression was not changed by stroke. In conclusion, increased arginase 1 expression is not restricted to macrophages in inflammation elicited by stroke but also occurs in activated astrocytes where it may contribute to neuroplasticity through the control of BDNF production.