Figure - available from: Cell Transplantation
This content is subject to copyright.
BIO-enhanced angiogenesis in perihematoma regions at 14 days after ICH. (A) Immunofluorescence staining showed BrdU (red) and glucose transporter 1 (GLUT1, green) colabeled cells (white arrow). (B) Three-dimensional image confirmed BrdU- and GLUT1-colabeled cells. (C) Quantification of GLUT1⁺/BrdU⁺-colabeled cells. BIO treatment resulted in greater numbers of GLUT1⁺/BrdU⁺-colabeled cells in the perihematoma region compared to the control group. GLUT1: green; BrdU: red; DAPI: blue. ∗p < 0.05. Mean ± SEM. n = 8–12 animals/group.
Source publication
Hemorrhagic stroke is a devastating disease that lacks effective therapies. In the present investigation, we tested 6-bromoindirubin-3'-oxime (BIO) as a selective glycogen synthase kinase-3β (GSK-3β) inhibitor in a mouse model of intracerebral hemorrhage (ICH). ICH was induced by injection of collagenase IV into the striatum of 8 to 10-week old C57...
Similar publications
Traumatic brain injury (TBI) induces cognitive impairments, motor and behavioral deficits. Previous evidences have suggested that neural stem cell (NSC) transplantation could facilitate functional recovery from brain insults, but their underlying mechanisms remains to be elucidated. Here, we established TBI model by an electromagnetic-controlled co...
Citations
... 6-bromoindirubin-3´-oxime (BIO) (GSK-3β inhibitor) found to be effective in intracerebral haemorrhagic stroke (ICH) because it significantly reduces the hematoma size. In the perihematomal regions, administration of BIO blocked GSK-3β activation and significantly increased the viability of neurons and shows the neuroprotective effects through Wnt activation [46]. Zhang and colleagues demonstrated that GSK-3β inhibition and activation of Wnt pathway elicits a neuroprotection by restoring lysosomal dysfunction in neurons via facilitation of transcription factor EB (TFEB) nuclear translocation after stroke. ...
A stroke is a complicated neurological illness that occurs when there is a disruption in the blood flow to the brain. This disruption results in the damage of neurons, which then leads to functional abnormalities. The Wnt signalling pathway, which is already well-known for its important function in development and tissue homeostasis, has recently been recognised as a critical factor in the pathophysiology of stroke. Recent studies have shown the Wnt pathway’s roles in stroke-related events. The complex-interactions between the Wnt pathway and stroke emphasising the pathway’s contributions to neuro-protection and synaptic plasticity. The Wnt pathway’s influence on neuro-genesis and synaptic plasticity underscores its potential for driving stroke recovery and rehabilitation strategies. The current review discusses about the Wnt signalling pathway in brain pathophysiology and stroke with special emphasis on the various pathways involved in the positive and negative modulation of Wnt pathway namely Phosphoinositide 3-kinase (PI3-K), Glycogen synthase kinase-3β (GSK-3β), Mitogen-activated protein kinase (MAPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
... VP3.15 successfully preserves axonal integrity in a model of primary progressive multiple sclerosis, and it has been suggested that the simultaneous inhibition of PDE7 and GSK-3β might account for its synergistic effect [41]. In line with these observations, neuroprotection mediated by inhibition of GSK-3β has been largely reported after different insults and neurodegenerative disorders [53][54][55], and similar results have been observed after PDE7 inhibition [56]. We detected an increase in tau phosphorylation in the cortex of mice with GM-IVH. ...
... VP3.15 improves proliferation and neurogenesis in mice with GM-IVH. a The number of BrdU + cells was significantly reduced in the SVZ from animals with GM-IVH at P14, and VP3.15 treatment increased the number of BrdU + cells [F(3,53) = 3.42, †p = 0.026 vs. Control and Control-VP3.15]. ...
