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Carvalho AVS, Sanches EF, Ribeiro RT, Durán-Carabali LE, Júnior OR, Muniz BD, Wajner M, Wyse AT, Netto CA, Sizonenko SV. Maternal lactoferrin supplementation prevents mitochondrial and redox homeostasis dysfunction, and improves antioxidant defenses through Nrf2 and UCP2 signaling after neonatal hypoxia-ischemia. Free Radic Biol Med 2025; 231:68-79. [PMID: 40010517 DOI: 10.1016/j.freeradbiomed.2025.02.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 02/20/2025] [Accepted: 02/23/2025] [Indexed: 02/28/2025]
Abstract
Neonatal hypoxia-ischemia (HI) is a major cause of mortality and neurological impairments in infants. Main HI-induced pathological mechanisms include mitochondrial dysfunction and oxidative stress due to insufficient oxygen and energetic substrates to the nervous cells. Bovine lactoferrin (Lf) has demonstrated neuroprotective effects in several experimental models of neonatal brain injury in rodents, however its mechanisms remain unclear. This study aimed to evaluate the early impact of maternal dietary supplementation with Lf on redox and hippocampal mitochondrial function following neonatal HI. From postnatal day 6 (PND6), pregnant Wistar rats were fed with a diet supplemented with Lf (1 g/kg) or with an isocaloric control diet until offspring euthanasia. At PND7, pups of both sexes were subjected to experimental HI through the occlusion of the right common carotid artery followed by 60 min of hypoxia (8 % oxygen). Lf prevented HI-induced increased levels of DCFH and lipoperoxidation in hippocampus. Furthermore, Lf enhanced antioxidant defenses including SOD, GPx, and GSH, counteracting HI-induced oxidative stress. HI injury altered the activities of enzymes in the mitochondrial respiratory chain and increased the mitochondrial membrane potential. Both effects were counteracted by Lf supplementation. Lactoferrin prevented oxidative stress and to restored mitochondrial function by upregulating Nrf2 and UCP2 expression following experimental HI. Our results show that even a shorter period of Lf delivery to rat pups is able to improve hippocampal response to neonatal hypoxia-ischemia, reversing initial mechanisms of damage in the cascade of HI injury.
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Affiliation(s)
- Andrey Vinicios S Carvalho
- Postgraduate Program in Biological Science: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
| | - Eduardo F Sanches
- Division of Child Development and Growth, Department of Pediatrics, Gynecology and Obstetrics, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Rafael T Ribeiro
- Postgraduate Program in Biological Science: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Luz Elena Durán-Carabali
- Department of Physiological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Osmar Ramires Júnior
- Postgraduate Program in Biological Science: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Bruna Dutra Muniz
- Postgraduate Program in Biological Science: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Moacir Wajner
- Postgraduate Program in Biological Science: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - Angela T Wyse
- Postgraduate Program in Biological Science: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Carlos Alexandre Netto
- Postgraduate Program in Biological Science: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Department of Physiological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Stéphane V Sizonenko
- Division of Child Development and Growth, Department of Pediatrics, Gynecology and Obstetrics, School of Medicine, University of Geneva, Geneva, Switzerland.
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Fang Y, Zheng Y, Gao Q, Pang M, Wu Y, Feng X, Tao X, Hu Y, Lin Z, Lin W. Activation of the Nrf2/Keap1 signaling pathway mediates the neuroprotective effect of Perillyl alcohol against cerebral hypoxic-ischemic damage in neonatal rats. Redox Rep 2024; 29:2394714. [PMID: 39284589 PMCID: PMC11407389 DOI: 10.1080/13510002.2024.2394714] [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] [Indexed: 09/19/2024] Open
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe disease with a poor prognosis, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. Perillyl alcohol (POH), a natural monoterpene found in various plant essential oils, has shown neuroprotective properties, though its effects on HIE are not well understood. This study investigates the neuroprotective effects of POH on HIE both in vitro and in vivo. We established an in vitro model using glucose deprivation and hypoxia/reperfusion (OGD/R) in PC12 cells, alongside an in vivo model via the modified Rice-Vannucci method. Results indicated that POH acted as an indirect antioxidant, reducing inducible nitric oxide synthase and malondialdehyde production, maintaining content of antioxidant molecules and enzymes in OGD/R-induced PC12 cells. In vivo, POH remarkably lessened infarct volume, reduced cerebral edema, accelerated tissue regeneration, and blocked reactive astrogliosis after hypoxic-ischemic brain injury. POH exerted antiapoptotic activities through both the intrinsic and extrinsic apoptotic pathways. Mechanistically, POH activated Nrf2 and inactivated its negative regulator Keap1. The use of ML385, a Nrf2 inhibitor, reversed these effects. Overall, POH mitigates neuronal damage in HIE by combating oxidative stress, reducing inflammation, and inhibiting apoptosis via the Nrf2/Keap1 pathway, suggesting its potential for HIE treatment.
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Affiliation(s)
- Yu Fang
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Yihui Zheng
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Qiqi Gao
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Mengdan Pang
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Yiqing Wu
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Xiaoli Feng
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Xiaoyue Tao
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Yingying Hu
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Zhenlang Lin
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Structural Malformations in Children of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Wei Lin
- Department of Pediatrics, The Second School of Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
- Key Laboratory of Perinatal Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
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Jiang XL, Zhang ZB, Feng CX, Lin CJ, Yang H, Tan LL, Ding X, Xu LX, Li G, Pan T, Qin ZH, Sun B, Feng X, Li M. PHLDA1 contributes to hypoxic ischemic brain injury in neonatal rats via inhibiting FUNDC1-mediated mitophagy. Acta Pharmacol Sin 2024; 45:1809-1820. [PMID: 38750074 PMCID: PMC11336168 DOI: 10.1038/s41401-024-01292-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/14/2024] [Indexed: 08/22/2024]
Abstract
Hypoxia-ischemia (HI) is one of the main causes of neonatal brain injury. Mitophagy has been implicated in the degradation of damaged mitochondria and cell survival following neonatal brain HI injury. Pleckstrin homology-like domain family A member 1 (PHLDA1) plays vital roles in the progression of various disorders including the regulation of oxidative stress, the immune responses and apoptosis. In the present study we investigated the role of PHLDA1 in HI-induced neuronal injury and further explored the mechanisms underlying PHLDA1-regulated mitophagy in vivo and in vitro. HI model was established in newborn rats by ligation of the left common carotid artery plus exposure to an oxygen-deficient chamber with 8% O2 and 92% N2. In vitro studies were conducted in primary hippocampal neurons subjected to oxygen and glucose deprivation/-reoxygenation (OGD/R). We showed that the expression of PHLDA1 was significantly upregulated in the hippocampus of HI newborn rats and in OGD/R-treated primary neurons. Knockdown of PHLDA1 in neonatal rats via lentiviral vector not only significantly ameliorated HI-induced hippocampal neuronal injury but also markedly improved long-term cognitive function outcomes, whereas overexpression of PHLDA1 in neonatal rats via lentiviral vector aggravated these outcomes. PHLDA1 knockdown in primary neurons significantly reversed the reduction of cell viability and increase in intracellular reactive oxygen species (ROS) levels, and attenuated OGD-induced mitochondrial dysfunction, whereas overexpression of PHLDA1 decreased these parameters. In OGD/R-treated primary hippocampal neurons, we revealed that PHLDA1 knockdown enhanced mitophagy by activating FUNDC1, which was abolished by FUNDC1 knockdown or pretreatment with mitophagy inhibitor Mdivi-1 (25 μM). Notably, pretreatment with Mdivi-1 or the knockdown of FUNDC1 not only increased brain infarct volume, but also abolished the neuroprotective effect of PHLDA1 knockdown in HI newborn rats. Together, these results demonstrate that PHLDA1 contributes to neonatal HI-induced brain injury via inhibition of FUNDC1-mediated neuronal mitophagy.
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Affiliation(s)
- Xiao-Lu Jiang
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
- Department of Neonatology, Children's Hospital of Soochow University, Suzhou, 215025, China
- Soochow Key Laboratory of Prevention and Treatment of Child Brain Injury, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Zu-Bin Zhang
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China.
- Jiangsu Key Laboratory for Translational Research and Therapeutics of NeuroPsycho Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
| | - Chen-Xi Feng
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Chen-Jie Lin
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Hui Yang
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Lan-Lan Tan
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Xin Ding
- Department of Neonatology, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Li-Xiao Xu
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Gen Li
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Tao Pan
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Zheng-Hong Qin
- Institute of Health Technology, Global Institute of Software Technology, Qingshan Road, Suzhou Science & Technology Tower, Hi-Tech Area, Suzhou, 215163, China
| | - Bin Sun
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China
| | - Xing Feng
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China.
- Department of Neonatology, Children's Hospital of Soochow University, Suzhou, 215025, China.
- Soochow Key Laboratory of Prevention and Treatment of Child Brain Injury, Children's Hospital of Soochow University, Suzhou, 215025, China.
| | - Mei Li
- Pediatrics Research Institute, Children's Hospital of Soochow University, Suzhou, 215025, China.
