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Ning W, Lv S, Wang Q, Xu Y. The pivotal role of microglia in injury and the prognosis of subarachnoid hemorrhage. Neural Regen Res 2025; 20:1829-1848. [PMID: 38993136 PMCID: PMC11691474 DOI: 10.4103/nrr.nrr-d-24-00241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/18/2024] [Accepted: 05/25/2024] [Indexed: 07/13/2024] Open
Abstract
Subarachnoid hemorrhage leads to a series of pathological changes, including vascular spasm, cellular apoptosis, blood-brain barrier damage, cerebral edema, and white matter injury. Microglia, which are the key immune cells in the central nervous system, maintain homeostasis in the neural environment, support neurons, mediate apoptosis, participate in immune regulation, and have neuroprotective effects. Increasing evidence has shown that microglia play a pivotal role in the pathogenesis of subarachnoid hemorrhage and affect the process of injury and the prognosis of subarachnoid hemorrhage. Moreover, microglia play certain neuroprotective roles in the recovery phase of subarachnoid hemorrhage. Several approaches aimed at modulating microglia function are believed to attenuate subarachnoid hemorrhage injury. This provides new targets and ideas for the treatment of subarachnoid hemorrhage. However, an in-depth and comprehensive summary of the role of microglia after subarachnoid hemorrhage is still lacking. This review describes the activation of microglia after subarachnoid hemorrhage and their roles in the pathological processes of vasospasm, neuroinflammation, neuronal apoptosis, blood-brain barrier disruption, cerebral edema, and cerebral white matter lesions. It also discusses the neuroprotective roles of microglia during recovery from subarachnoid hemorrhage and therapeutic advances aimed at modulating microglial function after subarachnoid hemorrhage. Currently, microglia in subarachnoid hemorrhage are targeted with TLR inhibitors, nuclear factor-κB and STAT3 pathway inhibitors, glycine/tyrosine kinases, NLRP3 signaling pathway inhibitors, Gasdermin D inhibitors, vincristine receptor α receptor agonists, ferroptosis inhibitors, genetic modification techniques, stem cell therapies, and traditional Chinese medicine. However, most of these are still being evaluated at the laboratory stage. More clinical studies and data on subarachnoid hemorrhage are required to improve the treatment of subarachnoid hemorrhage.
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Affiliation(s)
- Wenjing Ning
- Department of Rehabilitation, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
| | - Shi Lv
- Department of Rehabilitation, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
| | - Qian Wang
- Department of Central Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian, Shandong Province, China
| | - Yuzhen Xu
- Department of Rehabilitation, The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong Province, China
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Pfnür A, Mayer B, Dörfer L, Tumani H, Spitzer D, Huber-Lang M, Kapapa T. Regulatory T Cell- and Natural Killer Cell-Mediated Inflammation, Cerebral Vasospasm, and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage-A Systematic Review and Meta-Analysis Approach. Int J Mol Sci 2025; 26:1276. [PMID: 39941044 PMCID: PMC11818301 DOI: 10.3390/ijms26031276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/22/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) involves a significant influx of blood into the cerebrospinal fluid, representing a severe form of stroke. Despite advancements in aneurysm closure and neuro-intensive care, outcomes remain impaired due to cerebral vasospasm and delayed cerebral ischemia (DCI). Previous pharmacological therapies have not successfully reduced DCI while improving overall outcomes. As a result, significant efforts are underway to better understand the cellular and molecular mechanisms involved. This review focuses on the activation and effects of immune cells after SAH and their interactions with neurotoxic and vasoactive substances as well as inflammatory mediators. Particular attention is given to clinical studies highlighting the roles of natural killer (NK) cells and regulatory T cells (Treg) cells. Alongside microglia, astrocytes, and oligodendrocytes, NK cells and Treg cells are key contributors to the inflammatory cascade following SAH. Their involvement in modulating the neuro-inflammatory response, vasospasm, and DCI underscores their potential as therapeutic targets and prognostic markers in the post-SAH recovery process. We conducted a systematic review on T cell- and natural killer cell-mediated inflammation and their roles in cerebral vasospasm and delayed cerebral ischemia. We conducted a meta-analysis to evaluate outcomes and mortality in studies focused on NK cell- and T cell-mediated mechanisms.
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Affiliation(s)
- Andreas Pfnür
- Department of Neurosurgery, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany
| | - Benjamin Mayer
- Institute of Epidemiology and Medical Biometry, University of Ulm, Helmholtzstr. 22, 89081 Ulm, Germany
| | - Lena Dörfer
- Institute for Clinical and Experimental Trauma Immunology, University Hospital Ulm, Helmholtzstr. 8/, 89081 Ulm, Germany
| | - Hayrettin Tumani
- Department of Neurology, University Hospital Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany
| | - Daniel Spitzer
- Department of Neurology, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma Immunology, University Hospital Ulm, Helmholtzstr. 8/, 89081 Ulm, Germany
| | - Thomas Kapapa
- Department of Neurosurgery, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany
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Qiu Y, Cheng L, Xiong Y, Liu Z, Shen C, Wang L, Lu Y, Wei S, Zhang L, Yang SB, Zhang X. Advances in the Study of Necroptosis in Vascular Dementia: Focus on Blood-Brain Barrier and Neuroinflammation. CNS Neurosci Ther 2025; 31:e70224. [PMID: 39915907 PMCID: PMC11802338 DOI: 10.1111/cns.70224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/18/2024] [Accepted: 01/09/2025] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Vascular dementia (VaD) includes a group of brain disorders that are characterized by cerebrovascular pathology.Neuroinflammation, disruption of the blood-brain barrier (BBB) permeability, white matter lesions, and neuronal loss are all significant pathological manifestations of VaD and play a key role in disease progression. Necroptosis, also known asprogrammed necrosis, is a mode of programmed cell death distinct from apoptosis and is closely associated with ischemic injury and neurodegenerative diseases. Recent studies have shown that necroptosis in VaD exacerbates BBB destruction, activates neuroinflammation, promotes neuronal loss, and severely affects VaD prognosis. RESULTS AND CONCLUSIONS In this review, we outline the significant roles of necroptosis and its molecular mechanisms in the pathological process of VaD, with a particular focus on the role of necroptosis in modulating neuroinflammation and exacerbating the disruption of BBB permeability in VaD, and elaborate on the molecular regulatory mechanisms and the centrally involved cells of necroptosis mediated by tumor necrosis factor-α in neuroinflammation in VaD. We also analyze the possibility and specific strategy that targeting necroptosis would help inhibit neuroinflammation and BBB destruction in VaD. With a focus on necroptosis, this study delved into its impact on the pathological changes and prognosis of VaD to provide new treatment ideas.
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Affiliation(s)
- Yuemin Qiu
- Department of PathologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Lin Cheng
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
- Department of NeurologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
| | - Yinyi Xiong
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
- Department of RehabilitationAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
| | - Ziying Liu
- Department of PathologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Chunxiao Shen
- Department of PathologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Liangliang Wang
- Department of PathologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Yujia Lu
- Department of PathologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Shufei Wei
- Department of PathologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Lushun Zhang
- Department of PathologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
| | - Seung Bum Yang
- Department of Medical Non‐Commissioned OfficerWonkwang Health Science UniversityIksanRepublic of Korea
| | - Xiaorong Zhang
- Department of PathologyAffiliated Hospital of Jiujiang UniversityJiujiangJiangxiChina
- Department of PathologyJiujiang Clinical Precision Medicine Research CenterJiujiangJiangxiChina
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4
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Yan X, Yan Y, Liu J, Jing Y, Hao P, Chen X, Li X. Necrostatin-1 protects corneal epithelial cells by inhibiting the RIPK1/RIPK3/MLKL cascade in a benzalkonium chloride-induced model of necroptosis. Exp Eye Res 2024; 247:110030. [PMID: 39127236 DOI: 10.1016/j.exer.2024.110030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/13/2024] [Accepted: 08/07/2024] [Indexed: 08/12/2024]
Abstract
PURPOSE Benzalkonium chloride (BAC) is commonly used as a preservative in ophthalmic medications, despite its potential to induce chemical injury. Extensive research has demonstrated that BAC can lead to adverse effects, including injuries to the ocular surface. Our study aimed to elucidate the underlying mechanism of necroptosis induced by BAC. METHODS Human corneal epithelial (HCE) cells and mouse corneas were subjected to chemical injury, and the necrostatin-1 (Nec1) group was compared to the dimethylsulfoxide (DMSO) group. The extent of damage to HCE cells was assessed using CCK-8 and flow cytometry. Hematoxylin and eosin staining, as well as fluorescein sodium staining, were used to detect and characterize corneal injury. The activation of inflammatory cytokines and necroptosis-related proteins and genes was evaluated using Western blotting, immunofluorescence staining, and quantitative RT‒PCR. RESULTS In our study, the induction of necroptosis by a hypertonic solution was not observed. However, necroptosis was observed in HCE cells exposed to NaOH and BAC, which activated the receptor-interacting protein kinase 1 (RIPK1) - receptor-interacting protein kinase 3 (RIPK3) - mixed lineage kinase domain-like protein (MLKL) signaling pathway. In mouse corneal tissues, BAC could induce necroptosis and inflammation. The administration of Nec1 mitigated the inflammatory response and ocular surface damage caused by BAC-induced necroptosis in our experimental models. Furthermore, our in vivo experiments revealed that the severity of necroptosis was greater in the 3-day group than in the 7-day group. CONCLUSIONS Necroptosis plays a role in the pathological development of ocular surface injury caused by exposure to BAC. Furthermore, our study demonstrated that the administration of Nec1 could mitigate the pathological effects of necroptosis induced by BAC in clinical settings.
