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Background: The coexistence of autoimmune encephalitis (AE) with multiple neural auto-antibodies is of great clinical significance because overlying antibodies may cause superposition or variation of clinical syndrome, which increases the difficulty of diagnosis and treatment of the disease. To the best of our knowledge, the coexistence of anti-N-methyl d-aspartate Receptor (NMDAR) and anti-IgLON5 antibodies in AE has not been published previously. Case presentation: A 38-year-old female patient presented to our hospital due to headache and abnormal psychiatric behavior. Based on her clinical manifestations (psychiatric and behavioral abnormalities, involuntary limb movements, and sleep disorders) and laboratory assessment results (positive human leukocyte antigen (HLA)-DQB1*05:01 haplotype, anti-NMDAR, and anti-IgLON5 antibodies), she was diagnosed as AE with coexisting anti-NMDAR and anti-IgLON5 antibodies. After treatment with intravenous methylprednisolone and immunoglobulin, as well as plasmapheresis, her symptoms gradually improved with exception for the sleep disorders. Although oral prednisone acetate and mycophenolate mofetil were continued after discharge, her symptoms of sleep disorders did not improve at 6-month follow-up. Conclusion: This is the first case of AE co-existing with anti-NMDAR and anti-IgLON5 antibodies. Co-existence of neural auto-antibodies should be considered when patients present with overlapping or atypical symptoms. Special attention should be paid to the treatment of these patients as some anti-IgLON5 encephalitis patients may not benefit from immunotherapy treatment.
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Spontaneous subarachnoid hemorrhage (SAH) is one of the most devastating forms of stroke, with limited treatment modalities and poor patient outcomes. Previous studies have proposed multiple prognostic factors; however, relative research on treatment has not yet yielded favorable clinical outcomes. Moreover, recent studies have suggested that early brain injury (EBI) occurring within 72 h after SAH may contribute to its poor clinical outcomes. Oxidative stress is recognized as one of the main mechanisms of EBI, which causes damage to various subcellular organelles, including the mitochondria, nucleus, endoplasmic reticulum (ER), and lysosomes. This could lead to significant impairment of numerous cellular functions, such as energy supply, protein synthesis, and autophagy, which may directly contribute to the development of EBI and poor long-term prognostic outcomes. In this review, the mechanisms underlying the connection between oxidative stress and subcellular organelles after SAH are discussed, and promising therapeutic options based on these mechanisms are summarized.
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Lesões Encefálicas , Hemorragia Subaracnóidea , Ratos , Animais , Humanos , Hemorragia Subaracnóidea/tratamento farmacológico , Ratos Sprague-Dawley , Estresse Oxidativo , Lesões Encefálicas/metabolismo , Organelas/metabolismo , ApoptoseRESUMO
Spontaneous subarachnoid hemorrhage (SAH), primarily caused by ruptured intracranial aneurysms, remains a prominent clinical challenge with a high rate of mortality and morbidity worldwide. Accumulating clinical trials aiming at the prevention of cerebral vasospasm (CVS) have failed to improve the clinical outcome of patients with SAH. Therefore, a growing number of studies have shifted focus to the pathophysiological changes that occur during the periods of early brain injury (EBI). New pharmacological agents aiming to alleviate EBI have become a promising direction to improve outcomes after SAH. Caspases belong to a family of cysteine proteases with diverse functions involved in maintaining metabolism, autophagy, tissue differentiation, regeneration, and neural development. Increasing evidence shows that caspases play a critical role in brain pathology after SAH. Therefore, caspase regulation could be a potential target for SAH treatment. Herein, we provide an overview pertaining to the current knowledge on the role of caspases in EBI after SAH, and we discuss the promising therapeutic value of caspase-related agents after SAH.