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Feng X, Zheng Y, Mao N, Shen M, Chu L, Fang Y, Pang M, Wang Z, Lin Z. Menaquinone-4 alleviates hypoxic-ischemic brain damage in neonatal rats by reducing mitochondrial dysfunction via Sirt1-PGC-1α-TFAM signaling pathway. Int Immunopharmacol 2024; 134:112257. [PMID: 38759366 DOI: 10.1016/j.intimp.2024.112257] [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: 03/22/2024] [Revised: 05/01/2024] [Accepted: 05/10/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND Hypoxic-ischemic encephalopathy (HIE) is a major contributor to neonatal mortality and neurodevelopmental disorders, but currently there is no effective therapy drug for HIE. Mitochondrial dysfunction plays a pivotal role in hypoxic-ischemic brain damage(HIBD). Menaquinone-4 (MK-4), a subtype of vitamin K2 prevalent in the brain, has been shown to enhance mitochondrial function and exhibit protective effects against ischemia-reperfusion injury. However, the impact and underlying molecular mechanism of MK-4 in HIE have not been fully elucidated. METHODS In this study, we established the neonatal rats HIBD model in vivo and oxygen-glucose deprivation and reperfusion (OGD/R) of primary neurons in vitro to explore the neuroprotective effects of MK-4 on HI damage, and illuminate the potential mechanism. RESULTS Our findings revealed that MK-4 ameliorated mitochondrial dysfunction, reduced oxidative stress, and prevented HI-induced neuronal apoptosis by activating the Sirt1-PGC-1α-TFAM signaling pathway through Sirt1 mediation. Importantly, these protective effects were partially reversed by EX-527, a Sirt1 inhibitor. CONCLUSION Our study elucidated the potential therapeutic mechanism of MK-4 in neonatal HIE, suggesting its viability as an agent for enhancing recovery from HI-induced cerebral damage in newborns. Further exploration into MK-4 could lead to novel interventions for HIE therapy.
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Affiliation(s)
- Xiaoli Feng
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Yihui Zheng
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Niping Mao
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Ming Shen
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Liuxi Chu
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Affiliated Cixi Hospital, Wenzhou Medical University, Cixi, Zhejiang 315300, China
| | - Yu Fang
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Mengdan Pang
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China
| | - Zhouguang Wang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Zhenlang Lin
- Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Perinatal Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang 325027, China.
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Arnautovic T, Sinha S, Laptook AR. Neonatal Hypoxic-Ischemic Encephalopathy and Hypothermia Treatment. Obstet Gynecol 2024; 143:67-81. [PMID: 37797337 PMCID: PMC10841232 DOI: 10.1097/aog.0000000000005392] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/27/2023] [Indexed: 10/07/2023]
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is an important clinical entity because it is associated with death and long-term disability, including cognitive impairment, cerebral palsy, seizures, and neurosensory deficits. Over the past 40 years, there has been an intensive search to identify therapies to improve the prognosis of neonates with HIE. Hypothermia treatment represents the culmination of laboratory investigations including small and large animal studies, followed by pilot human studies, and, finally, randomized controlled trials to establish efficacy and safety. Clinical trials have demonstrated that hypothermia treatment reduces mortality and improves early childhood outcome among survivors. Hypoxic-ischemic encephalopathy is a multi-system disease process that requires intensive medical support for brain monitoring and monitoring of non-central nervous system organ dysfunction. Treatment must be conducted in a level III or IV neonatal intensive care unit with infrastructure for an integrated approach to care for critically ill neonates. Hypothermia treatment is the first and currently the only therapy to improve outcomes for neonates with HIE and indicates that HIE is modifiable. However, outcomes likely can be improved further. Hypothermia treatment has accelerated investigation of other therapies to combine with hypothermia. It has also stimulated a more intensive approach to brain monitoring, which allows earlier intervention for complications. Finally, HIE and hypothermia treatment negatively influences the psychological state of affected families, and there is growing recognition of the importance of trauma-informed principles to guide medical professionals.
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Affiliation(s)
- Tamara Arnautovic
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, and Warren Alpert Medical School of Brown University, Providence, Rhode Island
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Xu YH, Xu JB, Chen LL, Su W, Zhu Q, Tong GL. Protective mechanisms of quercetin in neonatal rat brain injury induced by hypoxic-ischemic brain damage (HIBD). Food Sci Nutr 2023; 11:7649-7663. [PMID: 38107093 PMCID: PMC10724619 DOI: 10.1002/fsn3.3684] [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: 07/13/2023] [Revised: 08/24/2023] [Accepted: 08/28/2023] [Indexed: 12/19/2023] Open
Abstract
Neonatal hypoxic-ischemic brain damage (HIBD) is a leading cause of infant mortality worldwide. This study explored whether quercetin (Que) exerts neuroprotective effects in a rat model of HIBD. A total of 36 seven-day-old Sprague-Dawley rats were divided into control, Que, HI, and HI + Que groups. The Rice method was used to establish HIBD in HI and HI + Que rats, which were treated with hypoxia (oxygen concentration of 8%) for 2 h after ligation of the left common carotid artery. The rats in the HI + Que group were intraperitoneally injected with Que (30 mg/kg) 1 h before hypoxia, and the rats in the Que group were only injected with the same amount of Que. Brain tissues were harvested 24 h postoperation and assessed by hematoxylin and eosin staining, 2,3,5-triphenyltetrazolium chloride staining, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay; relative gene and protein levels were evaluated by RT-qPCR, IHC, or western blot (WB) assay. Brain tissue morphologies were characterized by transmission electron microscopy (TEM); LC3B protein levels were assessed by immunofluorescence staining. Escape latencies and platform crossing times were significantly improved (p < .05) in HI + Que groups; infarct volume significantly decreased (p < .001), whereas the numbers of autophagic bodies and apoptotic cells increased and decreased, respectively. Meanwhile, NLRX1, ATG7, and Beclin1 expressions were significantly upregulated, and mTOR and TIM23 expressions, LC3B protein level, and LC 3II/LC 3I ratio were significantly downregulated. Que exerted neuroprotective effects in a rat model of HIBD by regulating NLRX1 and autophagy.
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Affiliation(s)
- Yan-Hong Xu
- Anhui Provincial Children's Hospital Hefei China
| | - Jin-Bo Xu
- Anhui Provincial Children's Hospital Hefei China
| | - Lu-Lu Chen
- Anhui Provincial Children's Hospital Hefei China
| | - Wei Su
- Anhui Provincial Children's Hospital Hefei China
| | - Qing Zhu
- Anhui Provincial Children's Hospital Hefei China
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Zhang Y, Chen D, Wang Y, Wang X, Zhang Z, Xin Y. Neuroprotective effects of melatonin-mediated mitophagy through nucleotide-binding oligomerization domain and leucine-rich repeat-containing protein X1 in neonatal hypoxic-ischemic brain damage. FASEB J 2023; 37:e22784. [PMID: 36692416 DOI: 10.1096/fj.202201523r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/14/2022] [Accepted: 01/09/2023] [Indexed: 01/25/2023]
Abstract
Hypoxia-ischemia (HI) is a major cause of brain damage in neonates. Mitochondrial dysfunction acts as a hub for a broad spectrum of signaling events, culminating in cell death triggered by HI. A neuroprotective role of melatonin (MT) has been proposed, and mitophagy regulation seems to be important for cell survival. However, the molecular mechanisms underlying MT-mediated mitophagy during HI treatment are poorly defined. Nucleotide-binding oligomerization domain and leucine-rich repeat-containing protein X1 (NLRX1) has emerged as a critical regulator of mitochondrial dynamics and neuronal death that participates in the pathology of diverse diseases. This study aimed to clarify whether NLRX1 participates in the regulation of mitophagy during MT treatment for hypoxic-ischemic brain damage (HIBD). We demonstrated that MT protected neonates from HIBD through NLRX1-mediated mitophagy in vitro and in vivo. Meanwhile, MT upregulated the expression of NLRX1, Beclin-1, and autophagy-related 7 (ATG7) but decreased the expression of the mammalian target of rapamycin (mTOR) and translocase of the inner membrane of mitochondrion 23 (TIM23). Moreover, the neuroprotective effects of MT were abolished by silencing NLRX1 after oxygen-glucose deprivation (OGD). In addition, the downregulation of mTOR and upregulation of Beclin-1 and ATG7 by MT were inhibited after silencing NLRX1 under OGD. In summary, MT modulates mitophagy induction through NLRX1 and plays a protective role in HIBD, providing insight into potential therapeutic targets for MT to exert neuroprotection.
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Affiliation(s)
- Yi Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang City, P.R. China
| | - Dan Chen
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang City, P.R. China
| | - Yiwei Wang
- Department of Human Anatomy, College of Basic Medical Sciences, Shenyang Medical College, Shenyang City, P.R. China.,Department of Pathology, College of Basic Medical Sciences, Shenyang Medical College, Shenyang City, P.R. China
| | - Xingzao Wang
- Department of Clinical Medicine, College of Basic Medical Sciences, Shenyang Medical College, Shenyang City, P.R. China
| | - Zhong Zhang
- Department of Pathology, College of Basic Medical Sciences, Shenyang Medical College, Shenyang City, P.R. China
| | - Ying Xin
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang City, P.R. China
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8
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Okazaki K, Nakamura S, Koyano K, Konishi Y, Kondo M, Kusaka T. Neonatal asphyxia as an inflammatory disease: Reactive oxygen species and cytokines. Front Pediatr 2023; 11:1070743. [PMID: 36776908 PMCID: PMC9911547 DOI: 10.3389/fped.2023.1070743] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 01/10/2023] [Indexed: 01/28/2023] Open
Abstract
Neonatologists resuscitate asphyxiated neonates by every available means, including positive ventilation, oxygen therapy, and drugs. Asphyxiated neonates sometimes present symptoms that mimic those of inflammation, such as fever and edema. The main pathophysiology of the asphyxia is inflammation caused by hypoxic-ischemic reperfusion. At birth or in the perinatal period, neonates may suffer several, hypoxic insults, which can activate inflammatory cells and inflammatory mediator production leading to the release of larger quantities of reactive oxygen species (ROS). This in turn triggers the production of oxygen stress-induced high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular patterns (DAMPs) protein bound to toll-like receptor (TLR) -4, which activates nuclear factor-kappa B (NF-κB), resulting in the production of excess inflammatory mediators. ROS and inflammatory mediators are produced not only in activated inflammatory cells but also in non-immune cells, such as endothelial cells. Hypothermia inhibits pro-inflammatory mediators. A combination therapy of hypothermia and medications, such as erythropoietin and melatonin, is attracting attention now. These medications have both anti-oxidant and anti-inflammatory effects. As the inflammatory response and oxidative stress play a critical role in the pathophysiology of neonatal asphyxia, these drugs may contribute to improving patient outcomes.