... Differences were no longer significant at P110 [F(3,46) = 0.756, p = 0.524]. b The area covered by DCX immunostaining was significantly reduced in the SVZ at P14 [F(3,53) = 3.24, ‡p = 0.029 vs. Control]. A similar profile was observed at P110, but the differences did not reach statistical significance [F(3,51) = 0.512, p = 0.676]. ...
Advances in neonatology have significantly reduced mortality rates due to prematurity. However, complications of prematurity have barely changed in recent decades. Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most severe complications of prematurity, and these children are prone to suffer short- and long-term sequelae, including cerebral palsy, cognitive and motor impairments, or neuropsychiatric disorders. Nevertheless, GM-IVH has no successful treatment. VP3.15 is a small, heterocyclic molecule of the 5-imino-1,2,4-thiadiazole family with a dual action as a phosphodiesterase 7 and glycogen synthase kinase-3β (GSK-3β) inhibitor. VP3.15 reduces neuroinflammation and neuronal loss in other neurodegenerative disorders and might ameliorate complications associated with GM-IVH. We administered VP3.15 to a mouse model of GM-IVH. VP3.15 reduces the presence of hemorrhages and microglia in the short (P14) and long (P110) term. It ameliorates brain atrophy and ventricle enlargement while limiting tau hyperphosphorylation and neuronal and myelin basic protein loss. VP3.15 also improves proliferation and neurogenesis as well as cognition after the insult. Interestingly, plasma gelsolin levels, a feasible biomarker of brain damage, improved after VP3.15 treatment. Altogether, our data support the beneficial effects of VP3.15 in GM-IVH by ameliorating brain neuroinflammatory, vascular and white matter damage, ultimately improving cognitive impairment associated with GM-IVH.
... semaglutide treatment resulting in a significant reduction in mRNA levels compared to age-matched untreated Pla2g6 −/− mice (Fig. 2B). The inhibition of the enzyme glycogen synthase kinase 3 beta (GSK3β) has been found to promote neuroprotection 23,24 . Inversely, cAMP response element-binding protein (CREB) mediates the expression of genes closely associated with neuronal survival, neural differentiation, and neurite outgrowth 25,26 . ...
Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson’s disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study.
... 6-bromoindirubin-3'-oxime (BIO) is a GSK-3β inhibitor. Low-dose BIO therapy can reduce the hematoma volume of subacute ICH by inhibiting GSK-3β and activating the Wnt/β-catenin pathway, protecting the BBB and significantly improving the survival rate of neurons ECs around the hematoma [102]. P-Akt phosphorylates GSK-3β at the Ser9 residue and inhibits GSK-3β activity. ...
... It is well known that treatment of ICH in the convalescence phase after the acute phase is essential. After ICH, the expression levels of VEGF and brain-derived neurotrophic factor (BDNF) are upregulated around the hematoma, stimulating EC proliferation and migration to promote angiogenesis and nerve regeneration [102,121]. The effects peaked 7-14 days after collagenase-induced ICH and then decreased [122]. ...
... The Wnt signaling pathway is crucial for cerebral neurogenesis, neurite outgrowth, axon remodeling, synaptic plasticity, and neuronal morphogenesis. Long-term treatment with BIO (14 days) upregulated VEGF and BDNF through the Wnt/β-catenin pathway, promoted neurogenesis and angiogenesis around the injured area, promoted the proliferation of neural stem cell (NSC) and migration of neonatal neuroblast, and increased the number of neonatal neurons and ECs around the hematoma [102]. The Wnt/GSK-3β/β-catenin pathway is useful in the treatment of acute or chronic ICH. ...