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Lesões Encefálicas , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Caspases/uso terapêuticoRESUMO
Current approved therapies for acute ischemic stroke have a restricted therapeutic time window. Delayed recanalization, which has been utilized clinically in patients who have missed the time window for administration, may be a promising alternative for stroke patients. However, the underlying molecular mechanisms remain undiscovered. Herein, we hypothesized that delayed recanalization would increase M2 microglial polarization through the IL-4R (interleukin-4 receptor)/STAT6 (signal transducer and activators of transcription 6)/PPARγ (peroxisome proliferator-activated receptor γ) pathway, subsequently promoting stroke recovery in rats. The permanent middle cerebral artery occlusion (pMCAO) model was induced via intravascular filament insertion. Recanalization was induced by withdrawing the filament at 3 days after MCAO (rMCAO). Interleukin (IL)-4 was administered intranasally at 3 days after pMCAO. AS1517499, a specific STAT6 inhibitor, was administered intranasally at 3 days after MCAO induction. Immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), western blot analysis, volumetric measurements of brain infarct, and neurological behavior tests were conducted. Delayed recanalization at 3 days after MCAO increased the polarization of M2 microglia, decreased inflammation, and improved neurological behavior. IL-4 treatment administered on the 3rd day after pMCAO increased M2 microglial polarization, improved neurological behavior, and reduced infarction volume of pMCAO rats. The inhibition of STAT6 decreased the level of p-STAT6 and PPARγ in rats treated with delayed recanalization. Delayed recanalization improved neurological function by increasing microglial M2 polarization, possibly involved with the IL-4R/STAT6/PPARγ pathway after MCAO in rats.
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Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Animais , Infarto da Artéria Cerebral Média/metabolismo , Microglia/metabolismo , PPAR gama , AVC Isquêmico/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológicoRESUMO
Stroke is a devastating disease associated with high mortality and disability worldwide, and is generally classified as ischemic or hemorrhagic, which share certain similar pathophysiological processes. Oxidative stress is a critical factor involved in stroke-induced injury, which not only directly damages brain tissue, but also enhances a series of pathological signaling cascades, contributing to inflammation, brain edema, and neuronal death. To alleviate these serious secondary brain injuries, neuroprotective agents targeting oxidative stress inhibition may serve as a promising treatment strategy. Melatonin is a hormone secreted by the pineal gland, and has various properties, such as antioxidation, anti-inflammation, circadian rhythm modulation, and promotion of tissue regeneration. Numerous animal experiments studying stroke have confirmed that melatonin exerts considerable neuroprotective effects, partially via anti-oxidative stress. In this review, we introduce the possible role of melatonin as an antioxidant in the treatment of stroke based on the latest published studies of animal experiments and clinical research.
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N6-methylation of adenosine (m6A) is one of the most frequent chemical modifications in eukaryotic RNAs and plays a vital role in tumorigenesis and progression. Recently, emerging studies have shown that m6A modification by ALKBH5 was associated with immunotherapy response in various types of cancer. However, whether m6A demethylases ALKBH5 participate in regulating the tumor immune microenvironment and the efficacy of immunotherapy in glioblastoma remain unknown. Here, we found that deletion of ALKBH5 significantly inhibited the growth of glioma allografts, rescued the antitumoral immune response, and increased cytotoxic lymphocyte infiltration and proinflammatory cytokines in CSF while significantly suppressing PD-L1 protein expression. m6A-methylated RNA immunoprecipitation sequencing and RNA sequencing identify ZDDHC3 as the direct target of ALKBH5. Mechanically, ALKBH5 deficiency impairs the YTHDF2-mediated stability of ZDHHC3 mRNA, thereby suppressing PD-L1 expression by accelerating PD-L1 degradation in glioma. In addition, genetic deletion or pharmacological inhibition of ALKBH5 with IOX1 enhances the therapeutic efficacy of anti-PD-1 treatment in preclinical mice models. These data suggest that the combination of anti-PD-1 therapy and ALKBH5 inhibition may be a promising treatment strategy in glioma.