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Affiliation(s)
- Kaoru Okazaki
- Department of Neonatology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Shinji Nakamura
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Kosuke Koyano
- Maternal Perinatal Center, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yukihiko Konishi
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Masatoshi Kondo
- Department of Neonatology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Takashi Kusaka
- Department of Pediatrics, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Chen T, Wang Y, Wang YH, Hang CH. The Mfn1-βIIPKC Interaction Regulates Mitochondrial Dysfunction via Sirt3 Following Experimental Subarachnoid Hemorrhage. Transl Stroke Res 2022; 13:845-857. [PMID: 35192161 DOI: 10.1007/s12975-022-00999-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 01/21/2022] [Accepted: 02/16/2022] [Indexed: 10/19/2022]
Abstract
Neuronal injury following subarachnoid hemorrhage (SAH) has been shown to be associated with mitochondrial dysfunction and oxidative stress. βIIPKC, a subtype of protein kinase C (PKC), accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Here, we investigated the role of Mfn1-βIIPKC interaction in brain damage and neurological function in both in vivo and in vitro experimental SAH models. The expression of βIIPKC protein and the interaction of Mfn1-βIIPKC were found to be increased after OxyHb treatment in primary cultured cortical neurons and were also observed in the brain following SAH in rats. Treatment with the βIIPKC inhibitor βIIV5-3 or SAMβA, a peptide that selectively antagonizes Mfn1-βIIPKC association, significantly attenuated the OxyHb-induced neuronal injury and apoptosis. These protective effects were accompanied by inhibited mitochondrial dysfunction and preserved mitochondrial biogenesis. The results of western blot showed that βIIV5-3 or SAMβA markedly increased the expression of Sirt3 and enhanced the activities of its downstream mitochondrial antioxidant enzymes in OxyHb-treated neurons. Knockdown of Sirt3 via specific targeted small interfering RNA (siRNA) partially prevented the βIIV5-3- or SAMβA-induced protection and antioxidative effects. In addition, treatment with βIIV5-3 or SAMβA in vivo was found to obviously reduce brain edema, alleviate neuroinflammation, and preserve neurological function after experimental SAH in rats. In congruent with in vitro data, the protection induced by βIIV5-3 or SAMβA was reduced by Sirt3 knockdown in vivo. In summary, our present results showed that blocking Mfn1-βIIPKC interaction protects against brain damage and mitochondrial dysfunction via Sirt3 following experimental SAH.
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Affiliation(s)
- Tao Chen
- Department of Neurosurgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210000, Jiangsu, China
- Department of Neurosurgery, The 904Th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, 214044, Jiangsu, China
| | - Yue Wang
- Department of Neurosurgery, The 904Th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, 214044, Jiangsu, China
| | - Yu-Hai Wang
- Department of Neurosurgery, The 904Th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, 214044, Jiangsu, China.
| | - Chun-Hua Hang
- Department of Neurosurgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210000, Jiangsu, China.
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10
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Mohammadi A, Higazy R, Gauda EB. PGC-1α activity and mitochondrial dysfunction in preterm infants. Front Physiol 2022; 13:997619. [PMID: 36225305 PMCID: PMC9548560 DOI: 10.3389/fphys.2022.997619] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
Extremely low gestational age neonates (ELGANs) are born in a relatively hyperoxic environment with weak antioxidant defenses, placing them at high risk for mitochondrial dysfunction affecting multiple organ systems including the nervous, respiratory, ocular, and gastrointestinal systems. The brain and lungs are highly affected by mitochondrial dysfunction and dysregulation in the neonate, causing white matter injury (WMI) and bronchopulmonary dysplasia (BPD), respectively. Adequate mitochondrial function is important in providing sufficient energy for organ development as it relates to alveolarization and axonal myelination and decreasing oxidative stress via reactive oxygen species (ROS) and reactive nitrogen species (RNS) detoxification. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a master regulator of mitochondrial biogenesis and function. Since mitochondrial dysfunction is at the root of WMI and BPD pathobiology, exploring therapies that can regulate PGC-1α activity may be beneficial. This review article describes several promising therapeutic agents that can mitigate mitochondrial dysfunction through direct and indirect activation and upregulation of the PGC-1α pathway. Metformin, resveratrol, omega 3 fatty acids, montelukast, L-citrulline, and adiponectin are promising candidates that require further pre-clinical and clinical studies to understand their efficacy in decreasing the burden of disease from WMI and BPD in preterm infants.
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Affiliation(s)
- Atefeh Mohammadi
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Randa Higazy
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
| | - Estelle B. Gauda
- The Hospital for Sick Children, Division of Neonatology, Department of Pediatrics and Translational Medicine Program, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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11
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Cable J, Weber-Ban E, Clausen T, Walters KJ, Sharon M, Finley DJ, Gu Y, Hanna J, Feng Y, Martens S, Simonsen A, Hansen M, Zhang H, Goodwin JM, Reggio A, Chang C, Ge L, Schulman BA, Deshaies RJ, Dikic I, Harper JW, Wertz IE, Thomä NH, Słabicki M, Frydman J, Jakob U, David DC, Bennett EJ, Bertozzi CR, Sardana R, Eapen VV, Carra S. Targeted protein degradation: from small molecules to complex organelles-a Keystone Symposia report. Ann N Y Acad Sci 2022; 1510:79-99. [PMID: 35000205 DOI: 10.1111/nyas.14745] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 12/10/2021] [Indexed: 12/15/2022]
Abstract
Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.
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Affiliation(s)
| | - Eilika Weber-Ban
- Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland
| | - Tim Clausen
- Research Institute of Molecular Pathology (IMP), Vienna BioCenter and Medical University of Vienna, Vienna, Austria
| | - Kylie J Walters
- Protein Processing Section, Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland
| | - Michal Sharon
- Department of Bimolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Daniel J Finley
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
| | - Yangnan Gu
- Department of Plant and Microbial Biology and Innovative Genomics Institute, University of California, Berkeley, California
| | - John Hanna
- Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts
| | - Yue Feng
- Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Sascha Martens
- Max Perutz Labs, University of Vienna, Vienna BioCenter (VBC), Vienna, Austria
| | - Anne Simonsen
- Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Malene Hansen
- Sanford Burnham Prebys Medical Discovery Institute, Program of Development, Aging, and Regeneration, La Jolla, California
| | - Hong Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences and College of Life Sciences, University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | | | - Alessio Reggio
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Chunmei Chang
- Molecular and Cell Biology, University of California, Berkeley, Berkeley, California
| | - Liang Ge
- State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Brenda A Schulman
- Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany
| | | | - Ivan Dikic
- Institute of Biochemistry II, School of Medicine and Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany
| | - J Wade Harper
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts
| | - Ingrid E Wertz
- Departments of Molecular Oncology and Early Discovery Biochemistry, Genentech, Inc., South San Francisco, California
- Bristol Myers Squibb, Brisbane, California
| | - Nicolas H Thomä
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Mikołaj Słabicki
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Division of Translational Medical Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Judith Frydman
- Biophysics Graduate Program, Department of Biology and Department of Genetics, Stanford University, Stanford, California
- Biohub, San Francisco, California
- Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Menlo Park, California
| | - Ursula Jakob
- Department of Molecular, Cellular and Developmental Biology, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan
| | - Della C David
- German Center for Neurodegenerative Diseases (DZNE), and Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Eric J Bennett
- Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, California
| | - Carolyn R Bertozzi
- Department of Chemistry and Stanford ChEM-H, Stanford University and Howard Hughes Medical Institute, Stanford, California
| | - Richa Sardana
- Weill Institute of Cell and Molecular Biology and Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York
| | - Vinay V Eapen
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
| | - Serena Carra
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
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12
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Nair S, Leverin AL, Rocha-Ferreira E, Sobotka KS, Thornton C, Mallard C, Hagberg H. Induction of Mitochondrial Fragmentation and Mitophagy after Neonatal Hypoxia-Ischemia. Cells 2022; 11:cells11071193. [PMID: 35406757 PMCID: PMC8997592 DOI: 10.3390/cells11071193] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 03/25/2022] [Accepted: 03/30/2022] [Indexed: 11/16/2022] Open
Abstract
Hypoxia-ischemia (HI) leads to immature brain injury mediated by mitochondrial stress. If damaged mitochondria cannot be repaired, mitochondrial permeabilization ensues, leading to cell death. Non-optimal turnover of mitochondria is critical as it affects short and long term structural and functional recovery and brain development. Therefore, disposal of deficient mitochondria via mitophagy and their replacement through biogenesis is needed. We utilized mt-Keima reporter mice to quantify mitochondrial morphology (fission, fusion) and mitophagy and their mechanisms in primary neurons after Oxygen Glucose Deprivation (OGD) and in brain sections after neonatal HI. Molecular mechanisms of PARK2-dependent and -independent pathways of mitophagy were investigated in vivo by PCR and Western blotting. Mitochondrial morphology and mitophagy were investigated using live cell microscopy. In primary neurons, we found a primary fission wave immediately after OGD with a significant increase in mitophagy followed by a secondary phase of fission at 24 h following recovery. Following HI, mitophagy was upregulated immediately after HI followed by a second wave at 7 days. Western blotting suggests that both PINK1/Parkin-dependent and -independent mechanisms, including NIX and FUNDC1, were upregulated immediately after HI, whereas a PINK1/Parkin mechanism predominated 7 days after HI. We hypothesize that excessive mitophagy in the early phase is a pathologic response which may contribute to secondary energy depletion, whereas secondary mitophagy may be involved in post-HI regeneration and repair.
