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Khaksar S, Bigdeli M, Mohammadi R. Expression of Na +/Ca 2+ exchangers was enhanced following pre-treatment of olive leaf extract and olive oil in animal model of ischemic stroke. Int J Neurosci 2025; 135:322-336. [PMID: 38153337 DOI: 10.1080/00207454.2023.2300732] [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: 07/25/2023] [Revised: 12/26/2023] [Accepted: 12/26/2023] [Indexed: 12/29/2023]
Abstract
BACKGROUND Neuroprotective role of olive and its natural products can introduce them as alternative candidates for the management of neurodegenerative diseases including stroke. The present study was designed to evaluate whether pretreatment of olive oil and leaf extract can attenuate the most important destructive processes in cerebral ischemia called excitotoxicity. MATERIAL AND METHODS The male rats were categorized into control, virgin olive oil (OVV), MCAO, MCAO + OVV (with doses of 0.25, 0.50 and 0.75 ml/kg as treatment groups), olive leaf extract, MCAO + olive leaf extract (with doses 50, 75 and 100 mg/kg as treatment groups) groups. Rats of treatment groups received gastric gavage with olive oil or leaf extract for 30 consecutive days. After pretreatment, the intraluminal filament technique was used to block middle cerebral artery (MCA) transiently. Neurological deficits, infarct volume and expression of Na+/Ca2+ exchangers (NCX1, NCX2 and NCX3) proteins were measured. RESULTS The results revealed that olive oil at doses of 0.50 and 0.75 ml/kg reduced the infarction and neurological score and upregulated NCXs expression in rat brain. In addition, olive leaf extract at doses of 75 and 100 mg/kg attenuated the infarction and neurological score and enhanced NCXs expression in rat brain. CONCLUSION These findings support the view that olive oil and leaf extract play the neuroprotective role in cerebral ischemia due to the upregulation of NCXs protein expression.
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Affiliation(s)
- Sepideh Khaksar
- Department of Plant Sciences, Faculty of biological Sciences, Alzahra University, Tehran, Iran
| | - Mohammadreza Bigdeli
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
- Institute for Cognitive and Brain Science, Shahid Beheshti University, Tehran, Iran
| | - Raziyeh Mohammadi
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
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Inagaki R, Kita S, Niwa N, Fukunaga K, Iwamoto T, Moriguchi S. Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice. FEBS J 2025; 292:426-444. [PMID: 39624860 PMCID: PMC11734882 DOI: 10.1111/febs.17339] [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: 03/13/2024] [Revised: 06/24/2024] [Accepted: 11/19/2024] [Indexed: 01/16/2025]
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that involves dopaminergic dysfunction in the prefrontal cortex (PFC), manifesting hyperactivity, inattention, and cognitive deficits. However, the ADHD-associated candidate genes underlying dopaminergic neurotransmission alterations remain poorly defined. Here, we identified the abundant localization of sodium-calcium exchanger 3 (NCX3) levels in the dopaminergic neurons of the ventral tegmental area, a major source of dopaminergic innervation to the PFC. We confirmed that NCX3 knockdown in N27 cells caused aberrant dopamine influx through the strong interaction between calcium/calmodulin-dependent protein kinase II alpha and dopamine transporter. In addition, we assessed behavioral changes and underlying molecular properties in NCX3 heterozygous (NCX3+/-) mice. NCX3+/- mice exhibited hyperactivity, cognitive deficits, and social dysfunction which were alleviated by treating with methylphenidate. Furthermore, NCX3+/- mice displayed a persistent elevation of basal dopamine levels and decreased extracellular levels of dopamine triggered by social stimuli in the PFC of NCX3+/- mice. In agreement with the rise in extracellular dopamine levels in the PFC, NCX3+/- mice showed activation of dopamine D1 receptor signaling pathways in the PFC compared to wild-type mice. Thus, deficiency of NCX3 leads to impaired dopaminergic neurotransmission in the PFC, which likely accounts for the ADHD-like behavior in NCX3+/- mice.
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Affiliation(s)
- Ryo Inagaki
- Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Satomi Kita
- Department of Pharmacology, Faculty of Pharmaceutical SciencesTokushima Bunri UniversityJapan
| | - Nozomu Niwa
- Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Kohji Fukunaga
- Department of Pharmacology, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Takahiro Iwamoto
- Department of Pharmacology, Faculty of MedicineFukuoka UniversityJapan
| | - Shigeki Moriguchi
- Research Center for Pharmaceutical Development, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
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Zhang C, Deng D, Wu Y, Song L, Geng J, Feng H, Jiang S, Zhang K, Cheng Y, Yin S. New insights into the neurophysiological effects of heat stress on the Chinese mitten crab (Eriocheir sinensis). J Therm Biol 2025; 127:104055. [PMID: 39818005 DOI: 10.1016/j.jtherbio.2025.104055] [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: 10/21/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/18/2025]
Abstract
Climate warming and frequent incidents of extreme high temperatures are serious global concerns. Heat stress induced by high temperature has many adverse effects on animal physiology, especially in aquatic poikilotherms. Chinese mitten crab (Eriocheir sinensis) is sensitive to high temperatures, this study evaluated the harmful effects of heat stress on the neurotoxicity, intestinal health, microbial diversity, and metabolite profiles. The results showed that heat stress caused histopathological damages and altered the ultrastructure of lesions in the cranial ganglia. Heat stress significantly upregulated the mRNA expression of apoptosis-related genes, and significantly altered the expression of neurotransmitter receptors. In addition, heat stress induced significant intestinal damages that mainly manifested as a significant increase in the activity of diamine oxidase in the serum and contents of histamine in the intestine. The diversity and abundance of intestinal microbiota altered abnormally in E. sinensis exposed to heat stress, and the bacteria that exhibited significant variations in abundance were closely related to the production of neurotransmitters and neuromodulators. Heat stress caused significant changes in the intestinal metabolite profiles, which mainly involved the amino acid and lipid metabolism pathways. Analysis of the correlation showed that the abnormal changes in metabolites were closely related to differences in the abundance of intestinal microbiota. Therefore, this study showed that heat stress could cause neurophysiological toxic effects, which may be related to intestinal ecological imbalance.
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Affiliation(s)
- Cong Zhang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China.
| | - Dunqian Deng
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Yi Wu
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Lexue Song
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Jiayin Geng
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Huixia Feng
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Su Jiang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Kai Zhang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China
| | - Yongxu Cheng
- Key Laboratory of Integrated Rice-Fish Farming Ecosystem, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, PR China
| | - Shaowu Yin
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing, 210023, PR China.
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Lee J, Geum D, Park DH, Kim JH. Molecular Targeting of Ischemic Stroke: The Promise of Naïve and Engineered Extracellular Vesicles. Pharmaceutics 2024; 16:1492. [PMID: 39771472 PMCID: PMC11678501 DOI: 10.3390/pharmaceutics16121492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 01/04/2025] Open
Abstract
Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Despite the success of early interventions, such as tissue-type plasminogen activator administration and mechanical thrombectomy, many patients continue to experience persistent neurological deficits. The pathophysiology of IS is multifaceted, encompassing excitotoxicity, oxidative and nitrosative stress, inflammation, and blood-brain barrier disruption, all of which contribute to neural cell death, further complicating the treatment of IS. Recently, extracellular vesicles (EVs) secreted naturally by various cell types have emerged as promising therapeutic agents because of their ability to facilitate selective cell-to-cell communication, neuroprotection, and tissue regeneration. Furthermore, engineered EVs, designed to enhance targeted delivery and therapeutic cargo, hold the potential to improve their therapeutic benefits by mitigating neuronal damage and promoting neurogenesis and angiogenesis. This review summarizes the characteristics of EVs, the molecular mechanisms underlying IS pathophysiology, and the emerging role of EVs in IS treatment at the molecular level. This review also explores the recent advancements in EV engineering, including the incorporation of specific proteins, RNAs, or pharmacological agents into EVs to enhance their therapeutic efficacy.
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Affiliation(s)
- Jihun Lee
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea;
| | - Dongho Geum
- Department of Medical Science, College of Medicine, Korea University, Seoul 02841, Republic of Korea;
| | - Dong-Hyuk Park
- Department of Neurosurgery, Anam Hospital, College of Medicine, Korea University, Seoul 02841, Republic of Korea;
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea;
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Ghasemi M, Mehranfard N. Neuroprotective actions of norepinephrine in neurological diseases. Pflugers Arch 2024; 476:1703-1725. [PMID: 39136758 DOI: 10.1007/s00424-024-02999-w] [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: 03/25/2024] [Revised: 06/24/2024] [Accepted: 07/24/2024] [Indexed: 10/09/2024]
Abstract
Precise control of norepinephrine (NE) levels and NE-receptor interaction is crucial for proper function of the brain. Much evidence for this view comes from experimental studies that indicate an important role for NE in the pathophysiology and treatment of various conditions, including cognitive dysfunction, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and sleep disorders. NE provides neuroprotection against several types of insults in multiple ways. It abrogates oxidative stress, attenuates neuroinflammatory responses in neurons and glial cells, reduces neuronal and glial cell activity, promotes autophagy, and ameliorates apoptotic responses to a variety of insults. It is beneficial for the treatment of neurodegenerative diseases because it improves the generation of neurotrophic factors, promotes neuronal survival, and plays an important role in the regulation of adult neurogenesis. This review aims to present the evidence supporting a principal role for NE in neuroprotection, and molecular mechanisms of neuroprotection.
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Affiliation(s)
- Maedeh Ghasemi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nasrin Mehranfard
- Nanokadeh Darooee Samen Private Joint Stock Company, Shafa Street, Urmia, 5715793731, Iran.
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Guo H, Zhang Y, Xiang X, Tang N, Gao W, Cui X. Single-cell RNA sequencing analysis provides novel insights into the role of apoptosis-related genes in muscle aging. Arch Gerontol Geriatr 2024; 125:105499. [PMID: 38852373 DOI: 10.1016/j.archger.2024.105499] [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: 04/05/2024] [Revised: 05/22/2024] [Accepted: 05/25/2024] [Indexed: 06/11/2024]
Abstract
OBJECTIVE This study employed a comprehensive single-cell analysis approach to explore the role of cell apoptosis-related genes in muscle aging. METHODS The single-cell RNA sequencing data from the GSE143704 dataset were used to identify distinct cell clusters and assess gene expression patterns related to apoptosis activation. The "limma" package was used to identify hub genes, after which we performed Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to identify relevant pathways. Additionally, Gene Set Enrichment Analysis(GSEA) and Gene Set Variation Analysis (GSVA) were used to uncover relevant biological pathways. The Receiver Operating Characteristic Curve (ROC) was used to evaluate the diagnostic value of the hub genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to analyze the immune cell infiltration levels. RESULTS Single-cell sequencing data from muscle aging patients allowed the identification of various cell types, including epithelial cells, adipocytes, and tissue-resident macrophages. By conducting a differential expression analysis that intersected active and nonactive apoptosis, as well as comparing elderly and young samples, a total of 22 hub genes were identified (p < 0.05). The 22 hub genes have discriminative ability as potential biomarkers for diagnosing muscle aging. The enrichment analysis indicated that these genes were closely associated with diverse pathways, including "response to UV-B" and "extracellular matrix organization" (p < 0.05). Furthermore, GSEA and GSVA indicated that multiple pathways emerged-for example, the "complement and coagulation cascades", "proteasome", "insulin signaling pathway", and "MAPK signaling pathway". Additionally, the analysis of immune cell infiltration revealed positive correlations between most of the hub genes and immune cells. CONCLUSION Our study identified 22 apoptosis-related genes involved in muscle aging and indicated their potential diagnostic value. These findings offer a novel perspective on the pathogenesis of muscle aging and present potential targets for therapeutic interventions.