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MESH Headings
- Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
- Necroptosis/drug effects
- Animals
- Mice
- Epithelium, Corneal/drug effects
- Epithelium, Corneal/pathology
- Epithelium, Corneal/metabolism
- Indoles/pharmacology
- Benzalkonium Compounds/toxicity
- Benzalkonium Compounds/pharmacology
- Imidazoles/pharmacology
- Protein Kinases/metabolism
- Humans
- Disease Models, Animal
- Mice, Inbred C57BL
- Blotting, Western
- Cells, Cultured
- Flow Cytometry
- Signal Transduction/drug effects
- Eye Burns/chemically induced
- Eye Burns/pathology
- Male
- Burns, Chemical/pathology
- Burns, Chemical/metabolism
- Burns, Chemical/drug therapy
- Preservatives, Pharmaceutical/toxicity
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Affiliation(s)
- Xinlin Yan
- School of Medicine, Nankai University, Tianjin, 300071, China; Nankai University Affiliated Eye Hospital, Tianjin, 300020, China; Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, 300020, China
| | - Yarong Yan
- Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, 300020, China; Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, 300020, China
| | - Jinghua Liu
- School of Medicine, Nankai University, Tianjin, 300071, China; Nankai University Affiliated Eye Hospital, Tianjin, 300020, China; Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, 300020, China
| | - Yapeng Jing
- School of Medicine, Nankai University, Tianjin, 300071, China; Nankai University Affiliated Eye Hospital, Tianjin, 300020, China; Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, 300020, China
| | - Peng Hao
- Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, 300020, China
| | - Xi Chen
- Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, 300020, China
| | - Xuan Li
- School of Medicine, Nankai University, Tianjin, 300071, China; Nankai University Affiliated Eye Hospital, Tianjin, 300020, China; Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin, 300020, China; Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, 300020, China.
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Wu Y, Xu Y, Sun J, Dai K, Wang Z, Zhang J. Inhibiting RIPK1-driven neuroinflammation and neuronal apoptosis mitigates brain injury following experimental subarachnoid hemorrhage. Exp Neurol 2024; 374:114705. [PMID: 38290652 DOI: 10.1016/j.expneurol.2024.114705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/14/2024] [Accepted: 01/26/2024] [Indexed: 02/01/2024]
Abstract
RIPK1, a receptor-interacting serine/threonine protein kinase, plays a crucial role in maintaining cellular and tissue homeostasis by integrating inflammatory responses and cell death signaling pathways including apoptosis and necroptosis, which have been implicated in diverse physiological and pathological processes. Suppression of RIPK1 activation is a promising strategy for restraining the pathological progression of many human diseases. Neuroinflammation and neuronal apoptosis are two pivotal factors in the pathogenesis of brain injury following subarachnoid hemorrhage (SAH). In this study, we established in vivo and in vitro models of SAH to investigate the activation of RIPK1 kinase in both microglia and neurons. We observed the correlation between RIPK1 kinase activity and microglia-mediated inflammation as well as neuronal apoptosis. We then investigated whether inhibition of RIPK1 could alleviate neuroinflammation and neuronal apoptosis following SAH, thereby reducing brain edema and ameliorating neurobehavioral deficits. Additionally, the underlying mechanisms were also explored. Our research findings revealed the activation of RIPK1 kinase in both microglia and neurons following SAH, as marked by the phosphorylation of RIPK1 at serine 166. The upregulation of p-RIPK1(S166) resulted in a significant augmentation of inflammatory cytokines and chemokines, including TNF-α, IL-6, IL-1α, CCL2, and CCL5, as well as neuronal apoptosis. The activation of RIPK1 in microglia and neurons following SAH could be effectively suppressed by administration of Nec-1 s, a specific inhibitor of RIPK1. Consequently, inhibition of RIPK1 resulted in a downregulation of inflammatory cytokines and chemokines and attenuation of neuronal apoptosis after SAH in vitro. Furthermore, the administration of Nec-1 s effectively mitigated neuroinflammation, neuronal apoptosis, brain edema, and neurobehavioral deficits in mice following SAH. Our findings suggest that inhibiting RIPK1 kinase represents a promising therapeutic strategy for mitigating brain injury after SAH by attenuating RIPK1-driven neuroinflammation and neuronal apoptosis.
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Affiliation(s)
- Yan Wu
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yao Xu
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jingshan Sun
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Kun Dai
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhong Wang
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Jian Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
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Galea I, Bandyopadhyay S, Bulters D, Humar R, Hugelshofer M, Schaer DJ. Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation. Stroke 2023; 54:1930-1942. [PMID: 37232189 PMCID: PMC10289236 DOI: 10.1161/strokeaha.123.040205] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/31/2023] [Accepted: 04/12/2023] [Indexed: 05/27/2023]
Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.
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Affiliation(s)
- Ian Galea
- Department of Clinical Neurosciences, Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Hampshire, United Kingdom (I.G., S.B., D.B.)
- Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom (I.G., S.B., D.B.)
| | - Soham Bandyopadhyay
- Department of Clinical Neurosciences, Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Hampshire, United Kingdom (I.G., S.B., D.B.)
- Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom (I.G., S.B., D.B.)
| | - Diederik Bulters
- Department of Clinical Neurosciences, Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Hampshire, United Kingdom (I.G., S.B., D.B.)
- Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom (I.G., S.B., D.B.)
| | - Rok Humar
- Division of Internal Medicine (R.H., D.J.S.), Universitätsspital and University of Zurich, Switzerland
| | - Michael Hugelshofer
- Department of Neurosurgery, Clinical Neuroscience Center (M.H.), Universitätsspital and University of Zurich, Switzerland
| | - Dominik J. Schaer
- Division of Internal Medicine (R.H., D.J.S.), Universitätsspital and University of Zurich, Switzerland
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Gupta R, Kumari S, Tripathi R, Ambasta RK, Kumar P. Unwinding the modalities of necrosome activation and necroptosis machinery in neurological diseases. Ageing Res Rev 2023; 86:101855. [PMID: 36681250 DOI: 10.1016/j.arr.2023.101855] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/09/2022] [Accepted: 01/15/2023] [Indexed: 01/20/2023]
Abstract
Necroptosis, a regulated form of cell death, is involved in the genesis and development of various life-threatening diseases, including cancer, neurological disorders, cardiac myopathy, and diabetes. Necroptosis initiates with the formation and activation of a necrosome complex, which consists of RIPK1, RIPK2, RIPK3, and MLKL. Emerging studies has demonstrated the regulation of the necroptosis cell death pathway through the implication of numerous post-translational modifications, namely ubiquitination, acetylation, methylation, SUMOylation, hydroxylation, and others. In addition, the negative regulation of the necroptosis pathway has been shown to interfere with brain homeostasis through the regulation of axonal degeneration, mitochondrial dynamics, lysosomal defects, and inflammatory response. Necroptosis is controlled by the activity and expression of signaling molecules, namely VEGF/VEGFR, PI3K/Akt/GSK-3β, c-Jun N-terminal kinases (JNK), ERK/MAPK, and Wnt/β-catenin. Herein, we briefly discussed the implication and potential of necrosome activation in the pathogenesis and progression of neurological manifestations, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, and others. Further, we present a detailed picture of natural compounds, micro-RNAs, and chemical compounds as therapeutic agents for treating neurological manifestations.
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Affiliation(s)
- Rohan Gupta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), India
| | - Smita Kumari
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), India
| | - Rahul Tripathi
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), India.
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8
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Abstract
Stroke is a sudden and rapidly progressing ischemic or hemorrhagic cerebrovascular disease. When stroke damages the brain, the immune system becomes hyperactive, leading to systemic inflammatory response and immunomodulatory disorders, which could significantly impact brain damage, recovery, and prognosis of stroke. Emerging researches suggest that ischemic stroke-induced spleen contraction could activate a peripheral immune response, which may further aggravate brain injury. This review focuses on hemorrhagic strokes including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) and discusses the central nervous system-peripheral immune interactions after hemorrhagic stroke induction. First, inflammatory progression after ICH and SAH is investigated. As a part of this review, we summarize the various kinds of inflammatory cell infiltration to aggravate brain injury after blood-brain barrier interruption induced by hemorrhagic stroke. Then, we explore hemorrhagic stroke-induced systemic inflammatory response syndrome (SIRS) and discuss the interactions of CNS and peripheral inflammatory response. In addition, potential targets related to inflammatory response for ICH and SAH are discussed in this review, which may lead to novel therapeutic strategies for hemorrhagic stroke.