Intracerebral hemorrhage (ICH) refers to hemorrhage caused by non-traumatic vascular rupture in the brain parenchyma, which is characterized by acute onset, severe illness, and high mortality and disability. The influx of blood into the brain tissue after cerebrovascular rupture causes severe brain damage, including primary injury caused by persistent hemorrhage and secondary brain injury (SBI) induced by hematoma. The mechanism of brain injury is complicated and is a significant cause of disability after ICH. Therefore, it is essential to understand the mechanism of brain injury after ICH to develop drugs to prevent and treat ICH. Studies have confirmed that many traditional Chinese medicines (TCM) can reduce brain injury by improving neurotoxicity, inflammation, oxidative stress (OS), blood-brain barrier (BBB), apoptosis, and neurological dysfunction after ICH. Starting from the pathophysiological process of brain injury after ICH, this paper summarizes the mechanisms by which TCM improves cerebral injury after ICH and its comparison with conventional western medicine, so as to provide clues and a reference for the clinical application of TCM in the prevention and treatment of hemorrhagic stroke and further research and development of new drugs.
... The active form of GSK3β induces apoptosis, aggravates neuronal injury [32,34], and also alters neuronal cytoarchitecture [35]. Other players are BDNF and VEGF, two critical growth factors promoting angiogenesis, neurogenesis, neuronal survival, and plasticity [31,36]. The inhibition of GSK3β or the upregulation of BDNF and VEGF is associated with an improvement in cognition [32,33,37]. ...
It has been suggested that cerebral microhemorrhages (CMHs) could be involved in cognitive decline. However, little is known about the sex-dependency of this effect. Using a multimodal approach combining behavioral tests, in vivo imaging, biochemistry, and molecular biology, we studied the cortical and hippocampal impact of a CMH in male and female mice (C57BL/6J) 6 weeks post-induction using a collagenase-induced model. Our work shows for the first time that a single cortical CMH exerts sex-specific effects on cognition. It notably induced visuospatial memory impairment in males only. This sex difference might be explained by cortical changes secondary to the lesion. In fact, the CMH induced an upregulation of ERα mRNA only in the female cortex. Besides, in male mice, we observed an impairment of pathways associated to neuronal, glial, or vascular functions: decrease in the P-GSK3β/GSK3β ratio, in BDNF and VEGF levels, and in microvascular water mobility. The CMH also exerted spatial remote effects in the hippocampus by increasing the number of astrocytes in both sexes, increasing the mean area occupied by each astrocyte in males, and decreasing hippocampal BDNF in females suggesting a cortical-hippocampal network impairment. This work demonstrates that a CMH could directly affect cognition in a sex-specific manner and highlights the need to study both sexes in preclinical models.
... Indeed, consisted with previous reports [31], we also found ICH enhances the number of BrdU-positive cells significantly in the acute phase following ICH, even though the Notch1 signaling decreased. This may be explained by many kinds of compensatory mechanism existed in the acute phase after ICH, including high-mobility group box1 pathway, Wnt/β-catenin pathway, etc. [32,33]. Moreover, Notch1 signaling could integrate with numerous other pathways thereby to regulate the maintenance of NSCs, including vascular niche factor PEDF and protein S [34]. ...
Intracerebral hemorrhage (ICH) is associated with high rate of mortality and morbidity, but lacks effective therapies. Accumulating studies indicated that the hippocampal neurogenesis plays an essential role in the recovery of neurological function after ICH. The Notch1 signaling pathway shows important roles in neurogenesis. However, the effects of Notch1 on the recovery of neurological function after ICH remain unclear. Here, we used ICH mice model to investigate whether Notch1 signaling was involved in the hippocampal neurogenesis and the recovery of neurological function post-ICH. Our results showed that the rate of symmetric division pattern of hippocampal neural stem cells (NSCs) decreased significantly at 3 days after ICH. Meanwhile, the expression of Notch1 in the hippocampus also was reduced significantly. However, Notch1 activator treatment enhanced the expression of Notch1 and increased the number of Sox2+GFAP+ cells. Further, the rate of symmetric division pattern of NSCs also increased after Notch1 activator treatment in mice with ICH. Importantly, the number of DCX+ cells and BrdU+NeuN+ in hippocampus were increased on 28 days post-ICH as the Notch1 expression was upregulated. The motor function and spatial memory ability in post-ICH mice following Notch1 activator treatment also were improved. Taken together, our results suggested that Notch1 signaling could influence the recovery of long-term neurological function by regulating the proliferation and differentiation of the hippocampal NSCs in mice after ICH. Our study may provide ideas for the improvement of neurological function and spatial memory defects after ICH.