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Affiliation(s)
- Hua Guo
- Department of General Medicine and Sleep Medicine Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University; Wuxi Medical Center, Nanjing Medical University Wuxi People's Hospital, Wuxi, Jiangsu Province, China
| | - Yunyun Zhang
- Department of General Medicine and Sleep Medicine Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University; Wuxi Medical Center, Nanjing Medical University Wuxi People's Hospital, Wuxi, Jiangsu Province, China
| | - Xin Xiang
- Nanjing Medical University, Nanjing, Jiangsu, China
| | - Na Tang
- Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wei Gao
- Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
| | - Xiaochuan Cui
- Department of General Medicine and Sleep Medicine Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University; Wuxi Medical Center, Nanjing Medical University Wuxi People's Hospital, Wuxi, Jiangsu Province, China.
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Zhang X, Zheng Y, Wang Z, Zhang G, Yang L, Gan J, Jiang X. Calpain: The regulatory point of cardiovascular and cerebrovascular diseases. Biomed Pharmacother 2024; 179:117272. [PMID: 39153432 DOI: 10.1016/j.biopha.2024.117272] [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: 05/12/2024] [Revised: 07/24/2024] [Accepted: 08/05/2024] [Indexed: 08/19/2024] Open
Abstract
Calpain, a key member of the Calpain cysteine protease superfamily, performs limited protein hydrolysis in a calcium-dependent manner. Its activity is tightly regulated due to the potential for non-specific cleavage of various intracellular proteins upon aberrant activation. A thorough review of the literature from 2010 to 2023 reveals 121 references discussing cardiovascular and cerebrovascular diseases. Dysregulation of the Calpain system is associated with various pathological phenomena, including lipid metabolism disorders, inflammation, apoptosis, and excitotoxicity. Although recent studies have revealed the significant role of Calpain in cardiovascular and cerebrovascular diseases, the precise mechanisms remain incompletely understood. Exploring the potential of Calpain inhibition as a therapeutic approach for the treatment of cardiovascular and cerebrovascular diseases may emerge as a compelling area of interest for future calpain research.
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Affiliation(s)
- Xiaolu Zhang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Yujia Zheng
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Ziyu Wang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Guangming Zhang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Lin Yang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Jiali Gan
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Xijuan Jiang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
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Li Z, Cao Z, Chen F, Li B, Jin H. Lutein inhibits glutamate-induced apoptosis in HT22 cells via the Nrf2/HO-1 signaling pathway. Front Neurosci 2024; 18:1432969. [PMID: 39193525 PMCID: PMC11347311 DOI: 10.3389/fnins.2024.1432969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/26/2024] [Indexed: 08/29/2024] Open
Abstract
Introduction Excessive glutamate levels induce oxidative stress, resulting in neuronal damage, and cell death. While natural antioxidants show promise for neuroprotection, their effectiveness in the central nervous system (CNS) is limited by the blood -brain barrier. Lutein, a neuroprotective carotenoid, has gained attention for its ability to traverse this barrier and accumulate in various brain regions. This study aimed to elucidate the mechanisms underlying the protective effects of lutein against glutamateinduced cell death in HT22 cells. Methods HT22 cells were treated with lutein (1.25-20 μM) for 24 hours. Cell viability, ROS levels, apoptosis, and mitochondrial membrane potential were assessed following lutein pretreatment and glutamate exposure. Protein expression of apoptotic markers was analyzed using Western blotting. Results Lutein effectively attenuated glutamate-induced apoptosis due to its antioxidant properties. Additionally, lutein inhibited glutamate-induced mitochondrial-mediated apoptosis. We observed that lutein modulated the nuclear translocation of nuclear factor erythroid 2 -related factor 2 (Nrf2) and upregulated the expression of heme oxygenase-1 (HO-1). Inhibition of HO-1 by tin protoporphyrin (SnPP), a synthetic inhibitor, weakened the protective effect of lutein. Furthermore, we demonstrated that lutein prevented the aberrant activation of MAPKs induced by glutamate, including ERK1/2, p38, and JNK, thereby conferring oxidative protection. Discussion Our study highlights the potent antioxidant properties of lutein, which effectively safeguards against glutamate-induced mitochondrial apoptotic cell death through the Nrf2/HO-1 signaling pathway and inhibition of MAPK activation. These findings demonstrate that lutein exerts a neuroprotective effect against glutamate-induced neuronal cell damage.
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Affiliation(s)
- Zhenhua Li
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, China
| | - Zhuohua Cao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, China
| | - Fangmei Chen
- Institute of Science and Technology Information Research of Tibet Autonomous Region, Lhasa, China
| | - Bin Li
- Key Laboratory of Pharmaceutical Research for Metabolic Diseases, Department of Pharmacy, Qingdao University of Science and Technology, Qingdao, China
- Department of Medicament, College of Medicine, Tibet University, Lhasa, China
| | - Hanyong Jin
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin, China
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Khan S, Bano N, Ahamad S, John U, Dar NJ, Bhat SA. Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms. Aging Dis 2024:AD.2024.0125-1. [PMID: 39122453 DOI: 10.14336/ad.2024.0125-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
Mitochondrial dysfunction plays a pivotal role in the development of age-related diseases, particularly neurodegenerative disorders. The etiology of mitochondrial dysfunction involves a multitude of factors that remain elusive. This review centers on elucidating the role(s) of excitotoxicity, oxytosis/ferroptosis and neurodegeneration within the context of mitochondrial bioenergetics, biogenesis, mitophagy and oxidative stress and explores their intricate interplay in the pathogenesis of neurodegenerative diseases. The effective coordination of mitochondrial turnover processes, notably mitophagy and biogenesis, is assumed to be critically important for cellular resilience and longevity. However, the age-associated decrease in mitophagy impedes the elimination of dysfunctional mitochondria, consequently impairing mitochondrial biogenesis. This deleterious cascade results in the accumulation of damaged mitochondria and deterioration of cellular functions. Both excitotoxicity and oxytosis/ferroptosis have been demonstrated to contribute significantly to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS). Excitotoxicity, characterized by excessive glutamate signaling, initiates a cascade of events involving calcium dysregulation, energy depletion, and oxidative stress and is intricately linked to mitochondrial dysfunction. Furthermore, emerging concepts surrounding oxytosis/ferroptosis underscore the importance of iron-dependent lipid peroxidation and mitochondrial engagement in the pathogenesis of neurodegeneration. This review not only discusses the individual contributions of excitotoxicity and ferroptosis but also emphasizes their convergence with mitochondrial dysfunction, a key driver of neurodegenerative diseases. Understanding the intricate crosstalk between excitotoxicity, oxytosis/ferroptosis, and mitochondrial dysfunction holds potential to pave the way for mitochondrion-targeted therapeutic strategies. Such strategies, with a focus on bioenergetics, biogenesis, mitophagy, and oxidative stress, emerge as promising avenues for therapeutic intervention.
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Affiliation(s)
- Sameera Khan
- Department of Zoology, Aligarh Muslim University, Aligarh-202002, India
| | - Nargis Bano
- Department of Zoology, Aligarh Muslim University, Aligarh-202002, India
| | - Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh-202002, India
| | - Urmilla John
- School of Studies in Neuroscience, Jiwaji University, Gwalior, India; School of Studies in Zoology, Jiwaji University, Gwalior, India
| | - Nawab John Dar
- CNB, SALK Institute of Biological Sciences, La Jolla, CA 92037, USA
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Matus V, Castro-Guarda M, Cárcamo-Fierro J, Morera FJ, Zambrano A. Interleukin 3 Inhibits Glutamate-Cytotoxicity in Neuroblastoma Cell Line. Neurochem Res 2024; 49:1373-1386. [PMID: 38512424 DOI: 10.1007/s11064-024-04123-x] [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: 09/23/2023] [Revised: 01/06/2024] [Accepted: 02/06/2024] [Indexed: 03/23/2024]
Abstract
Interleukin 3 (IL-3) is a well-known pleiotropic cytokine that regulates the proliferation and differentiation of hematopoietic progenitor cells, triggering classical signaling pathways such as JAK/STAT, Ras/MAPK, and PI3K/Akt to carry out its functions. Interestingly, the IL-3 receptor is also expressed in non-hematopoietic cells, playing a crucial role in cell survival. Our previous research demonstrated the expression of the IL-3 receptor in neuron cells and its protective role in neurodegeneration. Glutamate, a principal neurotransmitter in the central nervous system, can induce cellular stress and lead to neurotoxicity when its extracellular concentrations surpass normal levels. This excessive glutamate presence is frequently observed in various neurological diseases. In this study, we uncover the protective role of IL-3 as an inhibitor of glutamate-induced cell death, analyzing the cytokine's signaling pathways during its protective effect. Specifically, we examined the relevance of JAK/STAT, Ras/MAPK, and PI3 K signaling pathways in the molecular mechanism triggered by IL-3. Our results show that the inhibition of JAK, ERK, and PI3 K signaling pathways, using pharmacological inhibitors, effectively blocked IL-3's protective role against glutamate-induced cell death. Additionally, our findings suggest that Bcl-2 and Bax proteins may be involved in the molecular mechanism triggered by IL-3. Our investigation into IL-3's ability to protect neuronal cells from glutamate-induced damage offers a promising therapeutic avenue with potential clinical implications for several neurological diseases characterized by glutamate neurotoxicity.
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Affiliation(s)
- Verónica Matus
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, (P. O. Box) 567, 5090000, Casilla, Valdivia, Chile
| | - Marcos Castro-Guarda
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, (P. O. Box) 567, 5090000, Casilla, Valdivia, Chile
| | - Joaquín Cárcamo-Fierro
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, (P. O. Box) 567, 5090000, Casilla, Valdivia, Chile
| | - Francisco J Morera
- Applied Biochemistry Laboratory, Escuela de Medicina Veterinaria, Facultad de Agronomía y Sistemas Naturales, Facultad de Ciencias Biológicas y Facultad de Medicina, Pontificia Universidad Católica de Chile, 7820436, Santiago, Chile
| | - Angara Zambrano
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, (P. O. Box) 567, 5090000, Casilla, Valdivia, Chile.
- Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile.
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Li Y, Wu Y, Huang J, Cao X, An Q, Peng Y, Zhao Y, Luo Y. A variety of death modes of neutrophils and their role in the etiology of autoimmune diseases. Immunol Rev 2024; 321:280-299. [PMID: 37850797 DOI: 10.1111/imr.13284] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023]
Abstract
Neutrophils are important in the context of innate immunity and actively contribute to the progression of diverse autoimmune disorders. Distinct death mechanisms of neutrophils may exhibit specific and pivotal roles in autoimmune diseases and disease pathogenesis through the orchestration of immune homeostasis, the facilitation of autoantibody production, the induction of tissue and organ damage, and the incitement of pathological alterations. In recent years, more studies have provided in-depth examination of various neutrophil death modes, revealing nuances that challenge conventional understanding and underscoring their potential clinical utility in diagnosis and treatment. This review explores the multifaceted processes and characteristics of neutrophil death, with a focus on tailored investigations within various autoimmune diseases. It also highlights the potential interplay between neutrophil death and the landscape of autoimmune disorders. The review encapsulates the pertinent pathways implicated in various neutrophil death mechanisms across diverse autoimmune diseases while also charts possible avenues for future research.