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Affiliation(s)
- Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Stroke Research, Soochow University, Suzhou, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Stroke Research, Soochow University, Suzhou, China
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9
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Yuan G, Cao C, Cao D, Li B, Li X, Li H, Shen H, Wang Z, Chen G. Receptor-interacting protein 3-phosphorylated Ca 2+ /calmodulin-dependent protein kinase II and mixed lineage kinase domain-like protein mediate intracerebral hemorrhage-induced neuronal necroptosis. J Neurochem 2023; 164:94-114. [PMID: 36424866 DOI: 10.1111/jnc.15731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/15/2022] [Accepted: 11/13/2022] [Indexed: 11/26/2022]
Abstract
Necroptosis-mediated cell death is an important mechanism in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Our previous study has demonstrated that receptor-interacting protein 1 (RIP1) mediated necroptosis in SBI after ICH. However, further mechanisms, such as the roles of receptor-interacting protein 3 (RIP3), mixed lineage kinase domain-like protein (MLKL), and Ca2+ /calmodulin-dependent protein kinase II (CaMK II), remain unclear. We hypothesized that RIP3, MLKL, and CaMK II might participate in necroptosis after ICH, including their phosphorylation. The ICH model was induced by autologous blood injection. First, we found the activation of necroptosis after ICH in brain tissues surrounding the hematoma (propidium iodide staining). Meanwhile, the phosphorylation and expression of RIP3, MLKL, and CaMK II were differently up-regulated (western blotting and immunofluorescent staining). The specific inhibitors could suppress RIP3, MLKL, and CaMK II (GSK'872 for RIP3, necrosulfonamide for MLKL, and KN-93 for CaMK II). We found the necroptosis surrounding the hematoma and the concrete interactions in RIP3-MLKL/RIP3-CaMK II also both decreased after the specific intervention (co-immunoprecipitation). Then we conducted the short-/long-term neurobehavioral tests, and the rats with specific inhibition mostly had better performance. We also found less blood-brain barrier (BBB) injury, and less neuron loss (Nissl staining) in intervention groups, which supported the neurobehavioral tests. Besides, oxidative stress and inflammation were also alleviated with intervention, which had significant less reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, lactate dehydrogenase (LDH), Iba1, and GFAP surrounding the hematoma. These results confirmed that RIP3-phosphorylated MLKL and CaMK II participate in ICH-induced necroptosis and could provide potential targets for the treatment of ICH patients.
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Affiliation(s)
- Guiqiang Yuan
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Cheng Cao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Demao Cao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Bing Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
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Wang X, Xu P, Liu Y, Wang Z, Lenahan C, Fang Y, Lu J, Zheng J, Wang K, Wang W, Zhou J, Chen S, Zhang J. New Insights of Early Brain Injury after Subarachnoid Hemorrhage: A Focus on the Caspase Family. Curr Neuropharmacol 2023; 21:392-408. [PMID: 35450528 PMCID: PMC10190145 DOI: 10.2174/1570159x20666220420115925] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 02/10/2022] [Accepted: 04/14/2022] [Indexed: 11/22/2022] Open
Abstract
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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Affiliation(s)
- Xiaoyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Penglei Xu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yibo Liu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zefeng Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Cameron Lenahan
- Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA, USA
- Burrell College of Osteopathic Medicine, Las Cruces, New Mexico
| | - Yuanjian Fang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianan Lu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jingwei Zheng
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Kaikai Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jingyi Zhou
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Sheng Chen
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Neurosurgery, The Affiliated Huzhou Hospital, Zhejiang University School of Medicine (Huzhou Central Hospital), Huzhou, China
| | - Jianming Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China
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11
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Qiu X, Tao Q, Zhang L, Kuang C, Xie Y, Zhang L, Yin S, Peng J, Jiang Y. Deletion of Bak1 alleviates microglial necroptosis and neuroinflammation after experimental subarachnoid hemorrhage. J Neurochem 2022; 164:829-846. [PMID: 36583235 DOI: 10.1111/jnc.15751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/18/2022] [Accepted: 12/06/2022] [Indexed: 12/31/2022]
Abstract
Microglial necroptosis exacerbates neurodegenerative diseases, central nervous system (CNS) injury, and demonstrates a proinflammatory process, but its contribution to subarachnoid hemorrhage (SAH) is poorly characterized. BCL-2 homologous antagonist-killer protein (Bak1), a critical regulatory molecule of endogenous apoptosis, can be involved in the pathologic process of necroptosis by regulating mitochondrial permeability. In this study, we revealed microglia undergo necroptosis after SAH in vivo and vitro. Western blot revealed that Bak1 was elevated at 24 h after SAH. Knocked down of Bak1 by adeno-associated virus attenuates microglial necroptosis, alleviates neuroinflammation, and improves neurologic function after SAH in mice. Furthermore, oxyhemoglobin (10 μM) induced necroptosis in BV2 microglia, increasing Bak1 expression and mediating proinflammatory phenotype transformation, exacerbating oxidative stress and neuroinflammation. Abrogating BV2 Bak1 could reduce necroptosis by down-regulating the expression of phosphorylated pseudokinase mixed lineage kinase domain-like protein (p-MLKL), then down-regulating proinflammatory phenotype gene expression. RNA-Seq showed that disrupting BV2 Bak1 down-regulates multiple immune and inflammatory pathways and ameliorates cell injury by elevating thrombospondin 1 (THBS1) expression. In summary, we identified a critical regulatory role for Bak1 in microglial necroptosis and neuroinflammation after SAH. Bak1 is expected to be a potential target for the treatment strategy of SAH.
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Affiliation(s)
- Xiancheng Qiu
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Neurosurgery, Shifang City People's Hospital, Shifang, China
| | - Qianke Tao
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lihan Zhang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Chenghao Kuang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Yuke Xie
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China
| | - Lifang Zhang
- Sichuan Clinical Research Center for Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Shigang Yin
- Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jianhua Peng
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yong Jiang
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Laboratory of Neurological Diseases and Brain Function, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Institute of Epigenetics and Brain Science, Southwest Medical University, Luzhou, China.,Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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12
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Chen J, Li M, Liu Z, Wang Y, Xiong K. Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage. Front Cell Neurosci 2022; 16:1025708. [PMID: 36582214 PMCID: PMC9793715 DOI: 10.3389/fncel.2022.1025708] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/08/2022] [Indexed: 12/15/2022] Open
Abstract
Subarachnoid haemorrhage (SAH) is a common cerebrovascular disease with high disability and mortality rates worldwide. The pathophysiological mechanisms involved in an aneurysm rupture in SAH are complex and can be divided into early brain injury and delayed brain injury. The initial mechanical insult results in brain tissue and vascular disruption with hemorrhages and neuronal necrosis. Following this, the secondary injury results in diffused cerebral damage in the peri-core area. However, the molecular mechanisms of neuronal death following an aneurysmal SAH are complex and currently unclear. Furthermore, multiple cell death pathways are stimulated during the pathogenesis of brain damage. Notably, particular attention should be devoted to necrosis, apoptosis, autophagy, necroptosis, pyroptosis and ferroptosis. Thus, this review discussed the mechanism of neuronal death and its influence on brain injury after SAH.
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Affiliation(s)
- Junhui Chen
- Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, China
| | - Mingchang Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhuanghua Liu
- Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, China
| | - Yuhai Wang
- Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, China
| | - Kun Xiong
- Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China
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13
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Shao H, Wu W, Wang P, Han T, Zhuang C. Role of Necroptosis in Central Nervous System Diseases. ACS Chem Neurosci 2022; 13:3213-3229. [PMID: 36373337 DOI: 10.1021/acschemneuro.2c00405] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Necroptosis is a type of precisely regulated necrotic cell death activated in caspase-deficient conditions. Multiple factors initiate the necroptotic signaling pathway, including toll-like receptor 3/4, tumor necrosis factor (TNF), dsRNA viruses, and T cell receptors. Presently, TNF-induced necroptosis via the phosphorylation of three key proteins, receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like protein, is the best-characterized process. Necroptosis induced by Z-DNA-binding protein 1 (ZBP-1) and toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon (TRIF) plays a significant role in infectious diseases, such as influenza A virus, Zika virus, and herpesvirus infection. An increasing number of studies have demonstrated the close association of necroptosis with multiple diseases, and disrupting necroptosis has been confirmed to be effective for treating (or managing) these diseases. The central nervous system (CNS) exhibits unique physiological structures and immune characteristics. Necroptosis may occur without the sequential activation of signal proteins, and the necroptosis of supporting cells has more important implications in disease development. Additionally, necroptotic signals can be activated in the absence of necroptosis. Here, we summarize the role of necroptosis and its signal proteins in CNS diseases and characterize typical necroptosis regulators to provide a basis for the further development of therapeutic strategies for treating such diseases. In the present review, relevant information has been consolidated from recent studies (from 2010 until the present), excluding the patents in this field.