... GSK3β est une sérine/thréonine kinase ubiquitaire connue pour avoir un rôle important dans de nombreux processus biologiques dont la prolifération cellulaire, la migration, la différenciation, la polarité et la plasticité des neuroblastes et/ou des neurones et dans les voies de signalisation de l'apoptose (Zhao et al., 2017). GSK3β est notamment régulée négativement par les voies phosphoinositol-3-kinase (PI3K)-Akt et WNT (O'Leary and Nolan, 2015; Zhao et al., 2017).Sous forme active, GSK3β peut inhiber la voie de la β-caténine qui est notamment impliquée dans la neurogénèse ou la synthèse de facteurs de croissance comme le « brain-derived neurotrophic factor » (BDNF) ou le « vascular endothelial growth factor » (VEGF)(O'Leary and Nolan, 2015;Zhao et al., 2017). D'après la revue de O'Leary et Nolan(2015), GSK3β ...
Les microhémorragies cérébrales (MHC), petites lésions dont la prévalence augmenteavec l’âge sont associées à un risque augmenté de troubles cognitifs. Les mécanismes parlesquels les MHC pourraient altérer les fonctions cognitives ainsi que l’effet du sexe sur lesMHC ne sont pas bien élucidés. Le premier objectif de ce travail de thèse était d’étudier lesmécanismes mis en place après la formation d’une MHC corticale, chez des souris mâles etfemelles. Le deuxième objectif était de déterminer les effets de l’atorvastatine, médicamentconnu pour ses effets pléïotropes, sur la cognition et sur les mécanismes induits par la MHC.Six semaines après la formation d’une MHC induite par injection stéréotaxique de collagénasedans le cortex de souris C57BL/6J, des effets différents en fonction du sexe d’ordre cellulaire,protéique, génomique et métabolique étaient observés dans le cortex et l’hippocampe des sourismâles et femelles, conduisant à l’hypothèse d’une altération des réseaux corticohippocampiques,à l’origine de troubles de la cognition chez les mâles. L’atorvastatinecorrigeait les modifications induites par la MHC en fonction du sexe et améliorait les troublesde la cognition chez les mâles. Au total, cette étude a montré, à partir d’un travail précis portantsur l’impact cognitif d’une MHC, que la prise en compte du sexe dans un protocole précliniques’avère indispensable pour mieux élucider les mécanismes physiopathologiques de la maladiemodélisée dans le but de développer des traitements les plus adaptés possibles.
... The Wnt pathway is an evolutionarily conserved signaling pathway that plays a role in blood-brain barrier dysfunction, secondary brain damage, and angiogenesis after ICH Wang et al. 2019;Zhao et al. 2017). Importantly, the proteomic analysis revealed ICH-induced downregulation of a protein, axin-1, which is a key regulator of Wnt signaling (Jiang et al. 2018). ...
Intracerebral hemorrhage (ICH) is a non-traumatic cerebrovascular disorder with very high morbidity and mortality and regarded as one of the deadliest stroke subtypes. Notably, there is no effective treatment for ICH. Despite an overall increase in preclinical studies, the pathophysiology of ICH is complex and remains enigmatic. To this end, ICH was induced in male CD-1 mice and the ipsilateral brain tissue was characterized in an unbiased manner using a combination of proteomics and bioinformatics approaches. A total of 4833 proteins were revealed by quantitative proteomic analysis. Of those, 207 proteins exhibited significantly altered expression after ICH in comparison to sham. It was found that 46 proteins were significantly upregulated and 161 proteins were significantly downregulated after ICH compared to sham. The quantitative proteomics approach combined with bioinformatics revealed several novel molecular targets (cyclin-dependent-like kinase 5, E3 ubiquitin-protein ligase, protein phosphatase 2A-alpha, protein phosphatase 2A-beta, serine/threonine-protein kinase PAK1, alpha-actinin-4, calpain-8, axin-1, NCK1, and septin-4), and related signaling pathways, which could play roles in secondary brain injury and long-term neurobehavioral outcomes after ICH warranting further investigation.