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Affiliation(s)
- Syam Nair
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden; (A.-L.L.); (E.R.-F.); (K.S.S.); (C.M.); (H.H.)
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
- Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden
- Correspondence:
| | - Anna-Lena Leverin
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden; (A.-L.L.); (E.R.-F.); (K.S.S.); (C.M.); (H.H.)
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
| | - Eridan Rocha-Ferreira
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden; (A.-L.L.); (E.R.-F.); (K.S.S.); (C.M.); (H.H.)
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
- Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden
| | - Kristina S. Sobotka
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden; (A.-L.L.); (E.R.-F.); (K.S.S.); (C.M.); (H.H.)
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
| | - Claire Thornton
- Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK;
| | - Carina Mallard
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden; (A.-L.L.); (E.R.-F.); (K.S.S.); (C.M.); (H.H.)
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden
| | - Henrik Hagberg
- Centre of Perinatal Medicine and Health, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden; (A.-L.L.); (E.R.-F.); (K.S.S.); (C.M.); (H.H.)
- Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, 41685 Gothenburg, Sweden
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13
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Role of Mitophagy in the Pathogenesis of Stroke: From Mechanism to Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6232902. [PMID: 35265262 PMCID: PMC8898771 DOI: 10.1155/2022/6232902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 02/02/2022] [Indexed: 12/15/2022]
Abstract
Mitochondria can supply adenosine triphosphate (ATP) to the tissue, which can regulate metabolism during the pathologic process and is also involved in the pathophysiology of neuronal injury after stroke. Recent studies have suggested that selective autophagy could play important roles in the pathophysiological process of stroke, especially mitophagy. It is usually mediated by the PINK1/Parkin-independent pathway or PINK1/Parkin-dependent pathway. Moreover, mitophagy may be a potential target in the therapy of stroke because the control of mitophagy is neuroprotective in stroke in vitro and in vivo. In this review, we briefly summarize recent researches in mitophagy, introduce the role of mitophagy in the pathogenesis of stroke, then highlight the strategies targeting mitophagy in the treatment of stroke, and finally propose several issues in the treatment of stroke by targeting mitophagy.
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14
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Wang S, Tan J, Miao Y, Zhang Q. Mitochondrial Dynamics, Mitophagy, and Mitochondria–Endoplasmic Reticulum Contact Sites Crosstalk Under Hypoxia. Front Cell Dev Biol 2022; 10:848214. [PMID: 35281107 PMCID: PMC8914053 DOI: 10.3389/fcell.2022.848214] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 02/07/2022] [Indexed: 12/21/2022] Open
Abstract
Mitochondria are double membrane organelles within eukaryotic cells, which act as cellular power houses, depending on the continuous availability of oxygen. Nevertheless, under hypoxia, metabolic disorders disturb the steady-state of mitochondrial network, which leads to dysfunction of mitochondria, producing a large amount of reactive oxygen species that cause further damage to cells. Compelling evidence suggests that the dysfunction of mitochondria under hypoxia is linked to a wide spectrum of human diseases, including obstructive sleep apnea, diabetes, cancer and cardiovascular disorders. The functional dichotomy of mitochondria instructs the necessity of a quality-control mechanism to ensure a requisite number of functional mitochondria that are present to fit cell needs. Mitochondrial dynamics plays a central role in monitoring the condition of mitochondrial quality. The fission–fusion cycle is regulated to attain a dynamic equilibrium under normal conditions, however, it is disrupted under hypoxia, resulting in mitochondrial fission and selective removal of impaired mitochondria by mitophagy. Current researches suggest that the molecular machinery underlying these well-orchestrated processes are coordinated at mitochondria–endoplasmic reticulum contact sites. Here, we establish a holistic understanding of how mitochondrial dynamics and mitophagy are regulated at mitochondria–endoplasmic reticulum contact sites under hypoxia.
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15
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The Effects of In Utero Fetal Hypoxia and Creatine Treatment on Mitochondrial Function in the Late Gestation Fetal Sheep Brain. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3255296. [PMID: 35132347 PMCID: PMC8817846 DOI: 10.1155/2022/3255296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/13/2021] [Accepted: 01/05/2022] [Indexed: 12/21/2022]
Abstract
Near-term acute hypoxia in utero can result in significant fetal brain injury, with some brain regions more vulnerable than others. As mitochondrial dysfunction is an underlying feature of the injury cascade following hypoxia, this study is aimed at characterizing mitochondrial function at a region-specific level in the near-term fetal brain after a period of acute hypoxia. We hypothesized that regional differences in mitochondrial function would be evident, and that prophylactic creatine treatment would mitigate mitochondrial dysfunction following hypoxia; thereby reducing fetal brain injury. Pregnant Border-Leicester/Merino ewes with singleton fetuses were surgically instrumented at 118 days of gestation (dGa; term is ~145 dGA). A continuous infusion of either creatine (n = 15; 6 mg/kg/h) or isovolumetric saline (n = 16; 1.5 ml/kg/h) was administered to the fetuses from 121 dGa. After 10 days of infusion, a subset of fetuses (8 saline-, 7 creatine-treated) were subjected to 10 minutes of umbilical cord occlusion (UCO) to induce a mild global fetal hypoxia. At 72 hours after UCO, the fetal brain was collected for high-resolution mitochondrial respirometry and molecular and histological analyses. The results show that the transient UCO-induced acute hypoxia impaired mitochondrial function in the hippocampus and the periventricular white matter and increased the incidence of cell death in the hippocampus. Creatine treatment did not rectify the changes in mitochondrial respiration associated with hypoxia, but there was a negative relationship between cell death and creatine content following treatment. Irrespective of UCO, creatine increased the proportion of cytochrome c bound to the inner mitochondrial membrane, upregulated the mRNA expression of the antiapoptotic gene Bcl2, and of PCG1-α, a driver of mitogenesis, in the hippocampus. We conclude that creatine treatment prior to brief, acute hypoxia does not fundamentally modify mitochondrial respiratory function, but may improve mitochondrial structural integrity and potentially increase mitogenesis and activity of antiapoptotic pathways.
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16
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Sun D, Lu F, Sheldon A, Jiang X, Ferriero DM. Neuronal deficiency of hypoxia-inducible factor 2α increases hypoxic-ischemic brain injury in neonatal mice. J Neurosci Res 2021; 99:2964-2975. [PMID: 34487578 DOI: 10.1002/jnr.24943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/07/2021] [Accepted: 07/27/2021] [Indexed: 11/11/2022]
Abstract
The cellular responses to hypoxia or hypoxia-ischemia (HI) are governed largely by the hypoxia-inducible factor (HIF) family of transcription factors. Our previous studies show that HIF-1α induction is an important factor that mediates protective effects in the brain after neonatal HI. In the present study, we investigated the contribution of another closely related HIF α isoform, HIF-2α, specifically the neuronal HIF-2α, to brain HI injury. Homozygous transgenic mice with a floxed exon 2 of HIF-2α were bred with CaMKIIα-Cre mice to generate a mouse line with selective deletion of HIF-2α in forebrain neurons. These mice, along with their wildtype littermates, were subjected to HI at postnatal day 9. Brain injury at different ages was evaluated by the levels of cleaved caspase-3 and spectrin breakdown products at 24 hr; and histologically at 6 days or 3 months after HI. Multiple behavioral tests were performed at 3 months, prior to sacrifice. Loss of neuronal HIF-2α exacerbated brain injury during the acute (24 hr) and subacute phases (6 days), with a trend toward more severe volume loss in the adult brain. The long-term brain function for coordinated movement and recognition memory, however, were not impacted in the neuronal HIF-2α deficient mice. Our data suggest that, similar to HIF-1α, neuronal HIF-2α promotes cell survival in the immature mouse brain. The two HIF alpha isoforms may act through partially overlapping or distinct transcriptional targets to mediate their intrinsic protective responses against neonatal HI brain injury.
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Affiliation(s)
- Dawei Sun
- Department of Anesthesiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fuxin Lu
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Ann Sheldon
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Xiangning Jiang
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA
| | - Donna M Ferriero
- Department of Neurology, University of California San Francisco, San Francisco, CA, USA.,Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
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17
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Rayasam A, Fukuzaki Y, Vexler ZS. Microglia-leucocyte axis in cerebral ischaemia and inflammation in the developing brain. Acta Physiol (Oxf) 2021; 233:e13674. [PMID: 33991400 DOI: 10.1111/apha.13674] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 05/06/2021] [Accepted: 05/08/2021] [Indexed: 12/13/2022]
Abstract
Development of the Central Nervous System (CNS) is reliant on the proper function of numerous intricately orchestrated mechanisms that mature independently, including constant communication between the CNS and the peripheral immune system. This review summarizes experimental knowledge of how cerebral ischaemia in infants and children alters physiological communication between leucocytes, brain immune cells, microglia and the neurovascular unit (NVU)-the "microglia-leucocyte axis"-and contributes to acute and long-term brain injury. We outline physiological development of CNS barriers in relation to microglial and leucocyte maturation and the plethora of mechanisms by which microglia and peripheral leucocytes communicate during postnatal period, including receptor-mediated and intracellular inflammatory signalling, lipids, soluble factors and extracellular vesicles. We focus on the "microglia-leucocyte axis" in rodent models of most common ischaemic brain diseases in the at-term infants, hypoxic-ischaemic encephalopathy (HIE) and focal arterial stroke and discuss commonalities and distinctions of immune-neurovascular mechanisms in neonatal and childhood stroke compared to stroke in adults. Given that hypoxic and ischaemic brain damage involve Toll-like receptor (TLR) activation, we discuss the modulatory role of viral and bacterial TLR2/3/4-mediated infection in HIE, perinatal and childhood stroke. Furthermore, we provide perspective of the dynamics and contribution of the axis in cerebral ischaemia depending on the CNS maturational stage at the time of insult, and modulation independently and in consort by individual axis components and in a sex dependent ways. Improved understanding on how to modify crosstalk between microglia and leucocytes will aid in developing age-appropriate therapies for infants and children who suffered cerebral ischaemia.