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Affiliation(s)
- Yanhong Li
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yinlan Wu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jingang Huang
- Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xue Cao
- Department of Rheumatology and Immunology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, Henan, China
| | - Qiyuan An
- School of Inspection and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yun Peng
- Department of Rheumatology and Clinical Immunology, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Yi Zhao
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yubin Luo
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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12
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Khananshvili D. Neuronal and astrocyte NCX isoform/splice variants: How do they participate in Na + and Ca 2+ signalling? Cell Calcium 2023; 116:102818. [PMID: 37918135 DOI: 10.1016/j.ceca.2023.102818] [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: 10/16/2023] [Revised: 10/20/2023] [Accepted: 10/22/2023] [Indexed: 11/04/2023]
Abstract
NCX1, NCX2, and NCX3 gene isoforms and their splice variants are characteristically expressed in different regions of the brain. The tissue-specific splice variants of NCX1-3 isoforms show specific expression profiles in neurons and astrocytes, whereas the relevant NCX isoform/splice variants exhibit diverse allosteric modes of Na+- and Ca2+-dependent regulation. In general, overexpression of NCX1-3 genes leads to neuroprotective effects, whereas their ablation gains the opposite results. At this end, the partial contributions of NCX isoform/splice variants to neuroprotective effects remain unresolved. The glutamate-dependent Na+ entry generates Na+ transients (in response to neuronal cell activities), whereas the Na+-driven Ca2+ entry (through the reverse NCX mode) raises Ca2+ transients. This special mode of signal coupling translates Na+ transients into the Ca2+ signals while being a part of synaptic neurotransmission. This mechanism is of general interest since disease-related conditions (ischemia, metabolic stress, and stroke among many others) trigger Na+ and Ca2+ overload with deadly outcomes of downstream apoptosis and excitotoxicity. The recently discovered mechanisms of NCX allosteric regulation indicate that some NCX variants might play a critical role in the dynamic coupling of Na+-driven Ca2+ entry. In contrast, the others are less important or even could be dangerous under altered conditions (e.g., metabolic stress). This working hypothesis can be tested by applying advanced experimental approaches and highly focused computational simulations. This may allow the development of structure-based blockers/activators that can selectively modulate predefined NCX variants to lessen the life-threatening outcomes of excitotoxicity, ischemia, apoptosis, metabolic deprivation, brain injury, and stroke.
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Affiliation(s)
- Daniel Khananshvili
- Department of Physiology and Pharmacology, Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel.
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13
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Zhang L, Zhou T, Su Y, He L, Wang Z. Involvement of histone methylation in the regulation of neuronal death. J Physiol Biochem 2023; 79:685-693. [PMID: 37544979 DOI: 10.1007/s13105-023-00978-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 07/31/2023] [Indexed: 08/08/2023]
Abstract
Neuronal death occurs in various physiological and pathological processes, and apoptosis, necrosis, and ferroptosis are three major forms of neuronal death. Neuronal apoptosis, necrosis, and ferroptosis are widely identified to involve the progress of stroke, Parkinson's disease, and Alzheimer's disease. A growing body of evidence has pointed out that neuronal death is tightly associated with expression of related genes and alteration of signaling molecules. In addition, recently, epigenetics has been increasingly focused on as a vital regulatory mechanism for neuronal apoptosis, necrosis, and ferroptosis, providing a new direction for treating nervous system diseases. Moreover, growing researches suggest that histone methylation or demethylation is involved in the processes of neuronal apoptosis, necrosis, and ferroptosis. These researches may imply that studying the potential roles of histone methylation is essential for treating the nervous system diseases. Here, we review potential roles of histone methylation and demethylation in neuronal death, which may give us a new direction in treating the nervous system diseases.
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Affiliation(s)
- Lei Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, China
| | - Tai Zhou
- Department of Pathophysiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, China
| | - Yaxin Su
- Department of Pathophysiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, China
| | - Li He
- Department of Pathophysiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, China
| | - Zhongcheng Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, China.
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14
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Hua T, Robitaille M, Roberts-Thomson SJ, Monteith GR. The intersection between cysteine proteases, Ca 2+ signalling and cancer cell apoptosis. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119532. [PMID: 37393017 DOI: 10.1016/j.bbamcr.2023.119532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/19/2023] [Accepted: 06/26/2023] [Indexed: 07/03/2023]
Abstract
Apoptosis is a highly complex and regulated cell death pathway that safeguards the physiological balance between life and death. Over the past decade, the role of Ca2+ signalling in apoptosis and the mechanisms involved have become clearer. The initiation and execution of apoptosis is coordinated by three distinct groups of cysteines proteases: the caspase, calpain and cathepsin families. Beyond its physiological importance, the ability to evade apoptosis is a prominent hallmark of cancer cells. In this review, we will explore the involvement of Ca2+ in the regulation of caspase, calpain and cathepsin activity, and how the actions of these cysteine proteases alter intracellular Ca2+ handling during apoptosis. We will also explore how apoptosis resistance can be achieved in cancer cells through deregulation of cysteine proteases and remodelling of the Ca2+ signalling toolkit.
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Affiliation(s)
- Trinh Hua
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia.
| | - Mélanie Robitaille
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia.
| | | | - Gregory R Monteith
- School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia; Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia.
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15
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Sanghai N, Tranmer GK. Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View. Cells 2023; 12:2318. [PMID: 37759540 PMCID: PMC10527779 DOI: 10.3390/cells12182318] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/05/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are defined by a myriad of complex aetiologies. Understanding the common biochemical molecular pathologies among NDDs gives an opportunity to decipher the overlapping and numerous cross-talk mechanisms of neurodegeneration. Numerous interrelated pathways lead to the progression of neurodegeneration. We present evidence from the past pieces of literature for the most usual global convergent hallmarks like ageing, oxidative stress, excitotoxicity-induced calcium butterfly effect, defective proteostasis including chaperones, autophagy, mitophagy, and proteosome networks, and neuroinflammation. Herein, we applied a holistic approach to identify and represent the shared mechanism across NDDs. Further, we believe that this approach could be helpful in identifying key modulators across NDDs, with a particular focus on AD, PD, and ALS. Moreover, these concepts could be applied to the development and diagnosis of novel strategies for diverse NDDs.
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Affiliation(s)
- Nitesh Sanghai
- College of Pharmacy, Rady Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0T5, Canada;
| | - Geoffrey K. Tranmer
- College of Pharmacy, Rady Faculty of Health Science, University of Manitoba, Winnipeg, MB R3E 0T5, Canada;
- Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
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16
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Vergnes L, Foucaud B, Cepeda C, Espinosa-Jeffrey A. Metabolomics Profile of the Secretome of Space-Flown Oligodendrocytes. Cells 2023; 12:2249. [PMID: 37759473 PMCID: PMC10528075 DOI: 10.3390/cells12182249] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/06/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Intracranial hypertension (ICP) and visual impairment intracranial pressure (VIIP) are some of the sequels of long-term space missions. Here we sought to determine how space microgravity (µG) impacts the metabolomics profile of oligodendrocyte progenitors (OLPs), the myelin-forming cells in the central nervous system. We report increased glutamate and energy metabolism while the OLPs were in space for 26 days. We also show that after space flight, OLPs (SPC OLPs) display significantly increased mitochondrial respiration and glycolysis. These data are in agreement with our previous work using simulated microgravity. In addition, our global metabolomics approach allowed for the discovery of endogenous metabolites secreted by OLPs while in space that are significantly modulated by microgravity. Our results provide, for the first time, relevant information about the energetic state of OLPs while in space and after space flight. The functional and molecular relevance of these specific pathways are promising targets for therapeutic intervention for humans in long-term space missions to the moon, Mars and beyond.
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Affiliation(s)
- Laurent Vergnes
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA;
| | - Bernard Foucaud
- Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA; (B.F.); (C.C.)
| | - Carlos Cepeda
- Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA; (B.F.); (C.C.)
| | - Araceli Espinosa-Jeffrey
- Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA; (B.F.); (C.C.)
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17
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Preziuso A, Piccirillo S, Cerqueni G, Serfilippi T, Terenzi V, Vinciguerra A, Orciani M, Amoroso S, Magi S, Lariccia V. Exploring the Role of NCX1 and NCX3 in an In Vitro Model of Metabolism Impairment: Potential Neuroprotective Targets for Alzheimer's Disease. BIOLOGY 2023; 12:1005. [PMID: 37508434 PMCID: PMC10376230 DOI: 10.3390/biology12071005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/10/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023]
Abstract
Alzheimer's disease (AD) is a widespread neurodegenerative disorder, affecting a large number of elderly individuals worldwide. Mitochondrial dysfunction, metabolic alterations, and oxidative stress are regarded as cooperating drivers of the progression of AD. In particular, metabolic impairment amplifies the production of reactive oxygen species (ROS), resulting in detrimental alterations to intracellular Ca2+ regulatory processes. The Na+/Ca2+ exchanger (NCX) proteins are key pathophysiological determinants of Ca2+ and Na+ homeostasis, operating at both the plasma membrane and mitochondria levels. Our study aimed to explore the role of NCX1 and NCX3 in retinoic acid (RA) differentiated SH-SY5Y cells treated with glyceraldehyde (GA), to induce impairment of the default glucose metabolism that typically precedes Aβ deposition or Tau protein phosphorylation in AD. By using an RNA interference-mediated approach to silence either NCX1 or NCX3 expression, we found that, in GA-treated cells, the knocking-down of NCX3 ameliorated cell viability, increased the intracellular ATP production, and reduced the oxidative damage. Remarkably, NCX3 silencing also prevented the enhancement of Aβ and pTau levels and normalized the GA-induced decrease in NCX reverse-mode activity. By contrast, the knocking-down of NCX1 was totally ineffective in preventing GA-induced cytotoxicity except for the increase in ATP synthesis. These findings indicate that NCX3 and NCX1 may differently influence the evolution of AD pathology fostered by glucose metabolic dysfunction, thus providing a potential target for preventing AD.