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Oxidative stress and neuronal apoptosis contribute to pathological processes of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies demonstrated that the inhibition of prostaglandin E2 receptor EP3 suppressed oxidative stress and apoptotic effects after Alzheimer's disease and intracerebral hemorrhage. This study is aimed at investigating the antioxidative stress and antiapoptotic effect of EP3 inhibition and the underlying mechanisms in a rat mode of SAH. A total of 263 Sprague-Dawley male rats were used. SAH was induced by endovascular perforation. Selective EP3 antagonist L798106 was administered intranasally at 1 h, 25 h, and 49 h after SAH induction. EP3 knockout CRISPR and FOXO3 activation CRISPR were administered intracerebroventricularly at 48 h prior to SAH, while selective EP3 agonist sulprostone was administered at 1 h prior to SAH. SAH grade, neurological deficits, western blots, immunofluorescence staining, Fluoro-Jade C staining, TUNEL staining, 8-OHdG staining, and Nissl staining were conducted after SAH. The expression of endogenous PGES2 increased and peaked at 12 h while the expression of EP1, EP2, EP3, EP4, and Mul1 increased and peaked at 24 h in the ipsilateral brain after SAH. EP3 was expressed mainly in neurons. The inhibition of EP3 with L798106 or EP3 KO CRISPR ameliorated the neurological impairments, brain tissue oxidative stress, and neuronal apoptosis after SAH. To examine potential downstream mediators of EP3, we examined the effect of the increased expression of activated FOXO3 following the administration of FOXO3 activation CRISPR. Mechanism studies demonstrated that L798106 treatment significantly decreased the expression of EP3, p-p38, p-FOXO3, Mul1, 4-HNE, Bax, and cleaved caspase-3 but upregulated the expression of Mfn2 and Bcl-2 in SAH rats. EP3 agonist sulprostone or FOXO3 activation CRISPR abolished the neuroprotective effects of L798106 and its regulation on expression of p38MAPK/FOXO3/Mul1/Mfn2 in the ipsilateral brain after SAH. In conclusion, the inhibition of EP3 by L798106 attenuated oxidative stress and neuronal apoptosis partly through p38MAPK/FOXO3/Mul1/Mfn2 pathway post-SAH in rats. EP3 may serve as a potential therapeutic target for SAH patients.
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Fármacos Neuroprotetores , Hemorragia Subaracnóidea , Animais , Ratos , Masculino , Hemorragia Subaracnóidea/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Ratos Sprague-Dawley , Dinoprostona/metabolismo , Transdução de Sinais , Apoptose , Estresse Oxidativo , Fármacos Neuroprotetores/farmacologia , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Proteínas Mitocondriais/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Subarachnoid hemorrhage (SAH) is an important public health concern with high morbidity and mortality worldwide. SAH induces cell death, blood-brain barrier (BBB) damage, brain edema and oxidative stress. As the most abundant cell type in the central nervous system, astrocytes play an essential role in brain damage and recovery following SAH. This review describes astrocyte activation and polarization after SAH. Astrocytes mediate BBB disruption, glymphatic-lymphatic system dysfunction, oxidative stress, and cell death after SAH. Furthermore, astrocytes engage in abundant crosstalk with other brain cells, such as endothelial cells, neurons, pericytes, microglia and monocytes, after SAH. In addition, astrocytes also exert protective functions in SAH. Finally, we summarize evidence regarding therapeutic approaches aimed at modulating astrocyte function following SAH, which could provide some new leads for future translational therapy to alleviate damage after SAH.