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Affiliation(s)
- Aditya Rayasam
- Department of Neurology University of California San Francisco San Francisco CA USA
| | - Yumi Fukuzaki
- Department of Neurology University of California San Francisco San Francisco CA USA
| | - Zinaida S. Vexler
- Department of Neurology University of California San Francisco San Francisco CA USA
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18
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Nair S, Rocha‐Ferreira E, Fleiss B, Nijboer CH, Gressens P, Mallard C, Hagberg H. Neuroprotection offered by mesenchymal stem cells in perinatal brain injury: Role of mitochondria, inflammation, and reactive oxygen species. J Neurochem 2021; 158:59-73. [PMID: 33314066 PMCID: PMC8359360 DOI: 10.1111/jnc.15267] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 12/03/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022]
Abstract
Preclinical studies have shown that mesenchymal stem cells have a positive effect in perinatal brain injury models. The mechanisms that cause these neurotherapeutic effects are not entirely intelligible. Mitochondrial damage, inflammation, and reactive oxygen species are considered to be critically involved in the development of injury. Mesenchymal stem cells have immunomodulatory action and exert mitoprotective effects which attenuate production of reactive oxygen species and promote restoration of tissue function and metabolism after perinatal insults. This review summarizes the present state, the underlying causes, challenges and possibilities for effective clinical translation of mesenchymal stem cell therapy.
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Affiliation(s)
- Syam Nair
- Centre of Perinatal Medicine and Health, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Institute of Neuroscience and PhysiologySahlgrenska Academy, University of GothenburgGothenburgSweden
- Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Eridan Rocha‐Ferreira
- Centre of Perinatal Medicine and Health, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Institute of Neuroscience and PhysiologySahlgrenska Academy, University of GothenburgGothenburgSweden
- Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Bobbi Fleiss
- School of Health and Biomedical SciencesRMIT UniversityBundooraVictoriaAustralia
- Université de Paris, NeuroDiderotParisFrance
| | - Cora H Nijboer
- Department for Developmental Origins of DiseaseUniversity Medical Center Utrecht Brain Center and Wilhelmina Children’s Hospital, Utrecht UniversityUtrechtNetherlands
| | | | - Carina Mallard
- Centre of Perinatal Medicine and Health, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Institute of Neuroscience and PhysiologySahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Henrik Hagberg
- Centre of Perinatal Medicine and Health, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Institute of Clinical SciencesSahlgrenska Academy, University of GothenburgGothenburgSweden
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19
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Li K, Zheng Y, Wang X. Self-Regulation of Cerebral Metabolism and Its Neuroprotective Effect After Hypoxic-Ischemic Injury: Evidence From 1H-MRS. Front Neuroanat 2021; 15:672412. [PMID: 34220456 PMCID: PMC8247914 DOI: 10.3389/fnana.2021.672412] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/24/2021] [Indexed: 12/27/2022] Open
Abstract
1H-MRS technology can be used to non-invasively detect the content of cerebral metabolites, to assess the severity of hypoxic-ischemic (HI) injury, and to predict the recovery of compromised neurological function. However, changes to the cerebral self-regulation process after HI are still unclear. This study investigated the changes in cerebral metabolites and the potential relationship with the number of neurons and neural stem/progenitor cells (NSPC) using 1H-MRS, and finally clarifies the self-regulation of cerebral metabolism and neuroprotection after HI injury. Newborn Yorkshire pigs (28 males, 1.0–1.5 kg) aged 3–5 days were used for the HI model in this study. The pigs were randomly divided into the HI group (n = 24) and the control group (n = 4), then the experimental group was subdivided according to different recovery time after HI into the following groups: 0–2 h (n = 4), 2–6 h (n = 4), 6–12 h (n = 4), 12–24 h (n = 4), 24–48 h (n = 4), and 48–72 h (n = 4). Following the HI timepoints, 1H-MRS scans were performed and processed using LCModel software, and brain tissue was immunohistochemically stained for Nestin and NeuN. Immunofluorescence staining of creatine phosphokinase-BB (CK-BB), N-acetylaspartylglutamate synthetase (NAAGS), glutamate carboxypeptidase II (GCP-II), glutamate-cysteine ligase catalytic subunit (GCLC), glutathione synthase (GS), and excitatory amino acid carrier 1 (EAAC1) was then performed. The 1H-MRS results showed that cerebral N-acetylaspartylglutamate (NAAG), glutathione (GSH), and creatine (Cr) content reached their peaks at 12–24 h, which was consistent with the recovery time of hippocampal NSPCs and neurons, indicating a potential neuroprotective effect of NAAG, GSH, and Cr after HI injury.
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Affiliation(s)
- Kexin Li
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yang Zheng
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaoming Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
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20
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The role of mitochondria in cocaine addiction. Biochem J 2021; 478:749-764. [PMID: 33626141 DOI: 10.1042/bcj20200615] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 01/03/2023]
Abstract
The incidence of cocaine abuse is increasing especially in the U.K. where the rates are among the highest in Europe. In addition to its role as a psychostimulant, cocaine has profound effect on brain metabolism, impacting glycolysis and impairing oxidative phosphorylation. Cocaine exposure alters metabolic gene expression and protein networks in brain regions including the prefrontal cortex, the ventral tegmental area and the nucleus accumbens, the principal nuclei of the brain reward system. Here, we focus on how cocaine impacts mitochondrial function, in particular through alterations in electron transport chain function, reactive oxygen species (ROS) production and oxidative stress (OS), mitochondrial dynamics and mitophagy. Finally, we describe the impact of cocaine on brain energy metabolism in the developing brain following prenatal exposure. The plethora of mitochondrial functions altered following cocaine exposure suggest that therapies maintaining mitochondrial functional integrity may hold promise in mitigating cocaine pathology and addiction.
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21
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Bennett JP, Onyango IG. Energy, Entropy and Quantum Tunneling of Protons and Electrons in Brain Mitochondria: Relation to Mitochondrial Impairment in Aging-Related Human Brain Diseases and Therapeutic Measures. Biomedicines 2021; 9:225. [PMID: 33671585 PMCID: PMC7927033 DOI: 10.3390/biomedicines9020225] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/18/2021] [Accepted: 02/18/2021] [Indexed: 11/16/2022] Open
Abstract
Adult human brains consume a disproportionate amount of energy substrates (2-3% of body weight; 20-25% of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered by the proton gradient generated from proton-coupled electron transfer (PCET) in the multi-complex electron transport chain (ETC). ETC catalysis rates are reduced in brains from humans with neurodegenerative diseases (NDDs). Declines of ETC function in NDDs may result from combinations of nitrative stress (NS)-oxidative stress (OS) damage; mitochondrial and/or nuclear genomic mutations of ETC/OXPHOS genes; epigenetic modifications of ETC/OXPHOS genes; or defects in importation or assembly of ETC/OXPHOS proteins or complexes, respectively; or alterations in mitochondrial dynamics (fusion, fission, mitophagy). Substantial free energy is gained by direct O2-mediated oxidation of NADH. Traditional ETC mechanisms require separation between O2 and electrons flowing from NADH/FADH2 through the ETC. Quantum tunneling of electrons and much larger protons may facilitate this separation. Neuronal death may be viewed as a local increase in entropy requiring constant energy input to avoid. The ATP requirement of the brain may partially be used for avoidance of local entropy increase. Mitochondrial therapeutics seeks to correct deficiencies in ETC and OXPHOS.
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Affiliation(s)
| | - Isaac G. Onyango
- International Clinical Research Center, St. Anne’s University Hospital, CZ-65691 Brno, Czech Republic;
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22
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Yi Z, Wu Y, Zhang W, Wang T, Gong J, Cheng Y, Miao C. Activator-Mediated Pyruvate Kinase M2 Activation Contributes to Endotoxin Tolerance by Promoting Mitochondrial Biogenesis. Front Immunol 2021; 11:595316. [PMID: 33542713 PMCID: PMC7851049 DOI: 10.3389/fimmu.2020.595316] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 12/03/2020] [Indexed: 02/03/2023] Open
Abstract
Pyruvate kinase M2 (PKM2) is a key glycolysis enzyme, and its effect on macrophages has not been entirely elucidated. Here, we identified that the PKM2 small-molecule agonist TEPP-46 mediated PKM2 activation by inducing the formation of PKM2 tetramer and promoted macrophage endotoxin tolerance. Lipopolysaccharide (LPS)-tolerant mice had higher expression of the PKM2 tetramer, which was associated with a reduced in vivo immune response to LPS. Pretreatment of macrophages with TEPP-46 resulted in tolerance to LPS stimulation, as demonstrated by a significant reduction in the production of TNF-α and IL-6. We found that TEPP-46 induced mitochondrial biogenesis in macrophages. Inhibition of mitochondrial biogenesis by mtTFA knockdown effectively inhibited TEPP-46-mediated macrophage tolerance to endotoxins. We discovered that TEPP-46 promoted the expression of PGC-1α and that PGC-1α was the key regulator of mitochondrial biogenesis in macrophages induced by TEPP-46. PGC-1α was negatively regulated by the PI3K/Akt signaling pathway. Knockdown of PKM2 or PGC-1α uniformly inhibited TEPP-46-mediated endotoxin tolerance by inhibiting mitochondrial biogenesis. In addition, TEPP-46 protected mice from lethal endotoxemia and sepsis. Collectively, these findings reveal novel mechanisms for the metabolic control of inflammation and for the induction of endotoxin tolerance by promoting mitochondrial biogenesis. Targeting PKM2 appears to be a new therapeutic option for the treatment of sepsis and other inflammatory diseases.
