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Apoptosis of neurons in the perihematoma following ICH. (A) Protein expression levels and (B) semi-quantification of caspase-3 and cleaved caspase-3. Immunofluorescence of (C) NeuN, (D) cleaved caspase-3 and (E) Hoechst staining in the perihematoma region of the sham group. (F) Merged staining of the sham group (n=6). Immunofluorescence of (G) NeuN, (H) cleaved caspase-3 and (I) Hoechst staining in the perihematoma region at 2 d after ICH. (J) Merged staining at 2 d post-ICH. Immunofluorescence of (K) NeuN, (L) cleaved caspase-3 and (M) Hoechst staining in the perihematoma region at 7 d post-icH. (n) Merged staining at 7 d post-icH. * P<0.05 vs. sham. ICH, intracerebral hemorrhage; d, day.
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Intracerebral hemorrhage (ICH) refers to hemorrhage caused by spontaneous rupture of blood vessels in the brain. Brain injury due to ICH leads to catastrophic effects resulting from the formation of hematoma and oxidative stress caused by components of lysed erythrocytes. However, not all neurons in the area surrounding the hematoma die immediately...
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... impairment, levels of caspase-3 and cleaved caspase-3 were examined as indicators of neuronal apoptosis in the peripheral hematoma region (22). expression of cleaved caspase-3 in the sham group was low, although the expression level increased following icH, reaching a peak on day 2 post-icH, before the expression levels were downregulated (Fig. 2). compared with the sham group (2c-F), the levels of cleaved caspase-3 in the peripheral hematoma region at 2 days post-icH were markedly high (Fig. 2G-J). additionally, elevated levels of cleaved caspase-3 were primarily co-located with the neurons, which confirmed that the increase in activation of cleaved caspase-3 in the peripheral ...
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... expression of cleaved caspase-3 in the sham group was low, although the expression level increased following icH, reaching a peak on day 2 post-icH, before the expression levels were downregulated (Fig. 2). compared with the sham group (2c-F), the levels of cleaved caspase-3 in the peripheral hematoma region at 2 days post-icH were markedly high (Fig. 2G-J). additionally, elevated levels of cleaved caspase-3 were primarily co-located with the neurons, which confirmed that the increase in activation of cleaved caspase-3 in the peripheral hematoma region was primarily associated with the apoptosis of neurons (Fig. 2G-J). at 2 days post-icH in rats, the hematoma was elliptic, and there was ...
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... caspase-3 in the peripheral hematoma region at 2 days post-icH were markedly high (Fig. 2G-J). additionally, elevated levels of cleaved caspase-3 were primarily co-located with the neurons, which confirmed that the increase in activation of cleaved caspase-3 in the peripheral hematoma region was primarily associated with the apoptosis of neurons (Fig. 2G-J). at 2 days post-icH in rats, the hematoma was elliptic, and there was also clear edema of surrounding tissue, as shown by H&e staining (Fig. S1). This also revealed that the severest stage of neurological impairment occurred on day 2 ...
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... enhancer of kinase suppressor of ras 2; BaiaP2l1, Bar/iMd domain containing adaptor protein 2 like 1; TFaP2B, transcription factor aP-2β; Snca, synuclein α; PPia, peptidylprolyl isomerase a; SHoc2, SHoc2 leucine rich repeat scaffold protein; coMT, catechol-o-methyltransferase. and abnormalities', accounting for 11.5% of the total (5.3.5; Fig. S2; Table Viii). analysis of the association with 'neurological diseases' indicated that the changes in the perihematoma microenvironment following icH were associated with 'development (repair) of the nervous system'. Subsequently, iPa software was used to analyze the causal network of neural functional development. This analysis showed ...
Citations
... Currently, knowledge about the cellular composition of the outer membrane is incomplete. There is a general agreement that hemorrhage triggers inflammation [60,63,64]. ...
... This process causes physical disruption of neuronal cells and increases intracranial pressure, which can compress brain regions, potentially impacting blood flow and leading to herniation [4,5]. With the formation of hematoma, secondary injury caused by a cascade of events initiated by the primary injury, such as body/tissue response to the hematoma (e.g., inflammation) and the release of clot components (e.g., hemoglobin), will continually damage the brain [6,7]. Currently, the clinical treatment of ICH is focused on improving the survival rates of patients and preventing re-bleeding [8]. ...
Intracerebral hemorrhage (ICH) is the most lethal subtype of stroke and is associated with significant morbidity and mortality. Despite advances in the clinical treatment of ICH, limited progress has been made regarding endogenous brain regeneration after ICH. Failure of brain regeneration is mainly attributed to the inhibitive regenerative microenvironment caused by secondary injury after ICH. In this study, we investigated a three-dimensional biodegradable waterborne polyurethane (BWPU) scaffold as a tool to promote brain regeneration after ICH. After implantation into the cavity following hematoma evacuation, these implanted scaffolds could act as a reservoir; store a series of necrotic debris, cytokines, and chemokines; and attract microglia/macrophages to their pores. Subsequently, these microglia/macrophages were polarized into the M1-like subtype to eliminate these substances. This process disperses M1-like immune cells and prevents the formation of dense glial scar-free structures after ICH. Inflammatory cells in scaffolds include scar-free secreted growth factors and extracellular matrix (ECM) proteins, and further induce a M2-like immune cells enriched regeneration-predominant microenvironment to promote endogenous brain regeneration with functional recovery. In summary, in this work, we have revealed the potential and mechanism of the BWPU scaffold as a tool to promote endogenous brain tissue regeneration after ICH.
... All animal experiments were conducted with six rats in each group. The ICH model was established according to the method described in a previous study (Wang et al. 2021). The rat body was straightened and placed on a stereotaxic frame. ...
Intracerebral hemorrhage (ICH) is a devastating cerebrovascular associated with inflammation and BBB disruption. Pericytes plays a critical role in neurological diseases, while whether pericytes could be utilized to treat ICH remains to be elucidated. Here, we isolated CD146⁺CD34⁻ pericytes from rat adipose tissues (ADPs). Fluorescence-activated cells maintained their cell morphology and differentiation potential and expressed pericytes markers (CD146, NG2, and PDGFRβ) but not endothelial markers (CD31, CD34, and CD45). ADPs transplantation improved the neuro-behavioral functions in ICH rats and resulted in decreased hematoma volume and neuron loss after ICH. Besides, ADPs graft restrained the infiltration of neutrophils and reactive microgliosis after ICH injury around the peri-hematoma area of rats, as evidenced by increased Iba1- and MPO immunoreactivity. The transplanted pericytes were covered on endothelial cells, and promoted angiogenesis and vascular basement membrane formation in the peri-hematoma area of ICH rats, as shown by double staining of PDGFRβ and CD31/CollagenIV. The decreased brain water content and Evans Blue leakage proved the protective role of ADPs graft on BBB permeability. Finally, transplanted ADPs increased the expression of VE-cadherin, ZO-1, and claudin-5, leading to stable endothelial cell-cell adhesion and tight junction. In conclusion, the transplantation of APDs improved neuronal after ICH, which involved different mechanisms including neuroinflammation regulation and BBB dysfunction recovery. Our results supported that ADPs might be the ideal cell type for ICH therapy and provided insights into the potential cell therapy for further ICH treatment.
... To explore the relationship between p75 NTR and Glis2 in ICH in vivo, a rat model of ICH was established, which referred to our previous studies (Wang et al. 2021. Western blotting was used to detect the changes in expression of p75 NTR and Glis2 in the area adjacent to the hematoma of the rat ICH model. ...
Intracerebral hemorrhage (ICH) is a serious condition with a particularly high mortality rate. Gli-similar 2 (Glis2) has been reported to play an important role in the pathogenesis of ICH; however, its underlying mechanisms and biological significance remains unclear. In the present study, a specific interaction between Glis2 and p75NTR, a member of the tumor necrosis factor receptor superfamily, was identified both in vivo and in vitro. These experiments further indicated that p75NTR may interact with Glis2, and that the complex was transported into the nucleus, initially, inducing neuronal death. Furthermore, the mechanism of neuronal death was explored, and may have been mediated via the activation of the mitochondrial-dependent apoptotic pathway, and this was further investigated in the pathogenesis of ICH in rats in vivo. The study may provide evidences for regulating p75NTR-Glis2 complex as a potential reliable treatment for the secondary damage following ICH.
Acupuncture has obvious therapeutic effect on intracerebral hemorrhage (ICH). miR-34a-5p regulated by acupuncture was found to attenuate neurological deficits in ICH. However, the underlying mechanisms are unclear. Ubiquitin Like 4A (UBL4A) has not been studied in ICH. SD rats were injected with autologous blood to induce ICH and treated with Baihui-penetrating-Qubin acupuncture. Acupuncture resulted in an increase in forelimb placing test scores, and a decrease in corner test scores and brain water content of ICH rats. Histopathological examination showed that acupuncture inhibited ICH-induced inflammation, decreased damaged neurons and increased UBL4A expression. UBL4A overexpression increased cell viability, inhibited apoptosis, reduced ROS level and increased MnSOD activity, mitochondrial membrane potential and mtDNA level in rat embryonic primary cortical neurons. miR-34a-5p knockdown increased UBL4A expression, apoptosis rate and ROS level in hemin-treated neurons. Dual luciferase assays showed that miR-34a-5p bound to UBL4A. Apoptotic cells and ROS level were increased in hemin-treated neurons with UBL4A and miR-34a-5p knockdown. We firstly demonstrate the inhibitory effect of UBL4A on neuronal apoptosis, and the regulation relationship between UBL4A and miR-34a-5p. This study provides a new candidate target for ICH treatment and more basis for elucidating the molecular mechanism of acupuncture. In the future, we will conduct a deeper exploration of the effects of UBL4A on ICH.
La neurología, como disciplina médica en constante evolución, demanda una actualización continua por parte de los profesionales de la salud. En este contexto, el primer volumen de la serie "Actualización en Neurología" emerge como una obra imprescindible que aborda los últimos avances y conocimientos en el campo de las enfermedades del sistema nervioso central y periférico. Este libro se posiciona como un recurso esencial para neurólogos, residentes y estudiantes de medicina que buscan mantenerse al día con los desarrollos más recientes en la neurociencia clínica.
Intracerebral hemorrhage (ICH) is a cerebrovascular disease. Kallikrein-related peptidase 8 (KLK8) is a serine peptidase, while its role in ICH remains unclarified. Western blot (WB) showed that KLK8 was upregulated in rat perihematomal tissues 24 h following autologous blood injection. KLK8 overexpression aggravated behavioral deficits and increased water content and Fluoro-Jade B (FJB)-positive neuron numbers in brain tissue of rats. Immunofluorescence (IF) assay showed that overexpressed-KLK8 promoted Iba-1 and iNOS expression in perihematomal tissue of rats. Overexpressed-KLK8 increased COX-2, iNOS, and Arg-1 expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue of rats, confirmed by WB and ELISA. IF staining confirmed the expression of CCR5 was co-expressed with Iba-1, and the WB results shown increased CCR5 expression and decreased p-PKA and p-CREB expression in perihematomal tissue. Maraviroc (MVC, CCR5 inhibitor) administration rescued KLK8-induced behavioral deficits and brain injury (decreased water content and FJB-positive neuron numbers) in rats. Additionally, MVC suppressed p-PKA and p-CREB expression and the content of IL-6, IL-1β, and TNF-α in perihematomal tissue, induced by overexpressed-KLK8. Co-IP confirmed the binding of CCR5 and CCL14 in HMC3 cells. Transwell assay shown that KLK8 plus CCL4 promoted the chemotactic activity of cells, which was rescued by MVC. The biological function of KLK8/CCL14/CCR5 axis in ICH injury was also proved by MVC administration in HMC3 cells. Overall, our work revealed that KLK8 overexpression aggravated ICH process and involved in microglial activation. KLK8 might activate CCL14 thereby turning on downstream CCR5/PKA/CREB pathway, providing a theoretical basis for future therapy.
Intracerebral hemorrhage (ICH) is classified as a lethal neurological injury associated with cerebrovascular disorders. Ferroptosis is a unique form of cell death and participates in ICH pathogenesis. Herein, the role of SRY-box transcription factor 10 (SOX10) in ferroptosis of hippocampal neurons after ICH was investigated. The in vitro ICH models were established by treating immortalized mouse hippocampal cell line HT-22 with Hemin. Quantitative real-time polymerase chain reaction and Western blotting revealed that the transcription factor SOX10 and microRNA (miR)-29a-3p were decreased whilst acyl-CoA synthetase long chain family member 4 (ACSL4) was increased in the ICH cell models. Subsequently, the assays of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, the commercial kits, and fluorescent labeling revealed that SOX10 overexpression improved cell viability, decreased the amount of reactive oxygen species (ROS) and Fe2+, and increased the amount of glutathione (GSH) and glutathione peroxidase 4 (GPX4) in ICH models. Thereafter, chromatin immunoprecipitation and dual-luciferase assays showed that SOX10 binding to the miR-29a-3p promoter region increased miR-29a-3p expression, and miR-29a-3p targeted and limited ACSL4 transcription. Rescue experiments showed that miR-29a-3p downregulation or ACSL4 overexpression expedited ferroptosis of Hemin-treated HT-22 cells. Taken together, SOX10 contributed to ferroptosis of hippocampal neurons after ICH via increasing miR-29a-3p to limit ACSL4 transcription.
Intracerebral hemorrhage (ICH) is an incurable neurological disease. Microglia activation and its related inflammation contribute to ICH-associated brain damage. FERM domain containing kindlin 1 (FERMT1) is an integrin-binding protein that participates in microglia-associated inflammation, but its role in ICH is unclear. An ICH model was constructed by injecting 50 μl of autologous blood into the bregma of rats. FERMT1 siRNA was injected into the right ventricle of the rat for knockdown of FERMT1. A significant striatal hematoma was observed in ICH rats. FERMT1 knockdown reduced the water content of brain tissue, alleviated brain hematoma and improved behavioral function in ICH rats. FERMT1 knockdown reduced microglia activity, inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activity and decreased the expression of inflammatory factors including interleukin-1β (IL-1β) and interleukin 18 (IL-18) in the peri-hematoma tissues. BV2 microglial cells were transfected with FERMT1 siRNA and incubated with 60 μM Hemin for 24 h. Activation of NLRP3 inflammasome induced by hemin were reduced in microglia when FERMT1 was knocked down, leading to decreased production of inflammatory factors IL-1β and IL-18. In addition, knockdown of FERMT1 prevented the activation of nuclear factor kappa B (NF-κB) signaling pathway in vivo and in vitro. Our findings suggested that down-regulation of FERMT1 attenuated microglial inflammation and brain damage induced by ICH via NLRP3/NF-κB pathway. FERMT1 is a key regulator of inflammatory damage in rats after ICH.