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Hemorragia Subaracnóidea , Animais , Astrócitos/metabolismo , Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Humanos , Ratos , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/terapiaRESUMO
BACKGROUND: Pyroptosis is a programmed cell death mediated by inflammasomes. Previous studies have reported that inhibition of neurokinin receptor 1 (NK1R) exerted neuroprotection in several neurological diseases. Herein, we have investigated the role of NK1R receptor inhibition using Aprepitant to attenuate NLRC4-dependent neuronal pyroptosis after intracerebral hemorrhage (ICH), as well as the underlying mechanism. METHODS: A total of 182 CD-1 mice were used. ICH was induced by injection of autologous blood into the right basal ganglia. Aprepitant, a selective antagonist of NK1R, was injected intraperitoneally at 1 h after ICH. To explore the underlying mechanism, NK1R agonist, GR73632, and protein kinase C delta (PKCδ) agonist, phorbol 12-myristate 13-acetate (PMA), were injected intracerebroventricularly at 1 h after ICH induction, and small interfering ribonucleic acid (siRNA) for NLRC4 was administered via intracerebroventricular injection at 48 h before ICH induction, respectively. Neurobehavioral tests, western blot, and immunofluorescence staining were performed. RESULTS: The expression of endogenous NK1R and NLRC 4 were gradually increased after ICH. NK1R was expressed on neurons. Aprepitant significantly improved the short- and long-term neurobehavioral deficits after ICH, which was accompanied with decreased neuronal pyroptosis, as well as decreased expression of NLRC4, Cleaved-caspase-1, GSDMD (gasdermin D), IL-1ß, and IL-18. Activation of NK1R or PKCδ abolished these neuroprotective effects of Aprepitant after ICH. Similarly, knocking down NLRC4 using siRNA produced similar neuroprotective effects. CONCLUSION: Aprepitant suppressed NLRC4-dependent neuronal pyroptosis and improved neurological function, possibly mediated by inhibition of NK1R/PKCδ signaling pathways after ICH. The NK1R may be a promising therapeutic target for the treatment of ICH.
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Fármacos Neuroprotetores , Piroptose , Animais , Aprepitanto/uso terapêutico , Hemorragia Cerebral/metabolismo , Modelos Animais de Doenças , Camundongos , Neurônios/metabolismo , Fármacos Neuroprotetores/uso terapêutico , RNA Interferente Pequeno/uso terapêuticoRESUMO
INTRODUCTION: The melanoma-associated antigen D2 (MAGED2) is one of the melanoma-associated antigen family members. It is commonly overexpressed in a variety of malignancies. However, the mechanism and function of MAGED2 in glioma remain unknown. METHODS: The MAGED2 expression level and the correlations between clinical characteristics were analyzed with the data from the CGGA and TCGA datasets. MAGED2 expression in 98 glioma tissues was measured using RT-qPCR, Western blot, and immunohistochemistry. CCK-8, colony formation, and EdU assays were used to assess the effect of MAGED2 on U251-MG cell proliferation. Flow cytometry was used to track changes in the cell cycle and cell apoptosis following plasmid transfection with CRISPRi. RESULTS: MAGED2 was shown to be highly expressed in glioma tissues, and high MAGED2 expression predicted poor prognosis. Furthermore, MAGED2 knockdown significantly inhibited the proliferation of U251-MG cells by preventing cell cycle arrest at the G0/G1 phase and triggering apoptosis. In line with in vitro findings, the results of the xenograft experiment and immunohistochemistry also showed that MAGED2 suppression inhibited tumor development and decreased Ki-67 expression levels. CONCLUSIONS: MAGED2 may be a possible biomarker for glioma and an important prognostic factor for glioma patients.
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BACKGROUND AND PURPOSE: C-C motif chemokine ligand 17 (CCL17) presents an important role in immune regulation, which is critical in the pathophysiology of brain injury after subarachnoid haemorrhage (SAH). There is rare evidence to illustrate the function of CCL17 towards SAH. In this study, we try to reveal the therapeutic effects of CCL17 and its underlying mechanism in rat SAH model. METHODS: SAH rat models were assigned to receive recombinant CCL17 (rCCL17) or phosphate buffer saline (PBS). AZD2098 and JR-AB2-011 were applied to investigate the C-C motif chemokine receptor 4 (CCR4)/mammalian target of rapamycin complex 2 (mTORC2) axis in CCL17-mediated neuroprotection. To elucidate the underlying mechanism, the in vitro kinase assay was performed in primary microglia. Microglial-specific Rictor knockdown was administered via intracerebroventricular injection of adenovirus-associated virus. Brain water content, short-term neurobehavioural evaluation, western blot analysis, quantitative RT-PCR and histological staining were performed. RESULTS: The expression of CCL17 was increased and secreted from neurons after oxyhaemoglobin stimulation. Exogenous rCCL17 significantly alleviated neuronal apoptosis, and alleviated short-term neurofunction after SAH in rats. In addition, rCCL17 increased M2-like polarisation of microglia in rats post-SAH and in primary microglia culture. The neuroprotection of rCCL17 was abolished via inhibition of either CCR4 or mTORC2. CONCLUSION: CCL17 activated the CCR4/mTORC2 axis in microglia, which can alleviate SAH-induced neurological deficits by promoting M2-like polarisation of microglia.