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Affiliation(s)
| | | | | | | | | | - Yao Cheng
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chunmu Miao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7385458. [PMID: 34493950 PMCID: PMC8418694 DOI: 10.1155/2020/7385458] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 09/01/2020] [Accepted: 10/20/2020] [Indexed: 12/18/2022]
Abstract
Hepatic ischemia-reperfusion (HIR) has been proven to trigger oxidative stress and pyroptosis in the hippocampus. Sirtuin 3 (SIRT3) is an essential mitochondrial protein deacetylase regulating oxidative stress and mitophagy. Dexmedetomidine (Dex) has been demonstrated to confer neuroprotection in different brain injury models. However, whether the protective effects of Dex following HIR are orchestrated by activation of SIRT3-mediated mitophagy and inhibition of NOD-like receptor protein 3 (NLRP3) inflammasome activation remains unknown. Herein, two-week-old rats were treated with Dex or a selective SIRT3 inhibitor (3-TYP)/autophagy inhibitor (3-MA) and then subjected to HIR. The results revealed that Dex treatment effectively attenuated neuroinflammation and cognitive deficits via upregulating SIRT3 expression and activity. Furthermore, Dex treatment inhibited the activation of NLRP3 inflammasome, while 3-TYP and 3-MA eliminated the protective effects of Dex, suggesting that SIRT3-mediated mitophagy executes the protective effects of Dex. Moreover, 3-TYP treatment downregulated the expression level of SIRT3 downstream proteins: forkhead-box-protein 3α (FOXO3α), superoxide dismutase 2 (SOD2), peroxiredoxin 3 (PRDX3), and cyclophilin D (CYP-D), which were barely influenced by 3-MA treatment. Notably, both 3-TYP and 3-MA were able to offset the antioxidative and antiapoptosis effects of Dex, indicating that SIRT3-mediated mitophagy may be the last step and the major pathway executing the neuroprotective effects of Dex. In conclusion, Dex inhibits HIR-induced NLRP3 inflammasome activation mainly by triggering SIRT3-mediated mitophagy.
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Alterations in mitochondrial homeostasis in a potassium dichromate model of acute kidney injury and their mitigation by curcumin. Food Chem Toxicol 2020; 145:111774. [PMID: 32980475 DOI: 10.1016/j.fct.2020.111774] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/15/2020] [Accepted: 09/20/2020] [Indexed: 01/22/2023]
Abstract
Curcumin has protective effects in several acute kidney injury models, including that induced by potassium dichromate (K2Cr2O7). The protective effect of curcumin in this experimental model has been associated to the preservation of mitochondrial bioenergetics. This study is aimed at evaluating whether or not curcumin's protective effect in mitochondrial bioenergetics is related to the modulation of mitochondrial dynamics and biogenesis. Wistar rats were treated with a single subcutaneous dose of K2Cr2O7 (12.5 mg/kg) or received curcumin (400 mg/kg/day) by oral gavage 10 days before and one day after the K2Cr2O7 injection. K2Cr2O7 induced kidney dysfunction and increased mitochondrial hydrogen peroxide production, while decreasing the respiration directly attributable to oxidative phosphorylation and mitochondrial membrane potential. In mitochondria, K2Cr2O7 increased fission and reduced fusion. Structural analysis of mitochondria in the proximal tubular cells corroborated their fragmentation and loss of crests' integrity. Regarding mitochondrial biogenesis, K2Cr2O7 decreased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) levels. Conversely, curcumin treatment mitigated the aforementioned alterations and increased the expression of the mitochondrial transcription factor A (TFAM). Taken together, our results suggest that curcumin can protect against renal injury by modulating mitochondrial homeostasis, mitigating alterations in bioenergetics and dynamics, possibly by stimulating mitochondrial biogenesis.
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Rodríguez M, Valez V, Cimarra C, Blasina F, Radi R. Hypoxic-Ischemic Encephalopathy and Mitochondrial Dysfunction: Facts, Unknowns, and Challenges. Antioxid Redox Signal 2020; 33:247-262. [PMID: 32295425 DOI: 10.1089/ars.2020.8093] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Significance: Hypoxic-ischemic events due to intrapartum complications represent the second cause of neonatal mortality and initiate an acute brain disorder known as hypoxic-ischemic encephalopathy (HIE). In HIE, the brain undergoes primary and secondary energy failure phases separated by a latent phase in which partial neuronal recovery is observed. A hypoxic-ischemic event leads to oxygen restriction causing ATP depletion, neuronal oxidative stress, and cell death. Mitochondrial dysfunction and enhanced oxidant formation in brain cells are characteristic phenomena associated with energy failure. Recent Advances: Mitochondrial sources of oxidants in neurons include complex I of the mitochondrial respiratory chain, as a key contributor to O2•- production via succinate by a reverse electron transport mechanism. The reaction of O2•- with nitric oxide (•NO) yields peroxynitrite, a mitochondrial and cellular toxin. Quantitation of the redox state of cytochrome c oxidase, through broadband near-infrared spectroscopy, represents a promising monitoring approach to evaluate mitochondrial dysfunction in vivo in humans, in conjunction with the determination of cerebral oxygenation and their correlation with the severity of brain injury. Critical Issues: The energetic failure being a key phenomenon in HIE connected with the severity of the encephalopathy, measurement of mitochondrial dysfunction in vivo provides an approach to assess evolution, prognosis, and adequate therapies. Restoration of mitochondrial redox homeostasis constitutes a key therapeutic goal. Future Directions: While hypothermia is the only currently accepted therapy in clinical management to preserve mitochondrial function, other mitochondria-targeted and/or redox-based treatments are likely to synergize to ensure further efficacy.
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Affiliation(s)
- Marianela Rodríguez
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO) and Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay.,Departamento de Neonatología, Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Valeria Valez
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO) and Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Carolina Cimarra
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO) and Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Fernanda Blasina
- Departamento de Neonatología, Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Rafael Radi
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO) and Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
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Drp-1 as Potential Therapeutic Target for Lipopolysaccharide-Induced Vascular Hyperpermeability. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:5820245. [PMID: 32685096 PMCID: PMC7336239 DOI: 10.1155/2020/5820245] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/26/2020] [Accepted: 05/21/2020] [Indexed: 01/13/2023]
Abstract
Mitochondria-dependent apoptotic signaling has a critical role in the pathogenesis of vascular hyperpermeability (VH). Dynamin-related protein-1- (Drp-1-) mediated mitochondrial fission plays an important role in mitochondrial homeostasis. In the present study, we studied the involvement of Drp-1 in resistance to VH induced by lipopolysaccharide (LPS). To establish the model of LPS-induced VH, LPS at 15 mg/kg was injected into rats in vivo and rat pulmonary microvascular endothelial cells were exposed to 500 ng/ml LPS in vitro. We found that depletion of Drp-1 remarkedly exacerbated the mitochondria-dependent apoptosis induced by LPS, as evidenced by reduced apoptosis, mitochondrial membrane potential (MMP) depolarization, and activation of caspase-3 and caspase-9. Increased FITC-dextran flux indicated endothelial barrier disruption. In addition, overexpression of Drp-1 prevented LPS-induced endothelial hyperpermeability and upregulated mitophagy, as evidenced by the loss of mitochondrial mass and increased PINK1 expression and mitochondrial Parkin. However, the mitophagy inhibitor, 3-Methyladenine, blocked these protective effects of Drp-1. Furthermore, inhibition of Drp-1 using mitochondrial division inhibitor 1 markedly inhibited LPS-induced mitophagy and aggravated LPS-induced VH, as shown by increased FITC-dextran extravasation. These findings implied that Drp-1 strengthens resistance to mitochondria-dependent apoptosis by regulating mitophagy, suggesting Drp-1 as a possible therapeutic target in LPS-induced VH.
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27
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Palanisamy A, Giri T, Jiang J, Bice A, Quirk JD, Conyers SB, Maloney SE, Raghuraman N, Bauer AQ, Garbow JR, Wozniak DF. In utero exposure to transient ischemia-hypoxemia promotes long-term neurodevelopmental abnormalities in male rat offspring. JCI Insight 2020; 5:133172. [PMID: 32434985 DOI: 10.1172/jci.insight.133172] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 04/22/2020] [Indexed: 01/08/2023] Open
Abstract
The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI, we confirmed that oxytocin-induced aberrant uterine hypercontractility substantially compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 hour after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders.
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Affiliation(s)
- Arvind Palanisamy
- Department of Anesthesiology.,Department of Obstetrics and Gynecology
| | | | | | - Annie Bice
- Mallinckrodt Institute of Radiology, and
| | | | | | | | | | | | | | - David F Wozniak
- Department of Psychiatry, and.,Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri, USA
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28
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Qasim W, Li Y, Sun RM, Feng DC, Wang ZY, Liu DS, Yao JH, Tian XF. PTEN-induced kinase 1-induced dynamin-related protein 1 Ser637 phosphorylation reduces mitochondrial fission and protects against intestinal ischemia reperfusion injury. World J Gastroenterol 2020; 26:1758-1774. [PMID: 32351292 PMCID: PMC7183859 DOI: 10.3748/wjg.v26.i15.1758] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 03/17/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intestinal ischemia reperfusion (I/R) occurs in various diseases, such as trauma and intestinal transplantation. Excessive reactive oxygen species (ROS) accumulation and subsequent apoptotic cell death in intestinal epithelia are important causes of I/R injury. PTEN-induced putative kinase 1 (PINK1) and phosphorylation of dynamin-related protein 1 (DRP1) are critical regulators of ROS and apoptosis. However, the correlation of PINK1 and DRP1 and their function in intestinal I/R injury have not been investigated. Thus, examining the PINK1/DRP1 pathway may help to identify a protective strategy and improve the patient prognosis.