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Affiliation(s)
- Alessandra Preziuso
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Silvia Piccirillo
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Giorgia Cerqueni
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Tiziano Serfilippi
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Valentina Terenzi
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Antonio Vinciguerra
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Monia Orciani
- Department of Clinical and Molecular Sciences-Histology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Salvatore Amoroso
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Simona Magi
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
| | - Vincenzo Lariccia
- Department of Biomedical Sciences and Public Health-Pharmacology, School of Medicine, University "Politecnica delle Marche", Via Tronto 10/A, 60126 Ancona, Italy
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18
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Li MC, Tian Q, Liu S, Han SM, Zhang W, Qin XY, Chen JH, Liu CL, Guo YJ. The mechanism and relevant mediators associated with neuronal apoptosis and potential therapeutic targets in subarachnoid hemorrhage. Neural Regen Res 2023; 18:244-252. [PMID: 35900398 PMCID: PMC9396483 DOI: 10.4103/1673-5374.346542] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Subarachnoid hemorrhage (SAH) is a dominant cause of death and disability worldwide. A sharp increase in intracranial pressure after SAH leads to a reduction in cerebral perfusion and insufficient blood supply for neurons, which subsequently promotes a series of pathophysiological responses leading to neuronal death. Many previous experimental studies have reported that excitotoxicity, mitochondrial death pathways, the release of free radicals, protein misfolding, apoptosis, necrosis, autophagy, and inflammation are involved solely or in combination in this disorder. Among them, irreversible neuronal apoptosis plays a key role in both short- and long-term prognoses after SAH. Neuronal apoptosis occurs through multiple pathways including extrinsic, mitochondrial, endoplasmic reticulum, p53 and oxidative stress. Meanwhile, a large number of blood contents enter the subarachnoid space after SAH, and the secondary metabolites, including oxygenated hemoglobin and heme, further aggravate the destruction of the blood-brain barrier and vasogenic and cytotoxic brain edema, causing early brain injury and delayed cerebral ischemia, and ultimately increasing neuronal apoptosis. Even there is no clear and effective therapeutic strategy for SAH thus far, but by understanding apoptosis, we might excavate new ideas and approaches, as targeting the upstream and downstream molecules of apoptosis-related pathways shows promise in the treatment of SAH. In this review, we summarize the existing evidence on molecules and related drugs or molecules involved in the apoptotic pathway after SAH, which provides a possible target or new strategy for the treatment of SAH.
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19
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Mikhailova MM, Surin AM, Sobolevsky A, Yelshanskaya M, Bolshakov AP. Boris Izrailevich Khodorov: Scientist and Teacher. NEUROCHEM J+ 2022. [DOI: 10.1134/s1819712422040171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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20
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Song JL, Westover MB, Zhang R. A mechanistic model of calcium homeostasis leading to occurrence and propagation of secondary brain injury. J Neurophysiol 2022; 128:1168-1180. [PMID: 36197012 PMCID: PMC9621713 DOI: 10.1152/jn.00045.2022] [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: 02/08/2022] [Revised: 09/13/2022] [Accepted: 09/27/2022] [Indexed: 11/22/2022] Open
Abstract
Secondary brain injury (SBI) refers to new or worsening brain insult after primary brain injury (PBI). Neurophysiological experiments show that calcium (Ca2+) is one of the major culprits that contribute to neuronal damage and death following PBI. However, mechanistic details about how alterations of Ca2+ levels contribute to SBI are not well characterized. In this paper, we first build a biophysical model for SBI related to calcium homeostasis (SBI-CH) to study the mechanistic details of PBI-induced disruption of CH, and how these disruptions affect the occurrence of SBI. Then, we construct a coupled SBI-CH model by formulating synaptic interactions to investigate how disruption of CH affects synaptic function and further promotes the propagation of SBI between neurons. Our model shows how the opening of voltage-gated calcium channels (VGCCs), decreasing of plasma membrane calcium pump (PMCA), and reversal of the Na+/Ca2+ exchanger (NCX) during and following PBI, could induce disruption of CH and further promote SBI. We also show that disruption of CH causes synaptic dysfunction, which further induces loss of excitatory-inhibitory balance in the system, and this might promote the propagation of SBI and cause neighboring tissue to be injured. Our findings offer a more comprehensive understanding of the complex interrelationship between CH and SBI.NEW & NOTEWORTHY We build a mechanistic model SBI-CH for calcium homeostasis (CH) to study how alterations of Ca2+ levels following PBI affect the occurrence and propagation of SBI. Specifically, we investigate how the opening of VGCCs, decreasing of PMCA, and reversal of NCX disrupt CH, and further induce the occurrence of SBI. We also present a coupled SBI-CH model to show how disrupted CH causes synaptic dysfunction, and further promotes the propagation of SBI between neurons.
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Affiliation(s)
- Jiang-Ling Song
- The Medical Big Data Research Center, Northwest University, Xi'an, People's Republic of China
| | - M Brandon Westover
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Rui Zhang
- The Medical Big Data Research Center, Northwest University, Xi'an, People's Republic of China
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21
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Cunningham ME, McGonigal R, Barrie JA, Yao D, Willison HJ. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol 2022; 355:114127. [PMID: 35640716 PMCID: PMC7614209 DOI: 10.1016/j.expneurol.2022.114127] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/12/2022] [Accepted: 05/26/2022] [Indexed: 11/19/2022]
Abstract
The acute motor axonal variant of Guillain-Barré syndrome is associated with the attack of motor axons by anti-ganglioside antibodies which activate complement on the axonal plasma membrane. Animal models have indirectly implicated complement pore-mediated calcium influx as a trigger of axonal damage, through the activation of the protease calpain. However, this calcium influx has never been imaged directly. Herein we describe a method to detect changes in intra-axonal calcium in an ex vivo mouse model of axonal Guillain-Barré syndrome and describe the influence of calcium on axonal injury and the effects of calpain inhibition on axonal outcome. Using ex vivo nerve-muscle explants from Thy1-TNXXL mice which axonally express a genetically encoded calcium indicator, we studied the effect of the binding and activation of complement by an anti-GD1b ganglioside antibody which targets the motor axon. Using live multiphoton imaging, we found that a wave of calcium influx extends retrogradely from the motor nerve terminal as far back as the large bundles within the muscle explant. Despite terminal complement pores being detectable only at the motor nerve terminal and, to a lesser degree, the most distal node of Ranvier, disruption of axonal proteins occurred at more proximal sites implicating the intra-axonal calcium wave. Morphological analysis indicated two different types of calcium-induced changes: acutely, distal axons showed swelling and breakdown at sites where complement pores were present. Distally, in areas of raised calcium which lacked detectable complement pores, axons developed a spindly, vacuolated appearance suggestive of early signs of degeneration. All morphological changes were prevented with treatment with a calpain inhibitor. This is the first investigation of axonal calcium dynamics in a mouse model of Guillain-Barré syndrome and demonstrates the proximal reach of calcium influx following an injury which is confined to the most distal parts of the motor axon. We also demonstrate that calpain inhibition remains a promising candidate for both acute and sub-acute consequences of calcium-induced calpain activation.
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Affiliation(s)
- Madeleine E Cunningham
- Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Rhona McGonigal
- Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Jennifer A Barrie
- Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Denggao Yao
- Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Hugh J Willison
- Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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22
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Juibari AD, Rezadoost MH, Soleimani M. The key role of Calpain in COVID-19 as a therapeutic strategy. Inflammopharmacology 2022; 30:1479-1491. [PMID: 35635676 PMCID: PMC9149670 DOI: 10.1007/s10787-022-01002-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/24/2022] [Indexed: 12/02/2022]
Abstract
COVID-19 is one of the viral diseases that has caused many deaths and financial losses to humans. Using the available information, this virus appears to activate the host cell-death mechanism through Calpain activation. Calpain inhibition can stop its downstream cascade reactions that cause cell death. Given the main roles of Calpain in the entry and pathogenicity of the SARS-CoV-2, its inhibition can be effective in controlling the COVID-19. This review describes how the virus activates Calpain by altering calcium flow. When Calpain was activated, the virus can enter the target cell. Subsequently, many complications of the disease, such as inflammation, cytokine storm and pulmonary fibrosis, are caused by virus-activated Calpain function. Calpain inhibitors appear to be a potential drug to control the disease and prevent death from COVID-19.
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Affiliation(s)
- Aref Doozandeh Juibari
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran
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23
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Reza RN, Serra ND, Detwiler AC, Hanna-Rose W, Crook M. Noncanonical necrosis in 2 different cell types in a Caenorhabditis elegans NAD+ salvage pathway mutant. G3 (BETHESDA, MD.) 2022; 12:jkac033. [PMID: 35143646 PMCID: PMC8982427 DOI: 10.1093/g3journal/jkac033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 01/27/2022] [Indexed: 11/17/2022]
Abstract
Necrosis was once described as a chaotic unregulated response to cellular insult. We now know that necrosis is controlled by multiple pathways in response to many different cellular conditions. In our pnc-1 NAD+ salvage deficient Caenorhabditis elegans model excess nicotinamide induces excitotoxic death in uterine-vulval uv1 cells and OLQ mechanosensory neurons. We sought to characterize necrosis in our pnc-1 model in the context of well-characterized necrosis, apoptosis, and autophagy pathways in C. elegans. We confirmed that calpain and aspartic proteases were required for uv1 necrosis, but changes in intracellular calcium levels and autophagy were not, suggesting that uv1 necrosis occurs by a pathway that diverges from mec-4d-induced touch cell necrosis downstream of effector aspartic proteases. OLQ necrosis does not require changes in intracellular calcium, the function of calpain or aspartic proteases, or autophagy. Instead, OLQ survival requires the function of calreticulin and calnexin, pro-apoptotic ced-4 (Apaf1), and genes involved in both autophagy and axon guidance. In addition, the partially OLQ-dependent gentle nose touch response decreased significantly in pnc-1 animals on poor quality food, further suggesting that uv1 and OLQ necrosis differ downstream of their common trigger. Together these results show that, although phenotypically very similar, uv1, OLQ, and touch cell necrosis are very different at the molecular level.
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Affiliation(s)
- Rifath N Reza
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Nicholas D Serra
- Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ariana C Detwiler
- Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA
| | - Wendy Hanna-Rose
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Matt Crook
- Department of Life Sciences, Texas A&M University-San Antonio, San Antonio, TX 78224, USA
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24
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Zhang C, Wang X, He J, Huang Y, Huang Q, Qin C, Qin J, Chen L. Neural excitotoxicity and the toxic mechanism induced by acute hypoxia in Chinese mitten crab (Eriocheir sinensis). AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2022; 245:106131. [PMID: 35255275 DOI: 10.1016/j.aquatox.2022.106131] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 02/05/2022] [Accepted: 02/27/2022] [Indexed: 06/14/2023]
Abstract
Hypoxia can induce neural excitotoxicity in mammals, but this adverse effect has not been investigated in aquatic animals to date, especially in crustaceans. This study explored the induction effect and toxic mechanism of acute hypoxia stress (1.0 ± 0.1 mg dissolved oxygen /L) for 24 h on neural excitotoxicity in juvenile Chinese mitten crab, Eriocheir sinensis. The results showed that hemolymph glucose and serum lactic acid content were significantly increased, and the mRNA expression of crustacean hyperglycemic hormone and hypoxia-inducible factor 1α were significantly up-regulated in the hypoxia group compared with control. RNA-Seq results confirmed that acute hypoxia stress had a more significant impact on carbohydrate metabolism than lipid and protein metabolism. In addition, the TUNEL assay showed that the apoptosis rate of nerve cells was significantly higher in the hypoxia group than in the control, and similar trends were observed in the expression of apoptosis-related genes. RNA-Seq results also showed that acute hypoxia stress-induced neuronal apoptosis by regulating multiple apoptosis-related pathways. Moreover, free glutamate and GABA contents in the nerve tissue of thoracic ganglia were significantly higher in the hypoxia group than in the control group. Furthermore, the mRNA expression of NMDA related receptors was significantly up-regulated in the hypoxia group compared with the control. Similar trends were observed in the expression of calcium-dependent degrading enzymes and endogenous antioxidant-related proteins or enzymes. Meanwhile, the mRNA expression level of high-affinity neuronal glutamate transporter in the hypoxia group was significantly up-regulated compared with the control, whereas the vesicular glutamate transporter was significantly down-regulated. Furthermore, NMDA-R antagonists (MK-801 and Ro25-6981) injection showed that NMDA-R served as the bridge and core position of glutamate-induced neural neurotoxicity. This study provides a new perspective and theoretical guidance for exploring the regulation of hypoxic tolerance in E. sinensis.