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Affiliation(s)
- Hongming Shao
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Wenbin Wu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Pei Wang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Ting Han
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Chunlin Zhuang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.,School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
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14
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Chen P, Lin MH, Li YX, Huang ZJ, Rong YY, Lin QS, Ye ZC. Bexarotene enhances astrocyte phagocytosis via ABCA1-mediated pathways in a mouse model of subarachnoid hemorrhage. Exp Neurol 2022; 358:114228. [PMID: 36108713 DOI: 10.1016/j.expneurol.2022.114228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/31/2022] [Accepted: 09/08/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND AND PURPOSE Enhancing phagocytosis can facilitate the removal of inflammatory molecules, limit the toxicity of dead cells and debris, and promote recovery after brain injury. In this study, we aimed to explore the role of bexarotene (Bex), a retinoid X receptor (RXR) agonist, in promoting astrocyte phagocytosis and neurobehavioral recovery after subarachnoid hemorrhage (SAH). METHODS Mice SAH model was induced by pre-chiasmatic injection of blood. Modified Garcia score, novel object recognition, rotarod test, and Morris water maze were performed to assess neurological function. Immunofluorescence and electron microscopy were used to evaluate astrocyte phagocytosis in vivo. In addition， ABCA1/MEGF10&GULP1, the primary astrocyte phagocytosis pathway, were stimulated by Bex or suppressed by HX531 (a RXR antagonist) to evaluate their impacts on astrocyte phagocytosis and neurological recovery. RESULTS Astrocytes phagocytosis of blood components were observed in mice after SAH induction, which is further increased by Bex treatment. Bex dramatically attenuated neuroinflammation, reduced brain edema, improved early neurological performance and promoted neurocognitive recovery. Meanwhile, Bex decreased neurotoxic reactive astrocytes and preserved neurogenesis after SAH. Bex increased the expression of astrocyte phagocytosis-related proteins ABCA1, MEGF10, and GULP1. Bex also increased the lysosomal processing of engulfed blood components in astrocytes. Moreover, Bex significantly promoted astrocytes to phagocytize debris in vitro by increasing the expression of ABCA1, MEGF10 and GULP1, while HX531 inhibited astrocyte phagocytosis and decreased these protein levels. CONCLUSIONS Bex enhanced astrocyte phagocytosis through the ABCA1-mediated pathways, and promoted neurobehavior recovery in mice after SAH induction.
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Affiliation(s)
- Ping Chen
- Department of Anesthesiology, Anesthesiology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China; Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, China
| | - Mou-Hui Lin
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, China
| | - Yu-Xi Li
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, China
| | - Zhi-Jie Huang
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, China
| | - Yu-You Rong
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, China
| | - Qing-Song Lin
- Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
| | - Zu-Cheng Ye
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, The School of Basic Medical Sciences, Fujian Medical University, China.
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15
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Zhou B, Xu Q, Guo J, Chen Q, Lv Q, Xiao K, Zhu H, Zhao J, Liu Y. Necroptosis Contributes to LPS-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis in a Piglet Model. Int J Mol Sci 2022; 23:ijms231911218. [PMID: 36232518 PMCID: PMC9569845 DOI: 10.3390/ijms231911218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/08/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Stressors cause activation of the hypothalamic-pituitary-adrenal (HPA) axis and a systemic inflammatory response. As a newly proposed cell death manner in recent years, necroptosis occurs in a variety of tissue damage and inflammation. However, the role of necroptosis in HPA axis activation remains to be elucidated. The aim of this study was to investigate the occurrence of necroptosis and its role in HPA activation in a porcine stress model induced by Escherichia coli lipopolysaccharide (LPS). Several typical stress behaviors like fever, anorexia, shivering and vomiting were observed in piglets after LPS injection. HPA axis was activated as shown by increased plasma cortisol concentration and mRNA expression of pituitary corticotropin-releasing hormone receptor 1 (CRHR1) and adrenal steroidogenic acute regulatory protein (StAR). The mRNA expression of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and IL-6 in the hypothalamus, pituitary gland and adrenal gland was elevated by LPS, accompanied by the activation of necroptosis indicated by higher mRNA expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL). Furthermore, necrostatin-1 (Nec-1), an inhibitor of necroptosis, inhibited necroptosis indicated by decreased mRNA levels of RIP1, RIP3, MLKL, and phosphoglycerate mutase family member 5 (PGAM5) in the hypothalamus, pituitary gland and adrenal gland. Nec-1 also decreased the mRNA expression of TNF-α and IL-β and inhibited the activation of the HPA axis indicated by lower plasma cortisol concentration and mRNA expression of adrenal type 2 melanocortin receptor (MC2R) and StAR. These findings suggest that necroptosis is present and contributes to HPA axis activation induced by LPS. These findings provide a potential possibility for necroptosis as an intervention target for alleviating HPA axis activation and stress responses.
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Affiliation(s)
- Bei Zhou
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China
| | - Qilong Xu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China
| | - Junjie Guo
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China
| | - Qinliang Chen
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China
| | - Qingqing Lv
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China
| | - Kan Xiao
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China
| | - Huiling Zhu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China
| | - Jiangchao Zhao
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR 72701, USA
| | - Yulan Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan Polytechnic University, Wuhan 430023, China
- Correspondence: ; Tel./Fax: +86-027-8395-6175
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16
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Quinolinic Acid Induces Alterations in Neuronal Subcellular Compartments, Blocks Autophagy Flux and Activates Necroptosis and Apoptosis in Rat Striatum. Mol Neurobiol 2022; 59:6632-6651. [PMID: 35980566 DOI: 10.1007/s12035-022-02986-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 07/29/2022] [Indexed: 10/15/2022]
Abstract
Quinolinic acid (QUIN) is an agonist of N-methyl-D-aspartate receptor (NMDAr) used to study the underlying mechanism of excitotoxicity in animal models. There is evidence indicating that impairment in autophagy at early times contributes to cellular damage in excitotoxicity; however, the status of autophagy in QUIN model on day 7 remains unexplored. In this study, the ultrastructural analysis of subcellular compartments and the status of autophagy, necroptosis, and apoptosis in the striatum of rats administered with QUIN (120 nmol and 240 nmol) was performed on day 7. QUIN induced circling behavior, neurodegeneration, and cellular damage; also, it promoted swollen mitochondrial crests, spherical-like morphology, and mitochondrial fragmentation; decreased ribosomal density in the rough endoplasmic reticulum; and altered the continuity of myelin sheaths in axons with separation of the compact lamellae. Furthermore, QUIN induced an increase and a decrease in ULK1 and p-70-S6K phosphorylation, respectively, suggesting autophagy activation; however, the increased microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and sequestosome-1/p62 (SQSTM1/p62), the coexistence of p62 and LC3 in the same structures, and the decrease in Beclin 1 and mature cathepsin D also indicates a blockage in autophagy flux. Additionally, QUIN administration increased tumor necrosis factor alpha (TNFα) and receptor-interacting protein kinase 3 (RIPK3) levels and its phosphorylation (p-RIPK3), as well as decreased B-cell lymphoma 2 (Bcl-2) and increased Bcl-2-associated X protein (Bax) levels and c-Jun N-terminal kinase (JNK) phosphorylation, suggesting an activation of necroptosis and apoptosis, respectively. These results suggest that QUIN activates the autophagy, but on day 7, it is blocked and organelle and cellular damage, neurodegeneration, and behavior alterations could be caused by necroptosis and apoptosis activation.
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17
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Morin offsets PTZ-induced neuronal degeneration and cognitive decrements in rats: The modulation of TNF-α/TNFR-1/RIPK1,3/MLKL/PGAM5/Drp-1, IL-6/JAK2/STAT3/GFAP and Keap-1/Nrf-2/HO-1 trajectories. Eur J Pharmacol 2022; 931:175213. [PMID: 35981604 DOI: 10.1016/j.ejphar.2022.175213] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 08/02/2022] [Accepted: 08/11/2022] [Indexed: 11/21/2022]
Abstract
Morin is a bioactive flavonoid with prominent neuroprotective potentials, however, its impact on epilepsy-provoked cognitive dysregulations has not been revealed. Hence, the present investigation aims to divulge the potential anticonvulsant/neuroprotective effects of morin in rats using a pentylenetetrazole (PTZ)-induced kindling model with an emphasis on the possible signaling trajectories involved. Kindling was induced using a sub-convulsive dose of PTZ (35 mg/kg, i.p.), once every other day for 25 days (12 injections). The expression of targeted biomarkers and molecular signals were examined in hippocampal tissues by ELISA, Western blotting, immunohistochemistry, and histopathology. Contrary to PTZ effects, administration of morin (10 mg/kg, i.p., from day 15 of PTZ injection to the end of the experiment) significantly reduced the severity of seizures coupled with a delay in kindling acquisition. It also preserved hippocampal neurons, and diminished astrogliosis to counteract cognitive deficits, exhibited by the enhanced performance in MWM and PA tests. These favorable impacts of morin were mediated via the abrogation of the PTZ-induced necroptotic changes and mitochondrial fragmentation proven by the suppression of p-RIPK-1/p-RIPK-3/p-MLKL and PGAM5/Drp-1 cues alongside the enhancement of caspase-8. Besides, morin inhibited the inflammatory cascade documented by the attenuation of the pro-convulsant receptor/cytokines TNFR-1, TNF-α, I L-1β, and IL-6 and the marked reduction of hippocampal IL-6/p-JAK2/p-STAT3/GFAP cue. In tandem, morin signified its anti-oxidant capacity by lowering the hippocampal contents of MDA, NOX-1, and Keap-1 with the restoration of the impaired Nrf-2/HO-1 pathway. Together, these versatile neuro-modulatory effects highlight the promising role of morin in the management of epilepsy.