AIM To clarify the mechanism of the PINK1/DRP1 pathway in intestinal I/R injury.
METHODS Male C57BL/6 mice were used to generate an intestinal I/R model via superior mesenteric artery occlusion followed by reperfusion. Chiu’s score was used to evaluate intestinal mucosa damage. The mitochondrial fission inhibitor mdivi-1 was administered by intraperitoneal injection. Caco-2 cells were incubated in vitro in hypoxia/reoxygenation conditions. Small interfering RNAs and overexpression plasmids were transfected to regulate PINK1 expression. The protein expression levels of PINK1, DRP1, p-DRP1 and cleaved caspase 3 were measured by Western blotting. Cell viability was evaluated using a Cell Counting Kit-8 assay and cell apoptosis was analyzed by TUNEL staining. Mitochondrial fission and ROS were tested by MitoTracker and MitoSOX respectively.
RESULTS Intestinal I/R and Caco-2 cell hypoxia/reoxygenation decreased the expression of PINK1 and p-DRP1 Ser637. Pretreatment with mdivi-1 inhibited mitochondrial fission, ROS generation, and apoptosis and ameliorated cell injury in intestinal I/R. Upon PINK1 knockdown or overexpression in vitro, we found that p-DRP1 Ser637 expression and DRP1 recruitment to the mitochondria were associated with PINK1. Furthermore, we verified the physical combination of PINK1 and p-DRP1 Ser637.
CONCLUSION PINK1 is correlated with mitochondrial fission and apoptosis by regulating DRP1 phosphorylation in intestinal I/R. These results suggest that the PINK1/DRP1 pathway is involved in intestinal I/R injury, and provide a new approach for prevention and treatment.
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Affiliation(s)
- Wasim Qasim
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Yang Li
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Rui-Min Sun
- Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Dong-Cheng Feng
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Zhan-Yu Wang
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - De-Shun Liu
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Ji-Hong Yao
- Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Xiao-Feng Tian
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Exp Neurol 2020; 329:113309. [PMID: 32289315 DOI: 10.1016/j.expneurol.2020.113309] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/31/2020] [Accepted: 04/10/2020] [Indexed: 12/27/2022]
Abstract
Central nervous system (CNS) diseases, both traumatic and neurodegenerative, are characterized by impaired mitochondrial bioenergetics and often disturbed mitochondrial dynamics. The dysregulation observed in these pathologies leads to defective respiratory chain function and reduced ATP production, thereby promoting neuronal death. As such, attenuation of mitochondrial dysfunction through induction of mitochondrial biogenesis (MB) is a promising, though still underexplored, therapeutic strategy. MB is a multifaceted process involving the integration of highly regulated transcriptional events, lipid membrane and protein synthesis/assembly and replication of mtDNA. Several nuclear transcription factors promote the expression of genes involved in oxidative phosphorylation, mitochondrial import and export systems, antioxidant defense and mitochondrial gene transcription. Of these, the nuclear-encoded peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is the most commonly studied and is widely accepted as the 'master regulator' of MB. Several recent preclinical studies document that reestablishment of mitochondrial homeostasis through increased MB results in inhibited injury progression and increased functional recovery. This perspective will briefly review the role of mitochondrial dysfunction in the propagation of CNS diseases, while also describing current research strategies that mediate mitochondrial dysfunction and compounds that induce MB for the treatment of acute and chronic neuropathologies.
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30
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Jia L, Wang J, Cao H, Zhang X, Rong W, Xu Z. Activation of PGC-1α and Mitochondrial Biogenesis Protects Against Prenatal Hypoxic-ischemic Brain Injury. Neuroscience 2020; 432:63-72. [PMID: 32114097 DOI: 10.1016/j.neuroscience.2020.02.035] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/18/2020] [Accepted: 02/19/2020] [Indexed: 12/22/2022]
Abstract
Survivals after prenatal hypoxia-ischemia (HI) usually suffer long-lasting cognitive defects. Reduced blood-oxygen supplies and the following reperfusion cause mitochondrial injury. Damaged mitochondria could be replaced by mitochondrial biogenesis program and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) is the specific up-regulator. The objective of this study was to determine whether PGC-1α and mitochondrial biogenesis participate in the resistant responses of an immature brain to prenatal HI. We used a pregnant rat model of transient occlusion of uterine perfusion to induce intrauterine HI associated brain injury. SH-SY5Y cells exposed to oxygen-glucose deprivation was used to investigate the HI induced reactions in vitro. PGC-1α and its downstream signaling pathway (NRF-1 and TFAM) were examined by Western blot and quantitative Real-time PCR. Mitochondrial respiratory enzyme COX-IV was investigated by Western blot and immunohistochemistry. Mitochondrial density and morphology was detected by transmission electron microscopy. The hippocampal injury and cognitive function were examined. We found that the intrauterine HI triggered PGC-1α-NRF-1-TFAM pathway in both protein and mRNA levels. COX-IV expression significantly increased after HI injury. Intrauterine HI induced both mitochondrial impairment and mitochondrial biogenesis. Postnatal administration of pioglitazone further promoted PGC-1α and mitochondrial biogenesis, alleviated hippocampal injury, and improved performance in the behavioral tasks after intrauterine HI. Our investigation implicated activation of PGC-1α, and mitochondrial biogenesis is a neuroprotective mechanism against brain injury caused by systemic prenatal HI. Promotion of PGC-1α by pioglitazone might be a potential treatment for protecting against hippocampal injury and cognitive defects after intrauterine HI.
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Affiliation(s)
- Lijie Jia
- Department of Anesthesiology, the International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine, 910 Hengshan Road, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, 910 Hengshan Road, Shanghai 200030, China
| | - Jianwei Wang
- Department of Anesthesiology, the International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine, 910 Hengshan Road, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, 910 Hengshan Road, Shanghai 200030, China
| | - Huimin Cao
- Department of Anesthesiology, the International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine, 910 Hengshan Road, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, 910 Hengshan Road, Shanghai 200030, China
| | - Xiaoyu Zhang
- Department of Anesthesiology, the International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine, 910 Hengshan Road, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, 910 Hengshan Road, Shanghai 200030, China
| | - Weifang Rong
- Department of Anatomy and Physiology, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
| | - Zifeng Xu
- Department of Anesthesiology, the International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University School of Medicine, 910 Hengshan Road, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, 910 Hengshan Road, Shanghai 200030, China.
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Li T, Li K, Zhang S, Wang Y, Xu Y, Cronin SJF, Sun Y, Zhang Y, Xie C, Rodriguez J, Zhou K, Hagberg H, Mallard C, Wang X, Penninger JM, Kroemer G, Blomgren K, Zhu C. Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice. Cell Death Dis 2020; 11:77. [PMID: 32001673 PMCID: PMC6992638 DOI: 10.1038/s41419-020-2280-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 12/21/2022]
Abstract
Apoptosis inducing factor (AIF) has been shown to be a major contributor to neuron loss in the immature brain after hypoxia-ischemia (HI). Indeed, mice bearing a hypomorphic mutation causing reduced AIF expression are protected against neonatal HI. To further investigate the possible molecular mechanisms of this neuroprotection, we generated an AIF knock-in mouse by introduction of a latent transgene coding for flagged AIF protein into the Rosa26 locus, followed by its conditional activation by a ubiquitously expressed Cre recombinase. Such AIF transgenic mice overexpress the pro-apoptotic splice variant of AIF (AIF1) at both the mRNA (5.9 times higher) and protein level (2.4 times higher), but not the brain-specific AIF splice-isoform (AIF2). Excessive AIF did not have any apparent effects on the phenotype or physiological functions of the mice. However, brain injury (both gray and white matter) after neonatal HI was exacerbated in mice overexpressing AIF, coupled to enhanced translocation of mitochondrial AIF to the nucleus as well as enhanced caspase-3 activation in some brain regions, as indicated by immunohistochemistry. Altogether, these findings corroborate earlier studies demonstrating that AIF plays a causal role in neonatal HI brain injury.
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Affiliation(s)
- Tao Li
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.,Department of Pediatrics, Children's Hospital Affiliated of Zhengzhou University, Zhengzhou, 450018, China
| | - Kenan Li
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden
| | - Shan Zhang
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden
| | - Yafeng Wang
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.,Department of Pediatrics, Children's Hospital Affiliated of Zhengzhou University, Zhengzhou, 450018, China
| | - Yiran Xu
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden
| | - Shane J F Cronin
- Institute of Molecular Biotechnology, Austrian Academy of Sciences, 1030, Vienna, Austria
| | - Yanyan Sun
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden
| | - Yaodong Zhang
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.,Department of Pediatrics, Children's Hospital Affiliated of Zhengzhou University, Zhengzhou, 450018, China
| | - Cuicui Xie
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.,Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Juan Rodriguez
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden
| | - Kai Zhou
- Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.,Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Henrik Hagberg
- Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden
| | - Carina Mallard
- Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.,Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden
| | - Xiaoyang Wang
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China.,Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.,Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden
| | - Josef M Penninger
- Institute of Molecular Biotechnology, Austrian Academy of Sciences, 1030, Vienna, Austria.,Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | - Guido Kroemer
- Equipe labellisée par la Ligue contre le cancer, Université Paris Descartes, Université Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.,Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.,Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou, China.,Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden
| | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Changlian Zhu
- Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China. .,Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden. .,Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. .,Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 40530, Sweden.