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Puerarin was shown to exert anti-oxidative and anti-ferroptosis effects in multiple diseases. The goal of this study was to explore the neuroprotective effect of puerarin on early brain injury (EBI) after subarachnoid hemorrhage (SAH) in rats. A total of 177 adult male Sprague Dawley rats were used. SAH was included via endovascular perforation. Intranasal puerarin or intracerebroventricular dorsomorphin (AMPK inhibitor) and SR18292 (PGC1α inhibitor) were administered. The protein levels of pAMPK, PGC1α, Nrf2, 4HNE, HO1, MDA, ACSL4, GSSG, and iron concentration in the ipsilateral hemisphere were significantly increased, whereas SOD, GPX4, and GSH were decreased at 24 h after SAH. Moreover, puerarin treatment significantly increased the protein levels of pAMPK, PGC1α, Nrf2, HO1, SOD, GPX4, and GSH, but decreased the levels of 4HNE, MDA, ACSL4, GSSG, and iron concentration in the ipsilateral hemisphere at 24 h after SAH. Dorsomorphin or SR18292 partially abolished the beneficial effects of puerarin exerted on neurological dysfunction, oxidative stress injury, and ferroptosis. In conclusion, puerarin improved neurobehavioral impairments and attenuated oxidative-stress-induced brain ferroptosis after SAH in rats. The neuroprotection acted through the activation of the AMPK/PGC1α/Nrf2-signaling pathway. Thus, puerarin may serve as new therapeutics against EBI in SAH patients.
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Subarachnoid hemorrhage (SAH) is a worldwide devastating type of stroke with high mortality and morbidity. Accumulating evidence show early brain injury (EBI) as the leading cause of mortality after SAH. The pathological processes involved in EBI include decreased cerebral blood flow, increased intracranial pressure, vasospasm, and disruption of the blood-brain barrier. In addition, neuroinflammation, oxidative stress, apoptosis, and autophagy have also been proposed to contribute to EBI. Among the various processes involved in EBI, neuronal apoptosis has been proven to be a key factor contributing to the poor prognosis of SAH patients. Meanwhile, as another important catabolic process maintaining the cellular and tissue homeostasis, autophagy has been shown to be neuroprotective after SAH. Studies have shown that enhancing autophagy reduced apoptosis, whereas inhibiting autophagy aggravate neuronal apoptosis after SAH. The physiological substrates and mechanisms of neuronal autophagy and apoptosis by which defects in neuronal function are largely unknown. In this review, we summarize and discuss the role of autophagy and apoptosis after SAH and contribute to further study for investigation of the means to control the balance between them.
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Lesões Encefálicas , Hemorragia Subaracnóidea , Animais , Ratos , Humanos , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/patologia , Encéfalo/metabolismo , Ratos Sprague-Dawley , Autofagia , Apoptose/fisiologiaRESUMO
Adiponectin (APN), a fat-derived plasma hormone, is a classic anti-inflammatory agent. Multiple studies have demonstrated the beneficial role of APN in acute brain injury, but the effect of APN in germinal matrix hemorrhage (GMH) is unclear, and the underlying molecular mechanisms remain largely undefined. In the current study, we used a GMH rat model with rh-APN treatment, and we observed that APN demonstrated a protective effect on neurological function and an inhibitory effect on neuroinflammation after GMH. To further explore the underlying mechanisms of these effects, we found that the expression of Adiponectin receptor 1 (AdipoR1) primarily colocalized with microglia and neurons in the brain. Moreover, AdiopR1, but not AdipoR2, was largely increased in GMH rats. Meanwhile, further investigation showed that APN treatment promoted AdipoR1/APPL1-mediated AMPK phosphorylation, further increased peroxisome proliferator-activated receptor gamma (PPARγ) expression, and induced microglial M2 polarization to reduce the neuroinflammation and enhance hematoma resolution in GMH rats. Importantly, either knockdown of AdipoR1, APPL1, or LKB1, or specific inhibition of AMPK/PPARγ signaling in microglia abrogated the protective effect of APN after GMH in rats. In all, we propose that APN works as a potential therapeutic agent to ameliorate the inflammatory response following GMH by enhancing the M2 polarization of microglia via AdipoR1/APPL1/AMPK/PPARγ signaling pathway, ultimately attenuating inflammatory brain injury induced by hemorrhage.