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18
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Biological Effects and Mechanisms of Caspases in Early Brain Injury after Subarachnoid Hemorrhage. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3345637. [PMID: 35847583 PMCID: PMC9277153 DOI: 10.1155/2022/3345637] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/22/2022] [Indexed: 12/12/2022]
Abstract
Caspases are an evolutionarily conserved family of proteases responsible for mediating and initiating cell death signals. In the past, the dysregulated activation of caspases was reported to play diverse but equally essential roles in neurodegenerative diseases, such as brain injury and neuroinflammatory diseases. A subarachnoid hemorrhage (SAH) is a traumatic event that is either immediately lethal or induces a high risk of stroke and neurological deficits. Currently, the prognosis of SAH after treatment is not ideal. Early brain injury (EBI) is considered one of the main factors contributing to the poor prognosis of SAH. The mechanisms of EBI are complex and associated with oxidative stress, neuroinflammation, blood-brain barrier disruption, and cell death. Based on mounting evidence, caspases are involved in neuronal apoptosis or death, endothelial cell apoptosis, and increased inflammatory cytokine-induced by apoptosis, pyroptosis, and necroptosis in the initial stages after SAH. Caspases can simultaneously mediate multiple death modes and regulate each other. Caspase inhibitors (including XIAP, VX-765, and Z-VAD-FMK) play an essential role in ameliorating EBI after SAH. In this review, we explore the related pathways mediated by caspases and their reciprocal regulation patterns after SAH. Furthermore, we focus on the extensive crosstalk of caspases as a potential area of research on therapeutic strategies for treating EBI after SAH.
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19
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Wang Y, Xu J, You W, Shen H, Li X, Yu Z, Li H, Chen G. Roles of Rufy3 in experimental subarachnoid hemorrhage-induced early brain injury via accelerating neuronal axon repair and synaptic plasticity. Mol Brain 2022; 15:35. [PMID: 35461284 PMCID: PMC9034509 DOI: 10.1186/s13041-022-00919-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 04/06/2022] [Indexed: 11/25/2022] Open
Abstract
RUN and FYVE domain-containing 3 (Rufy3) is a well-known adapter protein of a small GTPase protein family and is bound to the activated Ras family protein to maintain neuronal polarity. However, in experimental subarachnoid hemorrhage (SAH), the role of Rufy3 has not been investigated. Consequently, we aimed to investigate the potential role of Rufy3 in an in vivo model of SAH-induced early brain injury (EBI). In addition, we investigated the relevant brain-protective mechanisms. Oxyhemoglobin (OxyHb) stimulation of cultured primary neurons simulated vitro SAH condition. The SAH rat model was induced by infusing autologous blood into the optic chiasma pool and treating the rats with lentivirus-negative control 1 (LV-NC1), lentivirus-Rufy3 shRNA (LV-shRNA), lentivirus-negative control 2 (LV-NC2), lentivirus-Rufy3 (LV-Rufy3), or 8-pCPT-2'-O-Me-cAMP (8p-CPT) (Rap1 agonist). In experiment one, we found that the protein level of Rufy3 decreased and neuronal axon injury in the injured neurons but was rectified by LV-Rufy3 treatment. In experiment two, mRNA and protein levels of Rufy3 were downregulated in brain tissue and reached the lowest level at 24 h after SAH. In addition, the expression of Myelin Basic Protein was downregulated and that of anti-hypophosphorylated neurofilament H (N52) was upregulated after SAH. In experiments three and four, Rufy3 overexpression (LV-Rufy3) increased the interactions between Rufy3 and Rap1, the level of Rap1-GTP, and the ratio of Rap1-GTP/total GTP. In addition, LV-Rufy3 treatment inhibited axon injury and accelerated axon repair by activating the Rap1/Arap3/Rho/Fascin signaling pathway accompanied by upregulated protein expression levels of ARAP3, Rho, Fascin, and Facin. LV-Rufy3 also enhanced synaptic plasticity by activating the Rap1/MEK/ERK/synapsin I signaling pathway accompanied by upregulated protein expression levels of ERK1, p-ERK1, MEK1, p-MEK1, synaspin I, and p-synaspin I. Moreover, LV-Rufy3 also alleviated brain damage indicators, including cortical neuronal cell apoptosis and degeneration, brain edema, and cognitive impairment after SAH. However, the downregulation of Rufy3 had the opposite effect and aggravated EBI induced by SAH. Notably, the combined application of LV-Rufy3 and 8p-CPT showed a significant synergistic effect on the aforementioned parameters. Our findings suggest that enhanced Rufy3 expression may reduce EBI by inhibiting axon injury and promoting neuronal axon repair and synaptic plasticity after SAH.
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Affiliation(s)
- Yang Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jianguo Xu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
| | - Wanchun You
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
| | - Zhengquan Yu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China.
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China.
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, China
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α-Lipoic Acid-Plus Ameliorates Endothelial Injury by Inhibiting the Apoptosis Pathway Mediated by Intralysosomal Cathepsins in an In Vivo and In Vitro Endothelial Injury Model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8979904. [PMID: 35450412 PMCID: PMC9018191 DOI: 10.1155/2022/8979904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 01/27/2022] [Accepted: 02/23/2022] [Indexed: 11/18/2022]
Abstract
α-Lipoic acid-plus (LAP), an amine derivative of α-lipoic acid, has been reported to protect cells from oxidative stress damage by reacting with lysosomal iron and is more powerful than desferrioxamine (DFO). However, the role of LAP in experimental carotid artery intimal injury (CAII) has not yet been well investigated. Therefore, we sought to uncover the role and potential endovascular protective mechanisms of LAP in endothelial injury. In vitro, oxyhemoglobin (OxyHb) stimulation of cultured human umbilical vein endothelial cells (HUVECs) simulated intimal injury. In vivo, balloon compression injury of the carotid artery was used to establish a rat CAII model. We found that the protein levels of cathepsin B/D, ferritin, transferrin receptor (TfR), cleaved caspase-3, and Bax increased in the injured endothelium and HUVECs but were rectified by DFO and LAP treatments, as revealed by western blotting and immunofluorescence staining. Additionally, DFO and LAP decreased oxidative stress levels and endothelial cell necrosis of the damaged endothelium. Moreover, DFO and LAP significantly ameliorated the increased oxidative stress, iron level, and lactic dehydrogenase activity of HUVECs and improved the reduced HUVEC viability induced by OxyHb. More importantly, DFO and LAP significantly reduced mitochondrial damage and were beneficial for maintaining lysosomal integrity, as indicated by acridine orange (AO), Lyso-Tracker Red, JC-1, and ATPB staining in HUVECs. Finally, LAP might offer more significant endovascular protective effects than DFO. Our data suggested that LAP exerted endovascular protective effects by inhibiting the apoptosis signaling pathway mediated by intralysosomal cathepsins by reacting with excessive iron in endothelial lysosomes after intimal injury.
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21
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Lin F, Li R, Tu WJ, Chen Y, Wang K, Chen X, Zhao J. An Update on Antioxidative Stress Therapy Research for Early Brain Injury After Subarachnoid Hemorrhage. Front Aging Neurosci 2021; 13:772036. [PMID: 34938172 PMCID: PMC8686680 DOI: 10.3389/fnagi.2021.772036] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/08/2021] [Indexed: 12/30/2022] Open
Abstract
The main reasons for disability and death in aneurysmal subarachnoid hemorrhage (aSAH) may be early brain injury (EBI) and delayed cerebral ischemia (DCI). Despite studies reporting and progressing when DCI is well-treated clinically, the prognosis is not well-improved. According to the present situation, we regard EBI as the main target of future studies, and one of the key phenotype-oxidative stresses may be called for attention in EBI after laboratory subarachnoid hemorrhage (SAH). We summarized the research progress and updated the literature that has been published about the relationship between experimental and clinical SAH-induced EBI and oxidative stress (OS) in PubMed from January 2016 to June 2021. Many signaling pathways are related to the mechanism of OS in EBI after SAH. Several antioxidative stress drugs were studied and showed a protective response against EBI after SAH. The systematical study of antioxidative stress in EBI after laboratory and clinical SAH may supply us with new therapies about SAH.
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Affiliation(s)
- Fa Lin
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Runting Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Wen-Jun Tu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- The General Office of Stroke Prevention Project Committee, National Health Commission of the People’s Republic of China, Beijing, China
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China
| | - Yu Chen
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Ke Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Xiaolin Chen
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Jizong Zhao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
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22
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Li S, Qu L, Wang X, Kong L. Novel insights into RIPK1 as a promising target for future Alzheimer's disease treatment. Pharmacol Ther 2021; 231:107979. [PMID: 34480965 DOI: 10.1016/j.pharmthera.2021.107979] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/30/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is an intractable neurodegenerative disease showing a clinical manifestation with memory loss, cognitive impairment and behavioral dysfunction. The predominant pathological characteristics of AD include neuronal loss, β-amyloid (Aβ) deposition and hyperphosphorylated Tau induced neurofibrillary tangles (NFTs), while considerable studies proved these could be triggered by neuronal death and neuroinflammation. Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase existed at the cross-point of cell death and inflammatory signaling pathways. Emerging investigations have shed light on RIPK1 for its potential role in AD progression. The present review makes a bird's eye view on the functions of RIPK1 and mainly focus on the underlying linkages between RIPK1 and AD from comprehensive aspects including neuronal death, Aβ and Tau, inflammasome activation, BBB rupture, AMPK/mTOR, mitochondrial dysfunction and O-glcNAcylation. Moreover, the discovery of RIPK1 inhibitors, ongoing clinical trials along with future RIPK1-targeted therapeutics are also reviewed.