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Affiliation(s)
- Cong Zhang
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China
| | - Xiaodan Wang
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China
| | - Jiaqi He
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China
| | - Yuxing Huang
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China
| | - Qincheng Huang
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China
| | - Chuanjie Qin
- Key Laboratory of Sichuan Province for Fishes Conservation and Utilization in the Upper Reaches of the Yangtze River, Neijiang Normal University, Sichuan, 641100, PR China
| | - Jianguang Qin
- College of Science and Engineering, Flinders University, Adelaide, SA, 5001, Australia
| | - Liqiao Chen
- Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China.
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25
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Che Mohd Nassir CMN, Zolkefley MKI, Ramli MD, Norman HH, Abdul Hamid H, Mustapha M. Neuroinflammation and COVID-19 Ischemic Stroke Recovery—Evolving Evidence for the Mediating Roles of the ACE2/Angiotensin-(1–7)/Mas Receptor Axis and NLRP3 Inflammasome. Int J Mol Sci 2022; 23:ijms23063085. [PMID: 35328506 PMCID: PMC8949282 DOI: 10.3390/ijms23063085] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/18/2022] [Accepted: 02/23/2022] [Indexed: 12/17/2022] Open
Abstract
Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1–7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.
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Affiliation(s)
- Che Mohd Nasril Che Mohd Nassir
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
- Correspondence: (C.M.N.C.M.N.); (M.M.)
| | - Mohd K. I. Zolkefley
- Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, Gambang Kuantan 26300, Pahang, Malaysia;
| | - Muhammad Danial Ramli
- Department of Diagnostic and Allied Health Science, Management and Science University (MSU), Shah Alam 40100, Selangor, Malaysia;
| | - Haziq Hazman Norman
- Anatomy Unit, International Medical School (IMS), Management and Science University (MSU), Shah Alam 40100, Selangor, Malaysia;
| | - Hafizah Abdul Hamid
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Selangor, Malaysia;
| | - Muzaimi Mustapha
- Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, Gambang Kuantan 26300, Pahang, Malaysia;
- Hospital Universiti Sains Malaysia, Jalan Raja Perempuan Zainab II, Kubang Kerian 16150, Kelantan, Malaysia
- Correspondence: (C.M.N.C.M.N.); (M.M.)
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26
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Multiparametric monitoring of early pathophysiological changes in a porcine model of sequential focal and global cerebral ischemia. World Neurosurg 2022; 161:e473-e481. [DOI: 10.1016/j.wneu.2022.02.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 02/10/2022] [Indexed: 11/23/2022]
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27
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Chen S, Xu D, Fan L, Fang Z, Wang X, Li M. Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy. Front Mol Neurosci 2022; 14:797253. [PMID: 35069111 PMCID: PMC8780133 DOI: 10.3389/fnmol.2021.797253] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Epilepsy is one of the most common neurological disorders characterized by recurrent seizures. The mechanism of epilepsy remains unclear and previous studies suggest that N-methyl-D-aspartate receptors (NMDARs) play an important role in abnormal discharges, nerve conduction, neuron injury and inflammation, thereby they may participate in epileptogenesis. NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. Despite numerous studies focusing on the role of NMDAR in epilepsy, the relationship appeared to be elusive. In this article, we reviewed the regulation of NMDAR and possible mechanisms of NMDAR in epilepsy and in respect of onset, development, and treatment, trying to provide more evidence for future studies.
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Affiliation(s)
| | | | | | | | | | - Man Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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28
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Calpain Inhibitors as Potential Therapeutic Modulators in Neurodegenerative Diseases. Neurochem Res 2022; 47:1125-1149. [PMID: 34982393 DOI: 10.1007/s11064-021-03521-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023]
Abstract
It is considered a significant challenge to understand the neuronal cell death mechanisms with a suitable cure for neurodegenerative disorders in the coming years. Calpains are one of the best-considered "cysteine proteases activated" in brain disorders. Calpain is an important marker and mediator in the pathophysiology of neurodegeneration. Calpain activation being the essential neurodegenerative factor causing apoptotic machinery activation, it is crucial to develop reliable and effective approaches to prevent calpain-mediated apoptosis in degenerating neurons. It has been recently seen that the "inhibition of calpain activation" has appeared as a possible therapeutic target for managing neurodegenerative diseases. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was conducted. The present article reviews the basic pathobiology and role of selective calpain inhibitors used in various neurodegenerative diseases as a therapeutic target.
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29
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Ottolia M, John S, Hazan A, Goldhaber JI. The Cardiac Na + -Ca 2+ Exchanger: From Structure to Function. Compr Physiol 2021; 12:2681-2717. [PMID: 34964124 DOI: 10.1002/cphy.c200031] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Ca2+ homeostasis is essential for cell function and survival. As such, the cytosolic Ca2+ concentration is tightly controlled by a wide number of specialized Ca2+ handling proteins. One among them is the Na+ -Ca2+ exchanger (NCX), a ubiquitous plasma membrane transporter that exploits the electrochemical gradient of Na+ to drive Ca2+ out of the cell, against its concentration gradient. In this critical role, this secondary transporter guides vital physiological processes such as Ca2+ homeostasis, muscle contraction, bone formation, and memory to name a few. Herein, we review the progress made in recent years about the structure of the mammalian NCX and how it relates to function. Particular emphasis will be given to the mammalian cardiac isoform, NCX1.1, due to the extensive studies conducted on this protein. Given the degree of conservation among the eukaryotic exchangers, the information highlighted herein will provide a foundation for our understanding of this transporter family. We will discuss gene structure, alternative splicing, topology, regulatory mechanisms, and NCX's functional role on cardiac physiology. Throughout this article, we will attempt to highlight important milestones in the field and controversial topics where future studies are required. © 2021 American Physiological Society. Compr Physiol 12:1-37, 2021.
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Affiliation(s)
- Michela Ottolia
- Department of Anesthesiology and Perioperative Medicine, Division of Molecular Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Scott John
- Department of Medicine (Cardiology), UCLA, Los Angeles, California, USA
| | - Adina Hazan
- Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Joshua I Goldhaber
- Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California, USA
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30
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Rosarda J, Baron KR, Nutsch K, Kline GM, Stanton C, Kelly JW, Bollong MJ, Wiseman RL. Metabolically Activated Proteostasis Regulators Protect against Glutamate Toxicity by Activating NRF2. ACS Chem Biol 2021; 16:2852-2863. [PMID: 34797633 PMCID: PMC8689639 DOI: 10.1021/acschembio.1c00810] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 10/29/2021] [Indexed: 12/11/2022]
Abstract
The extracellular accumulation of glutamate is a pathologic hallmark of numerous neurodegenerative diseases including ischemic stroke and Alzheimer's disease. At high extracellular concentrations, glutamate causes neuronal damage by promoting oxidative stress, which can lead to cellular death. This has led to significant interest in developing pharmacologic approaches to mitigate the oxidative toxicity caused by high levels of glutamate. Here, we show that the small molecule proteostasis regulator AA147 protects against glutamate-induced cell death in a neuronal-derived cell culture model. While originally developed as an activator of the activating transcription factor 6 (ATF6) arm of the unfolded protein response, this AA147-dependent protection against glutamate toxicity is primarily mediated through activation of the NRF2-regulated oxidative stress response. We demonstrate that AA147 activates NRF2 selectively in neuronal-derived cells through a mechanism involving metabolic activation to a reactive electrophile and covalent modification of KEAP1─a mechanism analogous to that involved in the AA147-dependent activation of ATF6. These results define the potential for AA147 to protect against glutamate-induced oxidative toxicity and highlight the potential for metabolically activated proteostasis regulators like AA147 to activate both protective ATF6 and NRF2 stress-responsive signaling pathways to mitigate oxidative damage associated with diverse neurologic diseases.
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Affiliation(s)
- Jessica
D. Rosarda
- Department
of Molecular Medicine, The Scripps Research
Institute, La Jolla, California 92037, United States
| | - Kelsey R. Baron
- Department
of Molecular Medicine, The Scripps Research
Institute, La Jolla, California 92037, United States
| | - Kayla Nutsch
- Department
of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
| | - Gabriel M. Kline
- Department
of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
- The
Skaggs Institute for Chemical Biology, The
Scripps Research Institute, La
Jolla, California 92037, United States
| | - Caroline Stanton
- Department
of Molecular Medicine, The Scripps Research
Institute, La Jolla, California 92037, United States
- Department
of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
| | - Jeffery W. Kelly
- Department
of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
- The
Skaggs Institute for Chemical Biology, The
Scripps Research Institute, La
Jolla, California 92037, United States
| | - Michael J. Bollong
- Department
of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States
| | - R. Luke Wiseman
- Department
of Molecular Medicine, The Scripps Research
Institute, La Jolla, California 92037, United States
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31
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Singer T, Ding S, Ding S. Astroglia Abnormalities in Post-stroke Mood Disorders. ADVANCES IN NEUROBIOLOGY 2021; 26:115-138. [PMID: 34888833 DOI: 10.1007/978-3-030-77375-5_6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Stroke is the leading cause of human death and disability. After a stroke, many patients may have some physical disability, including difficulties in moving, speaking, and seeing, but patients may also exhibit changes in mood manifested by depression, anxiety, and cognitive changes which we call post-stroke mood disorders (PSMDs). Astrocytes are the most diverse and numerous glial cell type in the central nervous system (CNS). They provide structural, nutritional, and metabolic support to neurons and regulate synaptic activity under normal conditions. Astrocytes are also critically involved in focal ischemic stroke (FIS). They undergo many changes after FIS. These changes may affect acute neuronal death and brain damage as well as brain recovery and PSMD in the chronic phase after FIS. Studies using postmortem brain specimens and animal models of FIS suggest that astrocytes/reactive astrocytes are involved in PSMD. This chapter provides an overview of recent advances in the molecular base of astrocyte in PSMD. As astrocytes exhibit high plasticity after FIS, we suggest that targeting local astrocytes may be a promising strategy for PSMD therapy.
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Affiliation(s)
- Tracey Singer
- Dalton Cardiovascular Research Center, Columbia, MO, USA
| | - Sarah Ding
- Dalton Cardiovascular Research Center, Columbia, MO, USA
| | - Shinghua Ding
- Dalton Cardiovascular Research Center, Columbia, MO, USA.
- Department of Biomedical, Biological and Chemical Engineering, University of Missouri, Columbia, MO, USA.