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Lesões Encefálicas , Microglia , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adiponectina/metabolismo , Adiponectina/farmacologia , Animais , Animais Recém-Nascidos , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Proteínas de Transporte/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Microglia/metabolismo , Proteínas do Tecido Nervoso/metabolismo , PPAR gama/metabolismo , Ratos , Transdução de SinaisRESUMO
The ketogenic diet (KD) is a low-carbohydrate, high-fat diet regarded as a potential intervention for cancers owing to its effects on tumor metabolism and behavior. Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer, and its management is worth investigating because of the high fatality rate. Additionally, as the liver is the glucose and lipid metabolism center where ketone bodies are produced, the application of KD to combat HCC is promising. Prior studies have reported that KD could reduce the energy supply and affect the proliferation and differentiation of cancer cells by lowering the blood glucose and insulin levels. Furthermore, KD can increase the expression of hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in hepatocytes and regulate lipid metabolism to inhibit the progression of HCC. In addition, ß-hydroxybutyrate can induce histone hyperacetylation and reduce the expression of inflammatory factors to alleviate damage to hepatocytes. However, there are few relevant studies at present, and the specific effects and safety of KD on HCC warrant further research. Optimizing the composition of KD and combining it with other therapies to enhance its anti-cancer effects warrant further exploration.
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The discovery of long noncoding RNAs (lncRNAs) has improved the understanding of development and progression in various cancer subtypes. However, the role of lncRNAs in temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) remains largely undefined. In this present study, the differential expression of lncRNAs was identified between U87 and U87 TMZ-resistant (TR) cells. lncRNA XLOC013218 (XLOC) was drastically upregulated in TR cells and was associated with poor prognosis in glioma. Overexpression of XLOC markedly increased TMZ resistance, promoted proliferation, and inhibited apoptosis in vitro and in vivo. In addition, RNA-seq analysis and gain-of-function or loss-of-function studies revealed that PIK3R2 was the potential target of XLOC. Mechanistically, XLOC recruited specificity protein 1 (Sp1) transcription factor and promoted the binding of Sp1 to the promoters of PIK3R2, which elevated the expression of PIK3R2 in both mRNA and protein levels. Finally, PIK3R2-mediated activation of the PI3K/AKT signaling pathway promoted TMZ resistance and cell proliferation, but inhibited cell apoptosis. In conclusion, these data highlight the vital role of the XLOC/Sp1/PIK3R2/PI3K/AKT axis in GBM TMZ resistance.
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Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Glioma , Fosfatidilinositol 3-Quinases , RNA Longo não Codificante , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioma/tratamento farmacológico , Glioma/genética , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Temozolomida/farmacologia , Fatores de Transcrição/genéticaRESUMO
Aims: Oxidative stress and neuronal apoptosis play crucial roles in the pathological processes of secondary injury after intracerebral hemorrhage (ICH). Aryl hydrocarbon receptor (AHR), together with its endogenous ligand kynurenine, is known to mediate free radical accumulation and neuronal excitotoxicity in central nervous systems. Herein, we investigate the pathological roles of kynurenine/AHR after ICH. Results: Endogenous AHR knockout alleviated reactive oxygen species accumulation and neuronal apoptosis in ipsilateral hemisphere at 48 h after ICH in mice. The ICH insult resulted in an increase of total and nucleus AHR protein levels and AHR transcriptional activity. Inhibition of AHR provided both short- and long- term neurological benefits by attenuating mitochondria-mediated oxidative stress and neuronal apoptosis after ICH in mice. RhoA-Bax signaling activated mitochondrial death pathway and participated in deleterious actions of AHR. Finally, we reported that exogenous kynurenine aggravated AHR activation and mediated the brain mentioned earlier. Male animals were used in the experiments. Innovation: We show for the first time that kynurenine/AHR mediates mitochondria death and free radical accumulation, at least partially via the RhoA/Bax signaling pathway. Pharmacological antagonists of AHR and kynurenine may ameliorate neurobehavioral function and improve the prognosis of patients with ICH. Conclusion: Kynurenine/AHR may serve as a potential therapeutic target to attenuate mitochondria-mediated oxidative stress and neuronal cells impairment in patients with ICH. Antioxid. Redox Signal. 37, 1111-1129.