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Affiliation(s)
- Shang Li
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Lailiang Qu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Xiaobing Wang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
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Liu C, Chen Y, Cui W, Cao Y, Zhao L, Wang H, Liu X, Fan S, Huang K, Tong A, Zhou L. Inhibition of neuronal necroptosis mediated by RIP1/RIP3/MLKL provides neuroprotective effects on kaolin-induced hydrocephalus in mice. Cell Prolif 2021; 54:e13108. [PMID: 34374150 PMCID: PMC8450124 DOI: 10.1111/cpr.13108] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 07/09/2021] [Accepted: 07/10/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Necroptosis is widespread in neurodegenerative diseases. Here, we examined necroptosis in the hippocampus and cortex after hydrocephalus and found that a necroptosis pathway inhibitor alleviates necroptosis and provides neuroprotective effects. MATERIALS AND METHODS Hydrocephalus was induced in C57BL/6 mice by kaolin. Haematoxylin and eosin (HE), Nissl, PI and Fluoro-Jade B (FJB) staining were used for general observations. Phosphorylated receptor-interacting protein kinase 3 (p-RIP3) and phosphorylated mixed lineage kinase domain-like (p-MLKL) were measured by Western blotting and immunohistochemistry. Scanning electron microscopy (SEM) was used to observe ependymal cilia. Magnetic resonance imaging (MRI) and the Morris water maze (MWM) test were used to assess neurobehavioral changes. Immunofluorescence was used to detect microglial and astrocyte activation. Inflammatory cytokines were measured by Western blotting and RT-PCR. RESULTS Obvious pathological changes appeared in the hippocampus and cortex after hydrocephalus, and expression of the necroptosis markers p-RIP3, p-MLKL and inflammatory cytokines increased. Necrostatin-1 (Nec-1) and GSK872 reduced necrotic cell death, attenuated p-RIP3 and p-MLKL levels, slightly improved neurobehaviours and inhibited microglial and astrocyte activation and inflammation. CONCLUSIONS RIP1/RIP3/MLKL mediates necroptosis in the cortex and hippocampus in a hydrocephalus mouse model, and Nec-1 and GSK872 have some neuroprotective effects.
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Affiliation(s)
- Chang Liu
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Yaxing Chen
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Wenyao Cui
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Cao
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
- Department of Neurosurgery, Chengdu Second People's hospital, Chengdu, China
| | - Long Zhao
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Haoxiang Wang
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyin Liu
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Shuangmin Fan
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Keru Huang
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
| | - Aiping Tong
- State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, China
| | - Liangxue Zhou
- Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, China
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24
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Cui J, Liu H, Xu S. Selenium-deficient diet induces necroptosis in the pig brain by activating TNFR1 via mir-29a-3p. Metallomics 2021; 12:1290-1301. [PMID: 32568328 DOI: 10.1039/d0mt00032a] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Selenium (Se) deficiency is one of the crucial factors related to nervous system disease and necroptosis. MicroRNAs (miRNAs) play vital roles in regulating necroptosis. However, the mechanism of Se deficiency-induced necroptosis in the pig brain tissue and the role that miRNAs play in this process are unclear. Therefore, in this study, in vitro and pig models of Se deficiency were replicated, and electron microscopy, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays were performed. The results showed that brain cells typically undergo necrotic changes, and that Se deficiency suppresses mir-29a-3p, which increases the levels of TNFRSF1A (TNFR1). Subsequently, a distinct increase in the necroptosis markers (RIPK1, RIPK3, and MLKL) and an evident decrease in caspase 8 was observed. And the expression of 10 selenoproteins was decreased. Moreover, the in vitro experiments showed that the expression of mir-29a-3p decreased as the Se content in the medium decreased and the application of an mir-29a-3p inhibitor increased the number of necrotic cells and the accumulation of ROS, and these effects were inhibited by necrostatin-1 (Nec-1) and N-acetyl-cysteine (NAC), respectively. Taken together, we proved that Se deficiency induced necroptosis both in vitro and in vivo through the targeted regulation of TNFR1 by mir-29a-3p in the pig brain.
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Affiliation(s)
- Jiawen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, P. R. China.
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Wang Y, Kong XQ, Wu F, Xu B, Bao DJ, Cheng CD, Wei XP, Dong YF, Niu CS. SOCS1/JAK2/STAT3 axis regulates early brain injury induced by subarachnoid hemorrhage via inflammatory responses. Neural Regen Res 2021; 16:2453-2464. [PMID: 33907034 PMCID: PMC8374552 DOI: 10.4103/1673-5374.313049] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The SOCS1/JAK2/STAT3 axis is strongly associated with tumor growth and progression, and participates in cytokine secretion in many diseases. However, the effects of the SOCS1/JAK2/STAT3 axis in experimental subarachnoid hemorrhage remain to be studied. A subarachnoid hemorrhage model was established in rats by infusing autologous blood into the optic chiasm pool. Some rats were first treated with JAK2/STAT3 small interfering RNA (Si-JAK2/Si-STAT3) or overexpression plasmids of JAK2/STAT3. In the brains of subarachnoid hemorrhage model rats, the expression levels of both JAK2 and STAT3 were upregulated and the expression of SOCS1 was downregulated, reaching a peak at 48 hours after injury. Simultaneously, the interactions between JAK2 and SOCS1 were reduced. In contrast, the interactions between JAK2 and STAT3 were markedly enhanced. Si-JAK2 and Si-STAT3 treatment alleviated cortical neuronal cell apoptosis and necrosis, destruction of the blood-brain barrier, brain edema, and cognitive functional impairment after subarachnoid hemorrhage. This was accompanied by decreased phosphorylation of JAK2 and STAT3 protein, decreased total levels of JAK2 and STAT3 protein, and increased SOCS1 protein expression. However, overexpression of JAK2 and STAT3 exerted opposite effects, aggravating subarachnoid hemorrhage-induced early brain injury. Si-JAK2 and Si-STAT3 inhibited M1-type microglial conversion and the release of pro-inflammatory factors (inducible nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α) and increased the release of anti-inflammatory factors (arginase-1, interleukin-10, and interleukin-4). Furthermore, primary neurons stimulated with oxyhemoglobin were used to simulate subarachnoid hemorrhage in vitro, and the JAK2 inhibitor AG490 was used as an intervention. The in vitro results also suggested that neuronal protection is mediated by the inhibition of JAK2 and STAT3 expression. Together, our findings indicate that the SOCS1/JAK2/STAT3 axis contributes to early brain injury after subarachnoid hemorrhage both in vitro and in vivo by inducing inflammatory responses. This study was approved by the Animal Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China (approval No. LLSC-20180202) on March 1, 2018.
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Affiliation(s)
- Yang Wang
- Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China
| | - Xiang-Qian Kong
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University; Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Fei Wu
- Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China
| | - Bin Xu
- Anhui Medical College, Anhui Provincial Medical Genetics Center, Hefei, Anhui Province, China
| | - De-Jun Bao
- Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China
| | - Chuan-Dong Cheng
- Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China
| | - Xiang-Ping Wei
- Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China
| | - Yong-Fei Dong
- Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China
| | - Chao-Shi Niu
- Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China; Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, Anhui Province, China
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26
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Gáll T, Pethő D, Nagy A, Balla G, Balla J. Therapeutic Potential of Carbon Monoxide (CO) and Hydrogen Sulfide (H 2S) in Hemolytic and Hemorrhagic Vascular Disorders-Interaction between the Heme Oxygenase and H 2S-Producing Systems. Int J Mol Sci 2020; 22:ijms22010047. [PMID: 33374506 PMCID: PMC7793096 DOI: 10.3390/ijms22010047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/18/2020] [Accepted: 12/19/2020] [Indexed: 02/07/2023] Open
Abstract
Over the past decades, substantial work has established that hemoglobin oxidation and heme release play a pivotal role in hemolytic/hemorrhagic disorders. Recent reports have shown that oxidized hemoglobins, globin-derived peptides, and heme trigger diverse biological responses, such as toll-like receptor 4 activation with inflammatory response, reprogramming of cellular metabolism, differentiation, stress, and even death. Here, we discuss these cellular responses with particular focus on their mechanisms that are linked to the pathological consequences of hemorrhage and hemolysis. In recent years, endogenous gasotransmitters, such as carbon monoxide (CO) and hydrogen sulfide (H2S), have gained a lot of interest in connection with various human pathologies. Thus, many CO and H2S-releasing molecules have been developed and applied in various human disorders, including hemolytic and hemorrhagic diseases. Here, we discuss our current understanding of oxidized hemoglobin and heme-induced cell and tissue damage with particular focus on inflammation, cellular metabolism and differentiation, and endoplasmic reticulum stress in hemolytic/hemorrhagic human diseases, and the potential beneficial role of CO and H2S in these pathologies. More detailed mechanistic insights into the complex pathology of hemolytic/hemorrhagic diseases through heme oxygenase-1/CO as well as H2S pathways would reveal new therapeutic approaches that can be exploited for clinical benefit.
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Affiliation(s)
- Tamás Gáll
- Division of Nephrology, Department of Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.G.); (D.P.); (A.N.)
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, 4032 Debrecen, Hungary;
| | - Dávid Pethő
- Division of Nephrology, Department of Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.G.); (D.P.); (A.N.)
- Faculty of Medicine, University of Debrecen, Kálmán Laki Doctoral School, 4032 Debrecen, Hungary
| | - Annamária Nagy
- Division of Nephrology, Department of Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.G.); (D.P.); (A.N.)
- Faculty of Medicine, University of Debrecen, Kálmán Laki Doctoral School, 4032 Debrecen, Hungary
| | - György Balla
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, 4032 Debrecen, Hungary;
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - József Balla
- Division of Nephrology, Department of Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (T.G.); (D.P.); (A.N.)