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Yu K, Kuang S, Wang C, Wang Y, Liu G, Xie H, Jiang C, Wu J, Wang N, Wu Y. Changes in Mitochondria-Associated Protein Expression and Mitochondrial Function in Response to 2 Weeks of Enriched Environment Training After Cerebral Ischaemia-Reperfusion Injury. J Mol Neurosci 2019; 70:413-421. [PMID: 31782057 DOI: 10.1007/s12031-019-01428-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 11/03/2019] [Indexed: 02/07/2023]
Abstract
An enriched environment (EE) can stimulate the recovery of neurological function following a cerebral ischaemia-reperfusion injury; however, the impact of EE's on mitochondrial function has been insufficiently studied. Our research aimed to assess whether EE's therapeutic impact involved the enhancement of mitochondrial dysfunction. Following 2 weeks of EE training, we tested both mitochondrial function and mitochondria-associated protein expression within the cerebral cortex following cerebral ischaemia-reperfusion injury. We subjected Sprague-Dawley rats to transient focal cerebral ischaemia and categorized the rats into three separate groups, i.e. an enriched environment (EE) group, a standard condition (SC) group and a sham control group (no middle cerebral artery embolization). The rats within the EE group were raised in enriched conditions for 2 weeks, while the rats within the SC group, in comparison, were reared in standard conditions for 2 weeks. After 2 weeks, the cerebral cortices of the rats were removed. We then measured a series of indices, i.e. the protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC-1α), nuclear respiratory factor-1 (NRF-1), mitochondrial transcription factor A (TFAM) and mitochondrial protein cytochrome C oxidase subunit IV (COX IV). Furthermore, the number of mitochondria was evaluated through electron microscopy.EE upregulated the protein expression of PGC-1α, NRF-1 as well as TFAM, which function as the master regulators of mitochondrial biogenesis, in comparison with the SC group. The EE group's COX IV protein expression also exhibited an increase. Moreover, the amount of mitochondria in the peri-infarct region of the cortex increased as result of EE training. Over 2 weeks, EE training significantly increased mitochondrial biogenesis-associated protein expression and mitochondrial function. A possible mechanism of the EE leading to the improvement of neurological function is that it increases brain mitochondrial biogenesis after the rats' cerebral ischaemia-reperfusion injury. Mitochondrial biogenesis stimulation or enhancement could become an innovative strategy for neuroprotection in future treatment.
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Affiliation(s)
- Kewei Yu
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Shenyi Kuang
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chuanjie Wang
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuyang Wang
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Gang Liu
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Hongyu Xie
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Congyu Jiang
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Junfa Wu
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Nianhong Wang
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yi Wu
- Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai, China.
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Bianchi M, D'Oria V, Braghini MR, Petrini S, Manco M. Liraglutide Treatment Ameliorates Neurotoxicity Induced by Stable Silencing of Pin1. Int J Mol Sci 2019; 20:ijms20205064. [PMID: 31614723 PMCID: PMC6829573 DOI: 10.3390/ijms20205064] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023] Open
Abstract
Post-translational modulation of peptidylprolyl isomerase Pin1 might link impaired glucose metabolism and neurodegeneration, being Pin1 effectors target for the glucagon-Like-Peptide1 analog liraglutide. We tested the hypotheses in Pin1 silenced cells (SH-SY5Y) treated with 2-deoxy-d-glucose (2DG) and methylglyoxal (MG), stressors causing altered glucose trafficking, glucotoxicity and protein glycation. Rescue by liraglutide was investigated. Pin1 silencing caused increased levels of reactive oxygen species, upregulated energy metabolism as suggested by raised levels of total ATP content and mRNA of SIRT1, PGC1α, NRF1; enhanced mitochondrial fission events as supported by raised protein expression of FIS1 and DRP1. 2DG and MG reduced significantly cell viability in all the cell lines. In Pin1 KD clones, 2DG exacerbated altered mitochondrial dynamics causing higher rate of fission events. Liraglutide influenced insulin signaling pathway (GSK3b/Akt); improved cell viability also in cells treated with 2DG; but it did not revert mitochondrial dysfunction in Pin1 KD model. In cells treated with MG, liraglutide enhanced cell viability, reduced ROS levels and cell death (AnnexinV/PI); and trended to reduce anti-apoptotic signals (BAX, BCL2, CASP3). Pin1 silencing mimics neuronal metabolic impairment of patients with impaired glucose metabolism and neurodegeneration. Liraglutide rescues to some extent cellular dysfunctions induced by Pin1 silencing.
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Affiliation(s)
- Marzia Bianchi
- Research Area for Multi-factorial Diseases, Obesity and Diabetes, Bambino Gesù Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy.
| | - Valentina D'Oria
- Confocal Microscopy Core Facility, Research Laboratories, Bambino Gesu' Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy.
| | - Maria Rita Braghini
- Molecular Genetics of Complex Phenotypes Research Unit, Bambino Gesù Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy.
| | - Stefania Petrini
- Confocal Microscopy Core Facility, Research Laboratories, Bambino Gesu' Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy.
| | - Melania Manco
- Research Area for Multi-factorial Diseases, Obesity and Diabetes, Bambino Gesù Children's Research Hospital, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), viale di San Paolo 15, 00146 Rome, Italy.
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Singh-Mallah G, Nair S, Sandberg M, Mallard C, Hagberg H. The Role of Mitochondrial and Endoplasmic Reticulum Reactive Oxygen Species Production in Models of Perinatal Brain Injury. Antioxid Redox Signal 2019; 31:643-663. [PMID: 30957515 PMCID: PMC6657303 DOI: 10.1089/ars.2019.7779] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/01/2019] [Accepted: 04/03/2019] [Indexed: 12/20/2022]
Abstract
Significance: Perinatal brain injury is caused by hypoxia-ischemia (HI) in term neonates, perinatal arterial stroke, and infection/inflammation leading to devastating long-term neurodevelopmental deficits. Therapeutic hypothermia is the only currently available treatment but is not successful in more than 50% of term neonates suffering from hypoxic-ischemic encephalopathy. Thus, there is an urgent unmet need for alternative or adjunct therapies. Reactive oxygen species (ROS) are important for physiological signaling, however, their overproduction/accumulation from mitochondria and endoplasmic reticulum (ER) during HI aggravate cell death. Recent Advances and Critical Issues: Mechanisms underlying ER stress-associated ROS production have been primarily elucidated using either non-neuronal cells or adult neurodegenerative experimental models. Findings from mature brain cannot be simply transferred to the immature brain. Therefore, age-specific studies investigating ER stress modulators may help investigate ER stress-associated ROS pathways in the immature brain. New therapeutics such as mitochondrial site-specific ROS inhibitors that selectively inhibit superoxide (O2•-)/hydrogen peroxide (H2O2) production are currently being developed. Future Directions: Because ER stress and oxidative stress accentuate each other, a combinatorial therapy utilizing both antioxidants and ER stress inhibitors may prove to be more protective against perinatal brain injury. Moreover, multiple relevant targets need to be identified for targeting ROS before they are formed. The role of organelle-specific ROS in brain repair needs investigation. Antioxid. Redox Signal. 31, 643-663.
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Affiliation(s)
- Gagandeep Singh-Mallah
- Institute of Biomedicine, Department of Medical Biochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Syam Nair
- Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Clinical Sciences, Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Mats Sandberg
- Institute of Biomedicine, Department of Medical Biochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carina Mallard
- Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Henrik Hagberg
- Centre of Perinatal Medicine and Health, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Institute of Clinical Sciences, Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Chen T, Zhu J, Wang YH, Hang CH. ROS-Mediated Mitochondrial Dysfunction and ER Stress Contribute to Compression-Induced Neuronal Injury. Neuroscience 2019; 416:268-280. [PMID: 31425734 DOI: 10.1016/j.neuroscience.2019.08.007] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/15/2019] [Accepted: 08/05/2019] [Indexed: 12/22/2022]
Abstract
Intracranial hypertension (IH) is a medical or surgical emergency that can be the common ending of various neurological disorders, such as traumatic brain injury, cerebral vascular diseases and brain tumors. However, the molecular mechanisms underlying IH-induced neuronal apoptosis have not been fully determined, and the treatments are symptomatic, insufficient and complicated by side-effects. In this study, a cellular model induced by compressed gas treatment in primary cultured rat cortical neurons was performed to mimic IH-induced neuronal injury in vitro. We found that compression induced cytotoxicity and apoptosis in cortical neurons in a dose- and time-dependent manner. Compression resulted in oxidative stress, which could be prevented by the ROS scavenger N-acetylcysteine (NAC). Compression produced mitochondrial oxidative stress, ATP loss and mitochondrial fragmentation. The results of western blot showed that compression differently regulated the expression of mitochondrial dynamic proteins, and the Drp1 inhibitor mdivi-1 partially reversed the compression-induced cytotoxicity. Compression significantly increased the expression of ER stress-associated factors in a time-dependent manner. The results of calcium imaging showed that compression induced intracellular calcium overload via promoting ER calcium release. Furthermore, the results using inhibitors of each signaling pathway demonstrated that ROS mediated the compression-induced ER stress and mitochondrial dysfunction in cortical neurons. In conclusion, our results demonstrated that compression induced apoptosis in primary cultured cortical neurons, which was associated with ROS mediated ER stress and mitochondrial dysfunction. Pharmacological compounds or agents targeting mitochondrial dysfunction and ER stress associated oxidative stress might be ideal candidates for the treatment of IH-related neurological diseases.
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Affiliation(s)
- Tao Chen
- Department of Neurosurgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China; Department of Neurosurgery, The 904th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, Jiangsu 214044, China
| | - Jie Zhu
- Department of Neurosurgery, The 904th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, Jiangsu 214044, China
| | - Yu-Hai Wang
- