Inhibition of Let7c microRNA is neuroprotective in a rat intracerebral hemorrhage model.
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ABSTRACT:
SUBMITTER: Kim JM
PROVIDER: S-EPMC4068982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As an essential constituent of the mitochondrial contact site and cristae organization system (MICOS), MIC19 plays a crucial role in maintaining the stability of mitochondrial function and microstructure. However, the mechanisms and functions of MIC19 in intracerebral hemorrhage (ICH) remain unknown and need to be investigated. Sprague Dawley (SD) rats injected with autologous blood obtained from the caudal artery, and cultured neurons exposed to oxygen hemoglobin (OxyHb) were used to establish and emulate the ICH model in vivo and in vitro. Lentiviral vector encoding MIC19 or MIC19 short hairpin ribonucleic acid (shRNA) was constructed and administered to rats by intracerebroventricular injection to overexpress or knock down MIC19, respectively. First, MIC19 protein levels were increased after ICH modeling. After virus transfection and subsequent ICH modeling, we observed that overexpression of MIC19 could mitigate cell apoptosis and neuronal death, as well as abnormalities in mitochondrial structure and function, oxidative stress within mitochondria, and neurobehavioral deficits in rats following ICH. Conversely, knockdown of MIC19 had the opposite effect. Moreover, we found that the connection between MIC19 and SAM50 was disrupted after ICH, which may be a reason for the impairment of the mitochondrial structure after ICH. In conclusion, MIC19 exerts a protective role in the subsequent injury induced by ICH. The investigation of MIC19 may offer clinicians novel therapeutic insights for patients afflicted with ICH.
| S-EPMC10380515 | biostudies-literature
Project description:Recent studies have shown that fingolimod (FTY720) is neuroprotective in CNS injury models of cerebral ischemia and spinal cord injury. The purpose of the study was to examine the effect of fingolimod in a mouse model of intracerebral hemorrhage. ICH was produced in adult CD1 mice by injecting collagenase VII-S (0.5 µL, 0.06 U) into the basal ganglia. Fingolimod (or saline) was given 30 min after surgery and once daily for two days. Three days after intracerebral hemorrhage, brain edema, hematoma volume and the number of apoptotic cells were quantified. In another cohort of mice, brain atrophy was evaluated two weeks following intracerebral hemorrhage. Neurobehavioral tests were performed on the 3rd, the 7th and the 14th day. Fingolimod significantly decreased edema, apoptosis and brain atrophy. More importantly, fingolimod enhanced neurobehavioral recovery. Preliminary experiments showed no difference in the number of inflammatory (CD68-positive) cells between the two groups. In conclusion, fingolimod exerts protective effects in a mouse model of intracerebral hemorrhage; the mechanisms underlying these neuroprotective effects deserve further study.
| S-EPMC3994537 | biostudies-literature
Project description:Apoptosis is an important factor during the early stage of intracerebral hemorrhage. MiR-181c plays a key regulatory role in apoptosis. However, whether miR-181c is involved in apoptosis of prophase cells after intracerebral hemorrhage remains unclear. Therefore, in vitro and in vivo experiments were conducted to test this hypothesis. In vivo experiments: collagenase type VII was injected into the basal ganglia of adult Sprague-Dawley rats to establish an intracerebral hemorrhage model. MiR-181c mimic or inhibitor was injected in situ 4 hours after intracerebral hemorrhage. Neurological functional defects (neurological severity scores) were assessed 1, 7, and 14 days after model establishment. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and western blot assay were conducted 14 days after model establishment. In vitro experiments: PC12 cells were cultured under oxygen-glucose deprivation, and hemins were added to simulate intracerebral hemorrhage in vitro. MiR-181c mimic or inhibitor was added to regulate miR-181c expression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, luciferase reporter system, and western blot assay were performed. Experimental results revealed differences in miR-181c expression in brain tissues of both patients and rats with cerebral hemorrhage. In addition, in vitro experiments found that miR-181c overexpression could upregulate the Bcl-2/Bax ratio to inhibit apoptosis, while inhibition of miR-181c expression could reduce the Bcl-2/Bax ratio and aggravate apoptosis of cells. Regulation of apoptosis occurred through the phosphoinositide 3 kinase (PI3K)/Akt pathway by targeting of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Higher miR-181c overexpression correlated with lower neurological severity scores, indicating better recovery of neurological function. In conclusion, miR-181c affects the prognosis of intracerebral hemorrhage by regulating apoptosis, and these effects might be directly mediated and regulated by targeting of the PTEN\PI3K/Akt pathway and Bcl-2/Bax ratio. Furthermore, these results indicated that miR-181c played a neuroprotective role in intracerebral hemorrhage by regulating apoptosis of nerve cells, thus providing a potential target for the prevention and treatment of intracerebral hemorrhage. Testing of human serum was authorized by the Ethics Committee of China Medical University (No. 2012-38-1) on February 20, 2012. The protocol was registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR-COC-17013559). The animal study was approved by the Institutional Animal Care and Use Committee of China Medical University (approval No. 2017008) on March 8, 2017.
| S-EPMC7047781 | biostudies-literature
Project description:After intracerebral hemorrhage (ICH), the brain parenchyma is exposed to blood containing red blood cells (RBCs) and consequently to its lysis products. Iron-rich hemoglobin (Hb) is the most abundant protein in RBCs. When released into the brain parenchyma during hemolysis, Hb becomes a central mediator of cytotoxicity. Our study indicates that haptoglobin (Hp), an acute-phase response protein primarily synthesized in the liver and known to bind and neutralize Hb in the bloodstream, is also expressed in brain in which it plays an important role in defending neurons from damage induced by hemolytic products after ICH. We demonstrate that the Hb-induced hypohaptoglobinemia aggravates ICH-induced brain damage while pharmacologic intervention with sulforaphane to induce brain Hp is linked to a reduction in brain damage. In agreement with these findings, Hp deficiency worsens whereas Hp overexpression alleviates ICH-mediated brain injury. We also identified that oligodendroglia are the primary source of brain-derived Hp among brain cells and that oligodendroglia-released Hp plays protective roles against Hb-mediated toxicity to neurons and oligodendrocytes. We conclude that Hp, particularly the brain-derived Hp, plays cytoprotective roles and represents a potential therapeutic target for ICH treatment.
| S-EPMC2831226 | biostudies-literature
Project description:Intracerebral hemorrhage (ICH) is a life-threatening condition associated with significant morbidity and mortality. Understanding the molecular mechanisms underlying ICH and its severe form is crucial for developing effective therapeutic strategies. This study investigates transcriptomic alterations in rodent models of ICH and severe intracerebral hemorrhage to shed light on the genetic pathways involved in hemorrhagic brain injury. We performed principal component analysis, revealing distinct principal component segments of normal rats compared to intracerebral hemorrhage and severe intracerebral hemorrhage rats. We further employed heatmaps and volcano plots to identify differentially expressed genes and utilized bar plots and KEGG pathway analysis to elucidate the different molecular pathways involved. Using comprehensive RNA sequencing and bioinformatics analyses, we identified a multitude of differentially expressed genes in both the ICH and severe ICH models. Our results revealed 5679 common genes among the normal, intracerebral hemorrhage, and severe intracerebral hemorrhage groups in the upregulated genes group, and 1196 common genes in the downregulated genes. A volcano plot comparing the groups further highlighted common genes, including PDPN, TIMP1, SERPINE1, TUBB6, and CD44. These findings underscore the complex interplay of genes involved in inflammation, oxidative stress, and neuronal damage. Furthermore, pathway enrichment analysis uncovered key signaling pathways, including the TNF signaling pathway, protein processing in the endoplasmic reticulum, MAPK signaling pathway, and Fc gamma R-mediated phagocytosis, implicated in the pathogenesis of ICH.
2024-06-11 | GSE264394 | GEO
Project description:Intracerebral hemorrhage (ICH) has high morbidity and mortality, with no effective treatment at present. One possible therapeutic strategy involves the use of mesenchymal stem cells (MSCs), which have shown promise in experimental models and have great potential for treating nervous illnesses in humans. However, many deficiencies in MSC treatment still need to be addressed, including their poor survival rate post-transplantation. Previously, we reported that the microRNA-21 (miR-21) is downregulated in ICH patients' blood and brain tissue. In this study, we aimed to examine its role and therapeutic efficacy in ICH using miR-21-overexpressing MSCs. We found that this microRNA can enhance MSC survival and recovery of neurological function in ICH rats. Its mechanism of action involves reduced neuronal apoptosis. In addition, we demonstrated that miR-21 can be transported to neurons through exosomes derived from MSCs and that it can target transient receptor potential melastatin 7 (TRPM7) to alleviate neuronal injury following ICH. We also observed that the NF-κB pathway is involved in the regulation of miR-21 in neural cells. In conclusion, miR-21 significantly enhances the survival of MSCs in ICH, and miR-21-overexpressing MSCs clearly improved neurological function in ICH rats. Transplantation of miR-21-overexpressing MSCs may, therefore, provide an effective strategy for neuroprotection and treatment of cerebrovascular diseases.
| S-EPMC6233525 | biostudies-literature
Project description:Krüppel-like zinc-finger transcription factor 5 (KLF5), known as BTEB2 or IKLF, has several biological functions that involve cell proliferation, development and apoptosis. Previous studies demonstrated that BTEB2 had anti-apoptotic effect in multiple diseases such as esophageal cancer and non-small cell lung cancers (NSCLCs). However, the distribution and function of BTEB2 in CNS diseases remain unknown. In this study, we show that BTEB2 down-regulates neuronal apoptosis during pathophysiological processes of intracerebral hemorrhage (ICH). A rat ICH model was established by behavioral tests. Western blot and immunohistochemistry revealed a remarkable up-regulation of BTEB2 expression surrounding the hematoma after ICH. Double-labeled immunofluorescence showed BTEB2 was mostly co-localized with neurons, rarely with activated astrocytes and microglia. Furthermore, we detected that neuronal apoptosis marker active caspase-3 had co-localizations with BTEB2. In addition, KLF5 knockdown in vitro specifically resulted in increasing neuronal apoptosis coupled with reduced Bad phosphorylation at both ser112 and ser136 residues. All our findings suggested that BTEB2 down-regulated neuronal apoptosis via promoting Bad phosphorylation after ICH.
| S-EPMC4289975 | biostudies-literature
Project description:AimsIntracerebral hemorrhage (ICH) is a known risk factor for the development of acute symptomatic as well as late unprovoked seizures. The underlying pathophysiology of post-ICH seizures is incompletely understood and there are no reliable predictive biomarkers. An animal model to study post-ICH seizures is currently lacking. The aim of this study was to investigate (1) the occurrence of seizures and interictal epileptiform activity in the ICH rat collagenase model using long-term video-EEG monitoring (VEM) and (2) whether seizure occurrence was associated with interictal epileptiform activity and histological features.MethodsMale Sprague-Dawley rats were implanted with epidural electrodes. After 1 week of baseline VEM, collagenase was injected in left striatum to induce an ICH. VEM was continued for 180 days to assess the occurrence of post-ICH seizures and interictal epileptiform activity (spikes and epileptiform discharges). At the end of the experiment, animals were euthanized for histological characterization of the hemorrhagic lesion, using cresyl violet, Prussian blue and immunofluorescence staining.ResultsAcute symptomatic seizures occurred in 4/12 animals between 46 and 80 h after ICH induction. Late unprovoked seizures were present in 2/12 animals and started at 90 and 103 days post-ICH. Animals with late unprovoked seizures did not have acute symptomatic seizures. All electrographic seizures were accompanied by clear behavioral changes. Interictal spikes and epileptiform discharges were observed in all animals but occurred more frequently in rats with late seizures (p = 0.019 and p < 0.001, respectively). Animals with acute symptomatic seizures had more extended hemorrhagic lesions and hemosiderin deposits in the piriform cortex.ConclusionBoth acute symptomatic and late unprovoked seizures were observed in the rat collagenase model. Interictal epileptiform activity was more frequently seen in animals with late seizures. Rats with acute symptomatic seizures showed more extensive lesions and hemosiderin deposits in the piriform cortex. This model could be used to further explore possible biomarkers for epileptogenesis.
| S-EPMC8249930 | biostudies-literature
Project description:Oxidative stress and neuroinflammation are the key factors leading to secondary brain injury after intracerebral hemorrhage (ICH). We investigated the effects of miR-27b, an oxidative stress-responsive microRNA, on ICH-induced brain injury in rats. The ICH model was induced by intracerebral injection of collagenase. Following ICH, miR-27b expression in the striatum was reduced, whereas expression of Nrf2 mRNA and protein was increased. In PC12 cells, overexpression of miR-27b reduced expression of Nrf2, Hmox1, Sod1 and Nqo1, while miR-27b inhibition had the opposite effects. Dual luciferase reporter assays showed that Nrf2 mRNA was a direct target of miR-27b. Intracerebroventricular injection of miR-27b antagomir and transfection of miR-27b inhibitor inhibited endogenous miR-27b in rats and PC12 cells, respectively. MiR-27b antagomir promoted activation of the ICH-induced Nrf2/ARE pathway and reduced the lipid peroxidation, neuroinflammation, cell death and neurological deficits otherwise seen after ICH. In PC12 cells, the miR-27b inhibitor diminished iron-induced oxidative stress, inflammation and apoptosis, and those effects were blocked by Nrf2 knockdown. These results demonstrate that miR-27b inhibition alleviates ICH-induced brain injury, which may be explained in part by its regulation on the Nrf2/ARE pathway.
| S-EPMC5642585 | biostudies-literature
Project description:BackgroundThe neuroprotective effects of neuroserpin (NSP) have been well documented in both patients and animal models with cerebral ischemia; however, have never been investigated in hemorrhagic stroke. The aim of this study is to verify the neuroprotection of NSP in the non-tPA-induced intracerebral hemorrhage (ICH) mouse model.MethodsC57BL/6J male mice (n = 198) were involved in this study. ICH models were established with infusion of autologous blood into the brain parenchyma. We then detected NSP expression in ICH brains by morphological methods and western blotting analysis. We measured the brain water content and detected blood-brain barrier (BBB) permeability to verify the neuroprotective effects of NSP.ResultsWe found that NSP protein expression was upregulated in ICH models, with a peak at 48 h after ICH induction. NSP local administration reduced the brain edema and the BBB permeability in ICH models. The neurological deficits were also ameliorated. Thus, the neuroprotection of NSP in ICH state was confirmed. Additionally, we also found that the distribution pattern of occludin-expressing cells was obviously changed by the ICH procedure but partly recovered after NSP administration. This finding indicated that protecting and/or repairing the injured vascular endothelial cells may be a potential mechanism involved in NSP neuroprotection, which needs further verification.ConclusionsOur results supported the fact that NSP may be considered as a potential therapy for ICH for the neuroprotective effects including amelioration of the edema.
| S-EPMC5688810 | biostudies-literature