- Correspondence: ; Tel.: +36-52-255-500/55004
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27
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Qu XF, Liang TY, Wu DG, Lai NS, Deng RM, Ma C, Li X, Li HY, Liu YZ, Shen HT, Chen G. Acyl-CoA synthetase long chain family member 4 plays detrimental role in early brain injury after subarachnoid hemorrhage in rats by inducing ferroptosis. CNS Neurosci Ther 2020; 27:449-463. [PMID: 33314758 PMCID: PMC7941219 DOI: 10.1111/cns.13548] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/10/2020] [Accepted: 11/23/2020] [Indexed: 12/19/2022] Open
Abstract
Aims Acyl‐CoA synthetase long chain family member 4 (ACSL4) is closely related to tumor genesis and development in certain tissues. However, the function of ACSL4 in early brain injury (EBI) caused by subarachnoid hemorrhage (SAH) is unclear. In this study, we investigated the expression patterns and role of ACSL4 in SAH and post‐SAH EBI using a rat model of SAH. Methods The rat model of SAH was induced by autologous blood injection into the prechiasmatic cistern of rats. We also used two specific inhibitors of ferroptosis (Ferrostatin‐1 and Liproxstatin‐1) to investigate the role of ferroptosis in EBI. Results We found that ACSL4 levels in brain tissue increased significantly in post‐SAH EBI. Inhibiting the expression of ACSL4 using small interfering RNAs alleviated inflammation, blood‐brain barrier (BBB) impairment, oxidative stress, brain edema, and behavioral and cognitive deficits, and increased the number of surviving neurons, after SAH. Similar effects were obtained by suppressing ferroptosis. Conclusions ACSL4 exacerbated SAH‐induced EBI by mediating ferroptosis. These findings may provide a theoretical basis for potential therapy aimed at alleviating post‐SAH EBI.
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Affiliation(s)
- Xiao-Feng Qu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.,Department of Neurology, The First People's Hospital of Yancheng, Yancheng, Jiangsu Province, China
| | - Tian-Yu Liang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - De-Gang Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.,Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Nian-Sheng Lai
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.,Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Ru-Ming Deng
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.,Department of Neurosurgery, The People's Hospital of Bozhou, Bozhou, Anhui Province, China
| | - Chao Ma
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Hai-Ying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Yi-Zhi Liu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Hai-Tao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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Cai GF, Sun ZR, Zhuang Z, Zhou HC, Gao S, Liu K, Shang LL, Jia KP, Wang XZ, Zhao H, Cai GL, Song WL, Xu SN. Cross electro-nape-acupuncture ameliorates cerebral hemorrhage-induced brain damage by inhibiting necroptosis. World J Clin Cases 2020; 8:1848-1858. [PMID: 32518774 PMCID: PMC7262720 DOI: 10.12998/wjcc.v8.i10.1848] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/01/2020] [Accepted: 04/21/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Receptor interacting protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, belongs to programmed cell death. It has been reported that RIPK1-mediated necroptosis exists in lesions of cerebral hemorrhage (CH). Electroacupuncture, a treatment derived from traditional Chinese medicine, could improve neurological impairment in patients with brain injury.
AIM To investigate the protective role of cross electro-nape acupuncture (CENA) in CH, and clarify the potential mechanism.
METHODS CH rat models were established, and CENA was applied to the experimental rats. Neurological functions and encephaledema were then measured. Necrotic cells in the brain of rats with CH were evaluated by propidium iodide staining. Necroptosis was assessed by immunofluorescence. Activation of the necroptosis-related pathway was detected by western blot. Extraction of brain tissue, cerebrospinal fluid and serum samples was conducted to measure the expression and secretion of inflammatory cytokines by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay.
RESULTS The necroptotic marker p-MLKL was detectable in the brains of rats with CH. Next, we found that CENA could ameliorate neurological functions in rat models of CH. Moreover, the upregulation of RIPK1-mediated necroptosis-related molecules in the brains of rats with CH were inhibited by CENA. Further investigation revealed that CENA partially blocked the interaction between RIPK1 and RIPK3. Finally, in vivo assays showed that CENA decreased the expression of the inflammatory cytokines tumor necrosis factor-α, interleukin-6 and interleukin-8 in CH rat models.
CONCLUSION These findings revealed that CENA exerts a protective role in CH models by inhibiting RIPK1-mediated necroptosis.
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Affiliation(s)
- Guo-Feng Cai
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, Heilongjiang Province, China
- Postdoctoral Research Station of Heilongjiang Academy of Traditional Chinese Medicine, Harbin 150001, Heilongjiang Province, China
| | - Zhong-Ren Sun
- Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Zhe Zhuang
- Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, Heilongjiang Province, China
| | - Hai-Chun Zhou
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, Heilongjiang Province, China
| | - Shan Gao
- First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Kai Liu
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, Heilongjiang Province, China
| | - Li-Li Shang
- Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, Heilongjiang Province, China
| | - Kun-Ping Jia
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, Heilongjiang Province, China
| | - Xiu-Zhen Wang
- Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, Heilongjiang Province, China
| | - Hui Zhao
- Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, Heilongjiang Province, China
| | - Guo-Liang Cai
- Harbin Sport University, Harbin 150001, Heilongjiang Province, China
| | - Wen-Li Song
- Harbin Sport University, Harbin 150001, Heilongjiang Province, China
| | - Sheng-Nan Xu
- Graduate School of Heilongjiang University of Traditional Chinese Medicine, Harbin 150040, Heilongjiang Province, China
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29
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Lin DQ, Cai XY, Wang CH, Yang B, Liang RS. Optimal concentration of necrostatin-1 for protecting against hippocampal neuronal damage in mice with status epilepticus. Neural Regen Res 2020; 15:936-943. [PMID: 31719260 PMCID: PMC6990772 DOI: 10.4103/1673-5374.268903] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 03/10/2019] [Accepted: 08/13/2019] [Indexed: 02/05/2023] Open
Abstract
Hippocampal neurons undergo various forms of cell death after status epilepticus. Necrostatin-1 specifically inhibits necroptosis mediated by receptor interacting protein kinase 1 (RIP1) and RIP3 receptors. However, there are no reports of necroptosis in mouse models of status epilepticus. Therefore, in this study, we investigated the effects of necrostatin-1 on hippocampal neurons in mice with status epilepticus, and, furthermore, we tested different amounts of the compound to identify the optimal concentration for inhibiting necroptosis and apoptosis. A mouse model of status epilepticus was produced by intraperitoneal injection of kainic acid, 12 mg/kg. Different concentrations of necrostatin-1 (10, 20, 40, and 80 μM) were administered into the lateral ventricle 15 minutes before kainic acid injection. Hippocampal damage was assessed by hematoxylin-eosin staining 24 hours after the model was successfully produced. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, western blot assay and immunohistochemistry were used to evaluate the expression of apoptosis-related and necroptosis-related proteins. Necrostatin-1 alleviated damage to hippocampal tissue in the mouse model of epilepsy. The 40 μM concentration of necrostatin-1 significantly decreased the number of apoptotic cells in the hippocampal CA1 region. Furthermore, necrostatin-1 significantly downregulated necroptosis-related proteins (MLKL, RIP1, and RIP3) and apoptosis-related proteins (cleaved-Caspase-3, Bax), and it upregulated the expression of anti-apoptotic protein Bcl-2. Taken together, our findings show that necrostatin-1 effectively inhibits necroptosis and apoptosis in mice with status epilepticus, with the 40 μM concentration of the compound having an optimal effect. The experiments were approved by the Animal Ethics Committee of Fujian Medical University, China (approval No. 2016-032) on November 9, 2016.
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Affiliation(s)
- Dong-Qi Lin
- Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong Province, China
- Department of Neurosurgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xin-Ying Cai
- Clinical Research Center, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, Guangdong Province, China
| | - Chun-Hua Wang
- Department of Neurosurgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Bin Yang
- Department of Neurosurgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Ri-Sheng Liang
- Department of Neurosurgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
- Correspondence to: Ri-Sheng Liang, .
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30
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Cerebral cavernous malformation 3 relieves subarachnoid hemorrhage-induced neuroinflammation in rats through inhibiting NF-kB signaling pathway. Brain Res Bull 2020; 160:74-84. [PMID: 32302649 DOI: 10.1016/j.brainresbull.2020.04.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 03/31/2020] [Accepted: 04/05/2020] [Indexed: 01/01/2023]
Abstract
Subarachnoid hemorrhage (SAH) is a severe acute cerebrovascular disease with high rates of disability and death. In recent years, a large number of studies has shown that early brain injury (EBI) may be a crucial cause of the poor prognosis of SAH and that microglia-mediated neuroinflammation is an important pathological process in EBI. Previous studies have indicated that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in microglia-mediated neuroinflammation after SAH. In addition, it has been reported that cerebral cavernous malformation 3/mammalian sterile20-like kinase 4 (CCM3/MST4) directly phosphorylates TRAF6 to inhibit its ubiquitination and to limit inflammatory responses. However, the association between CCM3/MST4 and SAH has not been reported. In our present study, we established a SAH model in adult male rats through injecting autologous arterial blood into the prechiasmatic cistern. Additionally, BV-2 cells, as well as primary microglial cultures from rats treated with oxygen hemoglobin (OxyHb) for 24 h, were used as in vitro models of SAH. Then, western blot, immunofluorescence, Fluoro-JadeC staining and Enzyme-linked immunosorbent assay (ELISA) and behavioral tests was applied in this study. We observed no significant change in the level of CCM3/MST4 in brain tissues, but a markedly decline of CCM3 in microglia of rats. We also found that the protein level of CCM3 was decreased in BV-2 cells after OxyHb treatment, reaching the lowest point at 6 h post-treatment. In contrast, there was no significant change in the protein level of MST4. Additionally, we recapitulated decreased expression of CCM3 and changes in subcellular localization of CCM3 in vitro model of SAH with primary microglial cultures treated with OxyHb. Overexpression of CCM3 decreased cellular degeneration, neurocognitive impairment, NF-κB p65 level in the nuclear, and inflammatory factors level (TNF-a and IL-1β). These results suggest that overexpression of CCM3 alleviated brain injury and neurological damage through the NF-κB signaling pathway.