... The neurogenic effect of Bcl2 was reversed by the administration of β-catenin siRNA, indicating the involvement of the Wnt signaling pathway [155]. A similar effect was observed in hemorrhagic stroke, where Wnt signaling activation promoted neurogenesis in the SVZ together with Bcl2 and β-catenin expression, suggesting that Wnt signaling plays similar roles in both ischemic and hemorrhagic stroke [156]. ...
Wnt signaling plays an important role in the self-renewal, fate-commitment and survival of the neural stem/progenitor cells (NS/PCs) of the adult central nervous system (CNS). Ischemic stroke impairs the proper functioning of the CNS and, therefore, active Wnt signaling may prevent, ameliorate, or even reverse the negative effects of ischemic brain injury. In this review, we provide the current knowledge of Wnt signaling in the adult CNS, its status in diverse cell types, and the Wnt pathway’s impact on the properties of NS/PCs and glial cells in the context of ischemic injury. Finally, we summarize promising strategies that might be considered for stroke therapy, and we outline possible future directions of the field.
... Signaling molecules such as TLR4, STAT3, JUN, FOS, and mTOR have been verified to be significantly upregulated in local ICH lesions, which promotes the occurrence of pathological changes like inflammatory response (combined with multiple cytokines and downstream PTGS2 synthesis) and local neuron apoptosis (through affecting Akt-or MAPKs-mediated caspases cascade reaction, HSP5-mediated ERS, and the downstream level of apoptin BCL2L1) [62][63][64]. The GSK-3b/b-catenin (CTNNB1) pathway has been verified to participate in maintaining the viability of neurons (CCND1-and CDKN2A-mediated), and upregulates BDNF and VEGF to promote angiogenesis, neurogenesis, and BBB repair (KDR-and EGFR-mediated) in ICH [65,66]. ...
Background
Intracerebral hemorrhage (ICH), a fatal type of stroke, profoundly affects public health. Yi-Qi-Huo-Xue decoction (YQHXD), a traditional Chinese medicine (TCM) prescription, is verified to be an efficient method to treat ICH stroke among the Chinese population. Nevertheless, the pharmacological mechanisms of YQHXD have been unclear.
Material/Methods
We used a strategy based on network pharmacology to explore the possible multi-component, multi-target, and multi-pathway pattern of YQHXD in treating ICH. First, candidate targets for YQHXD were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Then, these candidate YQHXD targets were used in combination with the known targets for the treatment of ICH stroke to construct the core network (cPPI) using data on protein–protein interaction (PPI). We calculated 5 topological parameters for identification of the main hubs. Pathway enrichment and GO biological process enrichment analyses were performed after the incorporation of the main hubs into ClueGO.
Results
In total, 55 candidate YQHXD targets for ICH were recognized to be the major hubs in accordance with their topological importance. As suggested by enrichment analysis, the YQHXD targets for ICH were roughly classified into several biological processes (related to redox equilibrium, cell–cell communication, adhesion and collagen biosynthesis, cytokine generation, lymphocyte differentiation and activation, neurocyte apoptosis and development, neuroendocrine system, and vascular development) and related pathways (VEGF, mTOR, NF-kB, RAS/MAPK, JAK/STAT and cytokine–cytokine receptors interaction), indicating those mechanisms underlying the therapeutic effect of YQHXD.
Conclusions
The present results may serve as a pharmacological framework for TCM studies in the future, helping to promote the use of YQHXD in clinical treatment of ICH.