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32
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Cammarota M, de Rosa V, Pannaccione A, Secondo A, Tedeschi V, Piccialli I, Fiorino F, Severino B, Annunziato L, Boscia F. Rebound effects of NCX3 pharmacological inhibition: A novel strategy to accelerate myelin formation in oligodendrocytes. Biomed Pharmacother 2021; 143:112111. [PMID: 34481380 DOI: 10.1016/j.biopha.2021.112111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/20/2021] [Accepted: 08/23/2021] [Indexed: 11/18/2022] Open
Abstract
The Na+/Ca2+ exchanger NCX3 is an important regulator of sodium and calcium homeostasis in oligodendrocyte lineage. To date, no information is available on the effects resulting from prolonged exposure to NCX3 blockers and subsequent drug washout in oligodendroglia. Here, we investigated, by means of biochemical, morphological and functional analyses, the pharmacological effects of the NCX3 inhibitor, the 5-amino-N-butyl-2-(4-ethoxyphenoxy)-benzamide hydrochloride (BED), on NCXs expression and activity, as well as intracellular [Na+]i and [Ca2+]i levels, during treatment and following drug washout both in human MO3.13 oligodendrocytes and rat primary oligodendrocyte precursor cells (OPCs). BED exposure antagonized NCX activity, induced OPCs proliferation and [Na+]i accumulation. By contrast, 2 days of BED washout after 4 days of treatment significantly upregulated low molecular weight NCX3 proteins, reversed NCX activity, and increased intracellular [Ca2+]i. This BED-free effect was accompanied by an upregulation of NCX3 expression in oligodendrocyte processes and accelerated expression of myelin markers in rat primary oligodendrocytes. Collectively, our findings show that the pharmacological inhibition of the NCX3 exchanger with BED blocker maybe followed by a rebound increase in NCX3 expression and reversal activity that accelerate myelin sheet formation in oligodendrocytes. In addition, they indicate that a particular attention should be paid to the use of NCX inhibitors for possible rebound effects, and suggest that further studies will be necessary to investigate whether selective pharmacological modulation of NCX3 exchanger may be exploited to benefit demyelination and remyelination in demyelinating diseases.
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Affiliation(s)
- Mariarosaria Cammarota
- Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Valeria de Rosa
- Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Anna Pannaccione
- Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Agnese Secondo
- Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Valentina Tedeschi
- Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, Federico II University of Naples, Naples, Italy
| | - Ilaria Piccialli
- Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, Federico II University of Naples, Naples, Italy
| | | | - Beatrice Severino
- Department of Pharmacy, Federico II University of Naples, Naples, Italy
| | | | - Francesca Boscia
- Division of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, Federico II University of Naples, Naples, Italy.
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33
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Schultz B, Taday J, Menezes L, Cigerce A, Leite MC, Gonçalves CA. Calpain-Mediated Alterations in Astrocytes Before and During Amyloid Chaos in Alzheimer's Disease. J Alzheimers Dis 2021; 84:1415-1430. [PMID: 34719501 DOI: 10.3233/jad-215182] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
One of the changes found in the brain in Alzheimer's disease (AD) is increased calpain, derived from calcium dysregulation, oxidative stress, and/or neuroinflammation, which are all assumed to be basic pillars in neurodegenerative diseases. The role of calpain in synaptic plasticity, neuronal death, and AD has been discussed in some reviews. However, astrocytic calpain changes sometimes appear to be secondary and consequent to neuronal damage in AD. Herein, we explore the possibility of calpain-mediated astroglial reactivity in AD, both preceding and during the amyloid phase. We discuss the types of brain calpains but focus the review on calpains 1 and 2 and some important targets in astrocytes. We address the signaling involved in controlling calpain expression, mainly involving p38/mitogen-activated protein kinase and calcineurin, as well as how calpain regulates the expression of proteins involved in astroglial reactivity through calcineurin and cyclin-dependent kinase 5. Throughout the text, we have tried to provide evidence of the connection between the alterations caused by calpain and the metabolic changes associated with AD. In addition, we discuss the possibility that calpain mediates amyloid-β clearance in astrocytes, as opposed to amyloid-β accumulation in neurons.
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Affiliation(s)
- Bruna Schultz
- Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Jéssica Taday
- Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Leonardo Menezes
- Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Anderson Cigerce
- Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Marina C Leite
- Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Carlos-Alberto Gonçalves
- Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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34
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Oikonomou KD, Donzis EJ, Bui MTN, Cepeda C, Levine MS. Calcium dysregulation and compensation in cortical pyramidal neurons of the R6/2 mouse model of Huntington's disease. J Neurophysiol 2021; 126:1159-1171. [PMID: 34469694 DOI: 10.1152/jn.00181.2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Huntington's disease (HD) is a fatal, hereditary neurodegenerative disorder that predominantly affects striatal medium-sized spiny neurons and cortical pyramidal neurons (CPNs). It has been proposed that perturbations in Ca2+ homeostasis could play a role in CPN alterations. To test this hypothesis, we used the R6/2 mouse model of juvenile HD at different stages of disease progression; presymptomatic, early symptomatic, and late symptomatic. We combined whole-cell patch-clamp recordings of layer 2/3 CPNs with two-photon laser scanning microscopy to image somatic and dendritic Ca2+ transients associated with evoked action potentials (APs). We found that the amplitude of AP-induced Ca2+ transients recorded at the somata of CPNs was significantly reduced in presymptomatic and late symptomatic R6/2 mice compared with wild-type (WT) littermates. However, reduced amplitudes were compensated by increases in decay times, so that Ca2+ transient areas were similar between genotypes. AP-induced Ca2+ transients in CPN proximal dendrites were variable and differences did not reach statistical significance, except for reduced areas in the late symptomatic group. In late symptomatic mice, a specific store-operated Ca2+ channel antagonist, EVP4593, reduced somatic Ca2+ transient amplitude similarly in WT and R6/2 CPNs. In contrast, dantrolene, a ryanodine receptor (RyR) antagonist, and nifedipine, an L-type Ca2+ channel blocker, significantly reduced both somatic Ca2+ transient amplitude and area in R6/2 but not WT CPNs. These findings demonstrate that perturbations of Ca2+ homeostasis and compensation occur in CPNs before and after the onset of overt symptoms, and suggest RyRs and L-type Ca2+ channels as potential targets for therapeutic intervention.NEW & NOTEWORTHY We used two-photon microscopy to examine calcium influx induced by action potentials in cortical pyramidal neurons from a mouse model of Huntington's disease (HD), the R6/2. The amplitude of somatic calcium transients was reduced in R6/2 mice compared with controls. This reduction was compensated by increased decay times, which could lead to reduced calcium buffering capacity. L-type calcium channel and ryanodine receptor blockers reduced calcium transient area in HD neurons, suggesting new therapeutic avenues.
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Affiliation(s)
- Katerina D Oikonomou
- IDDRC, Semel Institute for Neuroscience and Human Behavior, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
| | - Elissa J Donzis
- IDDRC, Semel Institute for Neuroscience and Human Behavior, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
| | - Minh T N Bui
- IDDRC, Semel Institute for Neuroscience and Human Behavior, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
| | - Carlos Cepeda
- IDDRC, Semel Institute for Neuroscience and Human Behavior, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
| | - Michael S Levine
- IDDRC, Semel Institute for Neuroscience and Human Behavior, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
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35
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Metwally E, Zhao G, Zhang YQ. The calcium-dependent protease calpain in neuronal remodeling and neurodegeneration. Trends Neurosci 2021; 44:741-752. [PMID: 34417060 DOI: 10.1016/j.tins.2021.07.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/04/2021] [Accepted: 07/06/2021] [Indexed: 12/30/2022]
Abstract
Calpains are evolutionarily conserved and widely expressed Ca2+-activated cysteine proteases that act at neutral pH. The activity of calpains is tightly regulated, given that their abnormal activation can have deleterious effects leading to promiscuous cleavage of various targets. Genetic mutations in the genes encoding calpains are associated with human diseases, while abnormally elevated Ca2+ levels promote Ca2+-dependent calpain activation in pathologies associated with ischemic insults and neurodegeneration. In this review, we discuss recent findings on the regulation of calpain activity and activation as revealed through pharmacological, genetic, and optogenetic approaches. Furthermore, we highlight studies elucidating the role of calpains in dendrite pruning and axon degeneration in the context of Ca2+ homeostasis. Finally, we discuss future directions for the study of calpains and potential therapeutic strategies for inhibiting calpain activity in neurodegenerative diseases.
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Affiliation(s)
- Elsayed Metwally
- State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10080, China; Department of Cytology and Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Guoli Zhao
- State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yong Q Zhang
- State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 10080, China.
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36
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Liu Y, Liu Z, Zhao F, Tian Y. Long-Term Tracking and Dynamically Quantifying of Reversible Changes of Extracellular Ca 2+ in Multiple Brain Regions of Freely Moving Animals. Angew Chem Int Ed Engl 2021; 60:14429-14437. [PMID: 33797152 DOI: 10.1002/anie.202102833] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Indexed: 11/11/2022]
Abstract
Understanding physiological and pathological processes in the brain requires tracking the reversible changes in chemical signals with long-term stability. We developed a new anti-biofouling microfiber array to real-time quantify extracellular Ca2+ concentrations together with neuron activity across many regions in the mammalian brain for 60 days, in which the signal degradation was < ca. 8 %. The microarray with high tempo-spatial resolution (ca. 10 μm, ca. 1.3 s) was implanted into 7 brain regions of free-moving mice to monitor reversible changes of extracellular Ca2+ upon ischemia-reperfusion processes. The changing sequence and rate of Ca2+ in 7 brain regions were different during the stroke. ROS scavenger could protect Ca2+ influx and neuronal activity after stroke, suggesting the significant influence of ROS on Ca2+ overload and neuron death. We demonstrated this microarray is a versatile tool for investigating brain dynamic during pathological processes and drug treatment.
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Affiliation(s)
- Yuandong Liu
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China
| | - Zhichao Liu
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China
| | - Fan Zhao
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China
| | - Yang Tian
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China
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37
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Liu Y, Liu Z, Zhao F, Tian Y. Long‐Term Tracking and Dynamically Quantifying of Reversible Changes of Extracellular Ca
2+
in Multiple Brain Regions of Freely Moving Animals. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202102833] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Yuandong Liu
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes School of Chemistry and Molecular Engineering East China Normal University Dongchuan Road 500 Shanghai 200241 China
| | - Zhichao Liu
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes School of Chemistry and Molecular Engineering East China Normal University Dongchuan Road 500 Shanghai 200241 China
| | - Fan Zhao
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes School of Chemistry and Molecular Engineering East China Normal University Dongchuan Road 500 Shanghai 200241 China
| | - Yang Tian
- Shanghai Key Laboratory of Green Chemistry and Chemical Processes School of Chemistry and Molecular Engineering East China Normal University Dongchuan Road 500 Shanghai 200241 China
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Xu Q, Zhao B, Ye Y, Li Y, Zhang Y, Xiong X, Gu L. Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke. J Neuroinflammation 2021; 18:123. [PMID: 34059091 PMCID: PMC8166383 DOI: 10.1186/s12974-021-02137-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/24/2021] [Indexed: 12/14/2022] Open
Abstract
The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a member of the NLR family of inherent immune cell sensors. The NLRP3 inflammasome can detect tissue damage and pathogen invasion through innate immune cell sensor components commonly known as pattern recognition receptors (PRRs). PRRs promote activation of nuclear factor kappa B (NF-κB) pathways and the mitogen-activated protein kinase (MAPK) pathway, thus increasing the transcription of genes encoding proteins related to the NLRP3 inflammasome. The NLRP3 inflammasome is a complex with multiple components, including an NAIP, CIITA, HET-E, and TP1 (NACHT) domain; apoptosis-associated speck-like protein containing a CARD (ASC); and a leucine-rich repeat (LRR) domain. After ischemic stroke, the NLRP3 inflammasome can produce numerous proinflammatory cytokines, mediating nerve cell dysfunction and brain edema and ultimately leading to nerve cell death once activated. Ischemic stroke is a disease with high rates of mortality and disability worldwide and is being observed in increasingly younger populations. To date, there are no clearly effective therapeutic strategies for the clinical treatment of ischemic stroke. Understanding the NLRP3 inflammasome may provide novel ideas and approaches because targeting of upstream and downstream molecules in the NLRP3 pathway shows promise for ischemic stroke therapy. In this manuscript, we summarize the existing evidence regarding the composition and activation of the NLRP3 inflammasome, the molecules involved in inflammatory pathways, and corresponding drugs or molecules that exert effects after cerebral ischemia. This evidence may provide possible targets or new strategies for ischemic stroke therapy.