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31
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Fang Y, Gao S, Wang X, Cao Y, Lu J, Chen S, Lenahan C, Zhang JH, Shao A, Zhang J. Programmed Cell Deaths and Potential Crosstalk With Blood-Brain Barrier Dysfunction After Hemorrhagic Stroke. Front Cell Neurosci 2020; 14:68. [PMID: 32317935 PMCID: PMC7146617 DOI: 10.3389/fncel.2020.00068] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/06/2020] [Indexed: 12/13/2022] Open
Abstract
Hemorrhagic stroke is a life-threatening neurological disease characterized by high mortality and morbidity. Various pathophysiological responses are initiated after blood enters the interstitial space of the brain, compressing the brain tissue and thus causing cell death. Recently, three new programmed cell deaths (PCDs), necroptosis, pyroptosis, and ferroptosis, were also found to be important contributors in the pathophysiology of hemorrhagic stroke. Additionally, blood-brain barrier (BBB) dysfunction plays a crucial role in the pathophysiology of hemorrhagic stroke. The primary insult following BBB dysfunction may disrupt the tight junctions (TJs), transporters, transcytosis, and leukocyte adhesion molecule expression, which may lead to brain edema, ionic homeostasis disruption, altered signaling, and immune infiltration, consequently causing neuronal cell death. This review article summarizes recent advances in our knowledge of the mechanisms regarding these new PCDs and reviews their contributions in hemorrhagic stroke and potential crosstalk in BBB dysfunction. Numerous studies revealed that necroptosis, pyroptosis, and ferroptosis participate in cell death after subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH). Endothelial dysfunction caused by these three PCDs may be the critical factor during BBB damage. Also, several signaling pathways were involved in PCDs and BBB dysfunction. These new PCDs (necroptosis, pyroptosis, ferroptosis), as well as BBB dysfunction, each play a critical role after hemorrhagic stroke. A better understanding of the interrelationship among them might provide us with better therapeutic targets for the treatment of hemorrhagic stroke.
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Affiliation(s)
- Yuanjian Fang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shiqi Gao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yang Cao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianan Lu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Chen
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Cameron Lenahan
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, United States.,Burrell College of Osteopathic Medicine, Las Cruces, NM, United States.,Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | - John H Zhang
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, United States.,Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA, United States.,Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA, United States.,Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianmin Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Brain Research Institute, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, China
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32
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Coulibaly AP, Provencio JJ. Aneurysmal Subarachnoid Hemorrhage: an Overview of Inflammation-Induced Cellular Changes. Neurotherapeutics 2020; 17:436-445. [PMID: 31907877 PMCID: PMC7283430 DOI: 10.1007/s13311-019-00829-x] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that leads to poor neurological outcomes and is characterized by both vascular and neural pathologies. Recent evidence demonstrates that inflammation mediates many of the vascular and neural changes observed after SAH. Although most studies focus on inflammatory mediators such as cytokines, the ultimate effectors of inflammation in SAH are parenchymal brain and peripheral immune cells. As such, the present review will summarize our current understanding of the cellular changes of both CNS parenchymal and peripheral immune cells after SAH.
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Affiliation(s)
- A P Coulibaly
- Department of Neurology, University of Virginia, Charlottesville, VA, USA
| | - J J Provencio
- Department of Neurology, University of Virginia, Charlottesville, VA, USA.
- Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
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33
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Zhang J, Yuan G, Liang T, Pan P, Li X, Li H, Shen H, Wang Z, Chen G. Nix Plays a Neuroprotective Role in Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats. Front Neurosci 2020; 14:245. [PMID: 32265644 PMCID: PMC7108665 DOI: 10.3389/fnins.2020.00245] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 03/04/2020] [Indexed: 01/13/2023] Open
Abstract
Nix is located in the outer membrane of mitochondria, mediates mitochondrial fission and implicated in many neurological diseases. However, the association between Nix and subarachnoid hemorrhage (SAH) has not previously been reported. Therefore, the present study was designed to evaluate the expression of Nix and its role in early brain injury (EBI) after SAH. Adult male Sprague-Dawley (SD) rats were randomly assigned to various time points for investigation after SAH. A rat model of SAH was induced by injecting 0.3 ml of autologous non-heparinized arterial blood into the prechiasmatic cistern. The expression of Nix was investigated by Western blot and immunohistochemistry. Next, Nix-specific overexpression plasmids and small interfering RNAs (siRNAs) were separately administered. Western blot, neurological scoring, Morris water maze, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and fluoro-jade B (FJB) staining were performed to evaluate the role of Nix in EBI following SAH. We found that Nix was expressed in neurons and its expression level in the SAH groups was higher than that in the Sham group, which peaked at 24 h after SAH. Overexpression of Nix following SAH significantly decreased the expression of translocase of outer mitochondrial membrane 20 (TOMM20, a marker of mitochondria), ameliorated neurological/cognitive deficits induced by SAH, and reduced the total number of apoptotic/neurodegenerative cells, whereas siRNA knockdown of Nix yielded opposite effects. Taken together, our findings demonstrated that the expression of Nix is increased in neurons after experimental SAH in rats, and may play a neuroprotective role in EBI following SAH.
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Affiliation(s)
- Juyi Zhang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Guiqiang Yuan
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Tianyu Liang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Pengjie Pan
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiang Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
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34
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Molecular mechanisms of necroptosis and relevance for neurodegenerative diseases. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 353:31-82. [PMID: 32381178 DOI: 10.1016/bs.ircmb.2019.12.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Necroptosis is a regulated cell death pathway morphologically similar to necrosis that depends on the kinase activity of receptor interacting protein 3 (RIP3) and the subsequent activation of the pseudokinase mixed lineage kinase domain-like protein (MLKL), being also generally dependent on RIP1 kinase activity. Necroptosis can be recruited during pathological conditions, usually following the activation of death receptors under specific cellular contexts. In this regard, necroptosis has been implicated in the pathogenesis of multiple disorders, including acute and chronic neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, and multiple sclerosis. Here, we summarize the molecular mechanisms regulating the induction of necroptosis and downstream effectors of this form of cell death, besides exploring non-necroptotic roles for necroptosis-related proteins that may impact on alternative cell death pathways and inflammatory mechanisms in disease. Finally, we outline the recent evidence implicating necroptosis in neurodegenerative conditions and the emerging therapeutic perspectives targeting necroptosis in these diseases.
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35
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Espinosa-Oliva AM, García-Revilla J, Alonso-Bellido IM, Burguillos MA. Brainiac Caspases: Beyond the Wall of Apoptosis. Front Cell Neurosci 2019; 13:500. [PMID: 31749689 PMCID: PMC6848387 DOI: 10.3389/fncel.2019.00500] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/22/2019] [Indexed: 01/04/2023] Open
Abstract
For the last two decades, caspases, a family of cysteine-aspartic proteases, have evolved from being considered solely as regulators of apoptosis or inflammation to having a wider range of functions. In this mini review, we focus on the most recent “non-apoptotic” roles of caspases in the CNS, particularly in neurons, astrocytes and oligodendrocytes. Non-apoptotic caspase functions in microglia have already been reviewed extensively elsewhere. Here we discuss the involvement of caspases in the activation of the inflammasome, autophagy, and non-apoptotic forms of cell death such as necroptosis and pyroptosis. Also, we review the involvement of caspases in synapses and the processing of aggregates key to neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s diseases. Likewise, we mention the recently described involvement of caspases in mitochondrial biogenesis, which is a function independent of the enzymatic activity. We conclude discussing the relevance that “new” functions of caspases have in the CNS and the future of this field of research.
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Affiliation(s)
- Ana María Espinosa-Oliva
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Seville, Spain
| | - Juan García-Revilla
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Seville, Spain
| | - Isabel María Alonso-Bellido
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Seville, Spain
| | - Miguel Angel Burguillos
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, Seville, Spain
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36
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Shao Z, Tu S, Shao A. Pathophysiological Mechanisms and Potential Therapeutic Targets in Intracerebral Hemorrhage. Front Pharmacol 2019; 10:1079. [PMID: 31607923 PMCID: PMC6761372 DOI: 10.3389/fphar.2019.01079] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 08/26/2019] [Indexed: 12/12/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a subtype of hemorrhagic stroke with high mortality and morbidity. The resulting hematoma within brain parenchyma induces a series of adverse events causing primary and secondary brain injury. The mechanism of injury after ICH is very complicated and has not yet been illuminated. This review discusses some key pathophysiology mechanisms in ICH such as oxidative stress (OS), inflammation, iron toxicity, and thrombin formation. The corresponding therapeutic targets and therapeutic strategies are also reviewed.
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Affiliation(s)
- Zhiwei Shao
- Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Tu
- Department of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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