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Cinurenina , Receptores de Hidrocarboneto Arílico , Masculino , Animais , Camundongos , Receptores de Hidrocarboneto Arílico/genética , Estresse Oxidativo , Apoptose , Hemorragia Cerebral , Radicais LivresRESUMO
Background: Oxidative stress and neuronal apoptosis have important roles in the pathogenesis after intracerebral hemorrhage (ICH). Previous studies have reported that low-density lipoprotein receptor-related protein 6 (LRP6) exerts neuroprotection in several neurological diseases. Herein, we investigate the role of LRP6 receptor activation with HLY78 to attenuate oxidative stress and neuronal apoptosis after ICH, as well as the underlying mechanism. Methods: A total of 199 CD1 mice were used. ICH was induced via injection of autologous blood into the right basal ganglia. HLY78 was administered via intranasal injection at 1 h after ICH. To explore the underlying mechanism, LRP6 siRNA and selisistat, a Sirt1 selective antagonist, were injected intracerebroventricularly at 48 h before ICH induction. Neurobehavioral tests, Western blot, and immunofluorescence staining were performed. Results: The expression of endogenous p-LRP6 was gradually increased and expressed on neurons after ICH. HLY78 significantly improved the short- and long-term neurobehavioral deficits after ICH, which was accompanied with decreased oxidative stress and neuronal apoptosis, as well as increased expression of p-GSK3ß, Sirt1, and PGC-1α, as well as downregulation of Romo-1 and C-Caspase-3. LRP6 knockdown or Sirt1 inhibition abolished these effects of HLY78 after ICH. Conclusion: Our results suggest that administration of HLY78 attenuated oxidative stress, neuronal apoptosis, and neurobehavioral impairments through the LRP6/GSK3ß/Sirt1/PGC-1α signaling pathway after ICH.
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Hemorragia Cerebral , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Estresse Oxidativo , Sirtuína 1 , Animais , Apoptose , Benzodioxóis , Hemorragia Cerebral/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fenantridinas , Sirtuína 1/metabolismoRESUMO
Stroke is the second leading cause of global death and is characterized by high rates of mortality and disability. Oxidative stress is accompanied by other pathological processes that together lead to secondary brain damage in stroke. As the major component of the brain, glial cells play an important role in normal brain development and pathological injury processes. Multiple connections exist in the pathophysiological changes of reactive oxygen species (ROS) metabolism and glia cell activation. Astrocytes and microglia are rapidly activated after stroke, generating large amounts of ROS via mitochondrial and NADPH oxidase pathways, causing oxidative damage to the glial cells themselves and neurons. Meanwhile, ROS cause alterations in glial cell morphology and function, and mediate their role in pathological processes, such as neuroinflammation, excitotoxicity, and blood-brain barrier damage. In contrast, glial cells protect the Central Nervous System (CNS) from oxidative damage by synthesizing antioxidants and regulating the Nuclear factor E2-related factor 2 (Nrf2) pathway, among others. Although numerous previous studies have focused on the immune function of glial cells, little attention has been paid to the role of glial cells in oxidative stress. In this paper, we discuss the adverse consequences of ROS production and oxidative-antioxidant imbalance after stroke. In addition, we further describe the biological role of glial cells in oxidative stress after stroke, and we describe potential therapeutic tools based on glia cells.