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Affiliation(s)
- Qingxue Xu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Bo Zhao
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yingze Ye
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yina Li
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yonggang Zhang
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiaoxing Xiong
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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Danese A, Leo S, Rimessi A, Wieckowski MR, Fiorica F, Giorgi C, Pinton P. Cell death as a result of calcium signaling modulation: A cancer-centric prospective. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:119061. [PMID: 33991539 DOI: 10.1016/j.bbamcr.2021.119061] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/19/2021] [Accepted: 04/26/2021] [Indexed: 12/14/2022]
Abstract
Calcium ions (Ca2+) and the complex regulatory system governed by Ca2+ signaling have been described to be of crucial importance in numerous aspects related to cell life and death decisions, especially in recent years. The growing attention given to this second messenger is justified by the pleiotropic nature of Ca2+-binding proteins and transporters and their consequent involvement in cell fate decisions. A growing number of works highlight that deregulation of Ca2+ signaling and homoeostasis is often deleterious and drives pathological conditions; in particular, a disruption of the main Ca2+-mediated death mechanisms may lead to uncontrolled cell growth that results in cancer. In this work, we review the latest useful evidence to better understand the complex network of pathways by which Ca2+ regulates cell life and death decisions.
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Affiliation(s)
- Alberto Danese
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy
| | - Sara Leo
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy
| | - Alessandro Rimessi
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy
| | - Mariusz R Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Pasteur 3 Str., 02-093 Warsaw, Poland
| | | | - Carlotta Giorgi
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy.
| | - Paolo Pinton
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy.
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40
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Xia Z, Wang C, Wang X, Yu H, Yao H, Shen H, Lan X, Wu X, Zhang G. NCX3 alleviates ethanol-induced apoptosis of SK-N-SH cells via the elimination of intracellular calcium ions. Toxicol In Vitro 2021; 72:105104. [PMID: 33516933 DOI: 10.1016/j.tiv.2021.105104] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/26/2020] [Accepted: 01/25/2021] [Indexed: 11/18/2022]
Abstract
Long-term alcohol intake may cause nerve cell apoptosis and induce various encephalopathies. Previously, we have shown that the expression of Na+/Ca2+ exchanger 3 (NCX3) was associated with the intracellular calcium concentration ([Ca2+]i) and apoptosis, involved in the spatial memory impairment in male C57BL/6 mice with chronic ethanol (EtOH) exposure. However, the mechanism involved is unclear. Here, we investigated the expression of NCX3 and its protective effect on SK-N-SH cells (a nerve cell line) after EtOH exposure. [Ca2+]i was measured using Fluo-3 AM reagent. Cell viability and the apoptotic rate were assayed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) and flow cytometry, respectively. The expression of p-cAMP-responsive element binding protein1(p-CREB 1), NCX3 protein, and mRNA were observed using Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Cleaved-caspase-3, caspase-3, rabbit anti- poly (ADP-ribose) polymerase-1 (PARP-1) and calpain-1 proteins were used to assess the degree of apoptosis. Our results showed that EtOH increased [Ca2+]i and apoptosis of SK-N-SH cells in a concentration- and time-dependent manner. The expression of NCX3 protein and mRNA was up regulated obviously after SK-N-SH cells were treated with EtOH. The phosphorylation levels of Akt and CREB 1 were up regulated in cells treated with EtOH. The expression of NCX3 protein was reduced in the SK-N-SH cells treated with Akt phosphorylation inhibitor (LY294002). The [Ca2+]i and apoptosis rate of SK-N-SH cells increased 1.31-fold and 1.52-fold after silencing NCX3 compared with those treated with 200 mM EtOH alone for 2 d. In contrast, the [Ca2+]i and apoptosis rate of SK-N-SH cells decreased 0.26-fold and 0.35-fold after overexpression of NCX3 in the 2 d-200 mM EtOH treatment group. These results suggest that NCX3 plays a critical role in neuronal protection via the elimination of intracellular Ca2+, which may be a promising target for the prevention and treatment of encephalopathy after ethanol exposure.
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Affiliation(s)
- Zhixiu Xia
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China; Department of General Surgery, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, PR China
| | - Changliang Wang
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China; The People's Procuratorate of Liaoning Province Judicial Authentication Center, Shenyang, Liaoning 110032, PR China
| | - Xiaolong Wang
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China
| | - Hao Yu
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China
| | - Hui Yao
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China
| | - Hui Shen
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China
| | - Xinze Lan
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China
| | - Xu Wu
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China
| | - Guohua Zhang
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, PR China.
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41
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Katoshevski T, Ben-Kasus Nissim T, Sekler I. Recent studies on NCLX in health and diseases. Cell Calcium 2021; 94:102345. [PMID: 33508514 DOI: 10.1016/j.ceca.2020.102345] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/29/2020] [Accepted: 12/29/2020] [Indexed: 12/27/2022]
Abstract
The mitochondria is a major hub for cellular Ca 2+ signaling. The identification of MCU, the mitochondrial Ca 2+ influx mediator, and the mitochondrial Ca 2+ extruder NCLX, were major breakthroughs in this field. Their identification provided novel molecular tools and animal models to interrogate their physiological function and mode of regulation. Here we will focus on the mitochondrial Na + / Ca 2+ exchanger NCLX that plays a dual role in mitochondrial Na + and Ca 2+ signaling. We will discuss recent advances in NCLX mods of regulation by kinases and mitochondrial ΔΨ. We will also focus on the heterogeneity of its expression in distinct mitochondrial populations and the pathophysiological implication of its excessive degradation. We will describe the ongoing debate on the stoichiometry of Na + to Ca 2+ transport, mediated by NCLX, and its physiological implication. We will focus on the major effects of mitochondrial Na + signaling by NCLX on mitochondrial metabolism in health; and finally, we will discuss the role NCLX plays in a wide range of health disorders, from heart failure and cancer to Parkinson and Alzheimer disease, making it a prime candidate for therapeutic targeting.
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Affiliation(s)
- Tomer Katoshevski
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Tsipi Ben-Kasus Nissim
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel
| | - Israel Sekler
- Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
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42
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Britti E, Delaspre F, Tamarit J, Ros J. Calpain-Inhibitors Protect Frataxin-Deficient Dorsal Root Ganglia Neurons from Loss of Mitochondrial Na +/Ca 2+ Exchanger, NCLX, and Apoptosis. Neurochem Res 2021; 46:108-119. [PMID: 32249386 DOI: 10.1007/s11064-020-03020-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 03/19/2020] [Accepted: 03/28/2020] [Indexed: 12/16/2022]
Abstract
Calpains are calcium-dependent proteases activated in apoptotic cell death and neurodegeneration. Friedreich Ataxia is a neurodegenerative rare disease caused by frataxin deficiency, a mitochondrial protein. Dorsal root ganglion (DRG) sensory neurons are among the cellular types most affected in this disease. We have previously demonstrated that frataxin-deficient DRGs show calpain activation, alteration in calcium levels and decreased content of the Na+/Ca2+ exchanger (NCLX). This transporter is involved in mitochondrial calcium efflux. In this study, we have performed a time-course analysis of several parameters altered in a frataxin-deficient DRGs. These include decline of NCLX levels, calcium accumulation, mitochondrial depolarization, α-fodrin fragmentation and apoptotic cell death. Furthermore, we have analysed the effect of the calpain inhibitors MDL28170 and Calpeptin on these parameters. We have observed that these inhibitors increase NCLX levels, protect sensory neurons from neurite degeneration and calcium accumulation, and restore mitochondrial membrane potential. In addition, calpain 1 reduction alleviated neurodegeneration in frataxin-deficient DRG neurons. These results strengthen the hypothesis of a central role for calcium homeostasis and calpains in frataxin-deficient dorsal root ganglia neurons.
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Affiliation(s)
- Elena Britti
- Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
| | - Fabien Delaspre
- Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
| | - Jordi Tamarit
- Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain
| | - Joaquim Ros
- Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, Lleida, Spain.
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43
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Wang J, Wang F, Mai D, Qu S. Molecular Mechanisms of Glutamate Toxicity in Parkinson's Disease. Front Neurosci 2020; 14:585584. [PMID: 33324150 PMCID: PMC7725716 DOI: 10.3389/fnins.2020.585584] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/28/2020] [Indexed: 01/07/2023] Open
Abstract
Parkinson’s disease (PD) is a common neurodegenerative disease, the pathological features of which include the presence of Lewy bodies and the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta. However, until recently, research on the pathogenesis and treatment of PD have progressed slowly. Glutamate and dopamine are both important central neurotransmitters in mammals. A lack of enzymatic decomposition of extracellular glutamate results in glutamate accumulating at synapses, which is mainly absorbed by excitatory amino acid transporters (EAATs). Glutamate exerts its physiological effects by binding to and activating ligand-gated ion channels [ionotropic glutamate receptors (iGluRs)] and a class of G-protein-coupled receptors [metabotropic glutamate receptors (mGluRs)]. Timely clearance of glutamate from the synaptic cleft is necessary because high levels of extracellular glutamate overactivate glutamate receptors, resulting in excitotoxic effects in the central nervous system. Additionally, increased concentrations of extracellular glutamate inhibit cystine uptake, leading to glutathione depletion and oxidative glutamate toxicity. Studies have shown that oxidative glutamate toxicity in neurons lacking functional N-methyl-D-aspartate (NMDA) receptors may represent a component of the cellular death pathway induced by excitotoxicity. The association between inflammation and excitotoxicity (i.e., immunoexcitotoxicity) has received increased attention in recent years. Glial activation induces neuroinflammation and can stimulate excessive release of glutamate, which can induce excitotoxicity and, additionally, further exacerbate neuroinflammation. Glutamate, as an important central neurotransmitter, is closely related to the occurrence and development of PD. In this review, we discuss recent progress on elucidating glutamate as a relevant neurotransmitter in PD. Additionally, we summarize the relationship and commonality among glutamate excitotoxicity, oxidative toxicity, and immunoexcitotoxicity in order to posit a holistic view and molecular mechanism of glutamate toxicity in PD.
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Affiliation(s)
- Ji Wang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China.,Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China
| | - Fushun Wang
- Institute of Brain and Psychological Science, Sichuan Normal University, Chengdu, China.,Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, United States
| | - Dongmei Mai
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China.,Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China
| | - Shaogang Qu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China.,Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China
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44
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Mao X, Fu P, Wang L, Xiang C. Mitochondria: Potential Targets for Osteoarthritis. Front Med (Lausanne) 2020; 7:581402. [PMID: 33324661 PMCID: PMC7726420 DOI: 10.3389/fmed.2020.581402] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/19/2020] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is a common and disabling joint disorder that is mainly characterized by cartilage degeneration and narrow joint spaces. The role of mitochondrial dysfunction in promoting the development of OA has gained much attention. Targeting endogenous molecules to improve mitochondrial function is a potential treatment for OA. Moreover, research on exogenous drugs to improve mitochondrial function in OA based on endogenous molecular targets has been accomplished. In addition, stem cells and exosomes have been deeply researched in the context of cartilage regeneration, and these factors both reverse mitochondrial dysfunctions. Thus, we hypothesize that biomedical approaches will be applied to the treatment of OA. Furthermore, we have summarized the global status of mitochondria and osteoarthritis research in the past two decades, which will contribute to the research field and the development of novel treatment strategies for OA.
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Affiliation(s)
- Xingjia Mao
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Panfeng Fu
- Department of Respiratory and Critical Care, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Linlin Wang
- Department of Basic Medicine Sciences, The School of Medicine of Zhejiang University, Hangzhou, China
| | - Chuan Xiang
- Department of Orthopedic, The Second Hospital of Shanxi Medical University, Taiyuan, China
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45
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Horvath AA, Csernus EA, Lality S, Kaminski RM, Kamondi A. Inhibiting Epileptiform Activity in Cognitive Disorders: Possibilities for a Novel Therapeutic Approach. Front Neurosci 2020; 14:557416. [PMID: 33177974 PMCID: PMC7593384 DOI: 10.3389/fnins.2020.557416] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
Abstract
Cognitive impairment is a common and seriously debilitating symptom of various mental and neurological disorders including autism, attention deficit hyperactivity disorder, multiple sclerosis, epilepsy, and neurodegenerative diseases, like Alzheimer's disease. In these conditions, high prevalence of epileptiform activity emerges as a common pathophysiological hallmark. Growing body of evidence suggests that this discrete but abnormal activity might have a long-term negative impact on cognitive performance due to neuronal circuitries' remodeling, altered sleep structure, pathological hippocampo-cortical coupling, and even progressive neuronal loss. In animal models, epileptiform activity was shown to enhance the formation of pathological amyloid and tau proteins that in turn trigger network hyperexcitability. Abolishing epileptiform discharges might slow down the cognitive deterioration. These findings might provide basis for therapeutic use of antiepileptic drugs in neurodegenerative cognitive disorders. The aim of our review is to describe the data on the prevalence of epileptiform activity in various cognitive disorders, to summarize the current knowledge of the mechanisms of epileptic activity in relation to cognitive impairment, and to explore the utility of antiepileptic drugs in the therapy of cognitive disorders. We also propose future directions for drug development and novel therapeutic interventions targeting epileptiform discharges in these disorders.
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Affiliation(s)
- Andras Attila Horvath
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
- Department of Neurology, National Institute of Clinical Neurosciences, Budapest, Hungary
| | | | - Sara Lality
- Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Rafal M. Kaminski
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Anita Kamondi
- Department of Neurology, National Institute of Clinical Neurosciences, Budapest, Hungary
- Department of Neurology, Semmelweis University, Budapest, Hungary
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46
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Filadi R, Pizzo P. Mitochondrial calcium handling and neurodegeneration: when a good signal goes wrong. CURRENT OPINION IN PHYSIOLOGY 2020. [DOI: 10.1016/j.cophys.2020.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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47
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Samantaray S, Knaryan VH, M Del Re A, Woodward JJ, Shields DC, Azuma M, Inoue J, Ray SK, Banik NL. Cell-Permeable Calpain Inhibitor SJA6017 Provides Functional Protection to Spinal Motoneurons Exposed to MPP . Neurotox Res 2020;38:640-649. [PMID: 32761446 PMCID: PMC9453439 DOI: 10.1007/s12640-020-00264-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/17/2020] [Accepted: 07/27/2020] [Indexed: 12/30/2022]
Abstract
Extra-nigral central nervous system sites have been found to be affected in Parkinson's disease (PD). In addition to substantia nigra, degeneration of spinal cord motor neurons may play a role in the motor symptoms of PD. To this end, hybrid rodent VSC 4.1 cells differentiated into motoneurons were used as a cell culture model following exposure to Parkinsonian neurotoxicant MPP+. SJA6017, a cell-permeable calpain inhibitor, was tested for its neuroprotective efficacy against the neurotoxicant. SJA6017 attenuated MPP+-induced rise in intracellular free Ca2+ and concomitant increases in the active form of calpain. It also significantly prevented increased levels of proteases and their activities, as shown by reduced levels of 145 kDa calpain-specific and 120 kDa caspase-3-specific spectrin breakdown products. Exposure to MPP+ elevated the levels of reactive oxygen species in VSC 4.1 motoneurons; this was significantly diminished with SJA6017. The motor proteins in spinal motoneurons, i.e., dynein and kinesin, were also impaired following exposure to MPP+ through calpain-mediated mechanisms; this process was partially ameliorated by SJA6017 pretreatment. Cytoprotection provided by SJA6017 against MPP+-induced damage to VSC 4.1 motoneurons was confirmed by restoration of membrane potential via whole-cell patch-clamp assay. This study demonstrates that calpain inhibition is a prospective route for neuroprotection in experimental PD; moreover, calpain inhibitor SJA6017 appears to be an effective neuroprotective agent against MPP+-induced damage in spinal motoneurons.
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Affiliation(s)
- Supriti Samantaray
- Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas St., MSC606 Suite 301, Charleston, SC, 29425, USA
| | - Varduhi H Knaryan
- Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas St., MSC606 Suite 301, Charleston, SC, 29425, USA
| | - Angelo M Del Re
- Division of Neuroscience Research and Center for Drug & Alcohol Programs, Medical University of South Carolina, Charleston, SC, USA
| | - John J Woodward
- Division of Neuroscience Research and Center for Drug & Alcohol Programs, Medical University of South Carolina, Charleston, SC, USA
| | - Donald C Shields
- Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas St., MSC606 Suite 301, Charleston, SC, 29425, USA
| | - Mitsuyoshi Azuma
- Kobe Creative Center, Senju Pharmaceutical Corporation Limited, Kobe, 651-2241, Japan
- Department of Integrative Biosciences, Oregon Health & Science University, Portland, OR, USA
| | - Jun Inoue
- Kobe Creative Center, Senju Pharmaceutical Corporation Limited, Kobe, 651-2241, Japan
| | - Swapan K Ray
- Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Naren L Banik
- Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas St., MSC606 Suite 301, Charleston, SC, 29425, USA.
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48
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Liu M, Wang L, Gao J, Dong Q, Perry G, Ma X, Wang X. Inhibition of Calpain Protects Against Tauopathy in Transgenic P301S Tau Mice. J Alzheimers Dis 2020; 69:1077-1087. [PMID: 31156179 DOI: 10.3233/jad-190281] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Alzheimer's disease (AD) and other tauopathies are characterized by intracellular accumulation of microtubule-associated tau protein leading to neurodegeneration. Calpastatin is the endogenous inhibitor of calpain, a calcium-dependent cysteine protease that has been increasingly implicated in tauopathies. In this study, we generated a neuron specific calpastatin overexpressing knock-in transgenic mouse model and crossed it with the PS19 tauopathy mouse model expressing human P301S mutant tau protein. The forced expression of calpastatin in neurons significantly alleviated tau hyperphosphorylation measured by immunocytochemistry and immunoblot. The genetic inhibition of calpain by calpastatin also greatly suppressed characteristic hippocampal neuron loss and widespread astrogliosis and microgliosis in PS19 mice. Consistently, PS19 mice with neuronal calpastatin overexpression exhibited remarkably alleviated cognitive deficits, muscle weakness, skeletal muscle atrophy, and neuromuscular denervation, together implying the neuroprotective effects of neuronal calpastatin in PS19 mice of tauopathy. In sum, this study provides additional evidence supporting the pathological role of calpain in neurodegenerative diseases associated with tau pathology, and suggests that targeting calpain is likely a promising therapeutic approach for these devastating diseases.
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Affiliation(s)
- Mengyu Liu
- College of Life Science and Bio-engineering, Beijing University of Technology, Beijing, China.,Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Luwen Wang
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Ju Gao
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - Qing Dong
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA
| | - George Perry
- College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA
| | - Xuemei Ma
- College of Life Science and Bio-engineering, Beijing University of Technology, Beijing, China
| | - Xinglong Wang
- Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.,Center for Mitochondrial Diseases, Case Western Reserve University, Cleveland, OH, USA
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49
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Ttm50 facilitates calpain activation by anchoring it to calcium stores and increasing its sensitivity to calcium. Cell Res 2020; 31:433-449. [PMID: 32848200 DOI: 10.1038/s41422-020-0388-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 07/20/2020] [Indexed: 11/08/2022] Open
Abstract
Calcium-dependent proteolytic calpains are implicated in a variety of physiological processes, as well as pathologies associated with calcium overload. However, the mechanism by which calpain is activated remains elusive since intracellular calcium levels under physiological conditions do not reach the high concentration range required to trigger calpain activation. From a candidate screening using the abundance of the calpain target glutamate receptor GluRIIA at the Drosophila neuromuscular junction as a readout, we uncovered that calpain activity was inhibited upon knockdown of Ttm50, a subunit of the Tim23 complex known to be involved in the import of proteins across the mitochondrial inner membrane. Unexpectedly, Ttm50 and calpain are co-localized at calcium stores Golgi and endoplasmic reticulum (ER), and Ttm50 interacts with calpain via its C-terminal domain. This interaction is required for calpain localization at Golgi/ER, and increases calcium sensitivity of calpain by roughly an order of magnitude. Our findings reveal the regulation of calpain activation by Ttm50, and shed new light on calpain-associated pathologies.
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Bruce JIE, James AD. Targeting the Calcium Signalling Machinery in Cancer. Cancers (Basel) 2020; 12:cancers12092351. [PMID: 32825277 PMCID: PMC7565467 DOI: 10.3390/cancers12092351] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/30/2020] [Accepted: 08/08/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer is caused by excessive cell proliferation and a propensity to avoid cell death, while the spread of cancer is facilitated by enhanced cellular migration, invasion, and vascularization. Cytosolic Ca2+ is central to each of these important processes, yet to date, there are no cancer drugs currently being used clinically, and very few undergoing clinical trials, that target the Ca2+ signalling machinery. The aim of this review is to highlight some of the emerging evidence that targeting key components of the Ca2+ signalling machinery represents a novel and relatively untapped therapeutic strategy for the treatment of cancer.
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Affiliation(s)
- Jason I. E. Bruce
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
- Correspondence: ; Tel.: +44-(0)-161-275-5484
| | - Andrew D. James
- Department of Biology, University of York, Heslington, York YO10 5DD, UK;
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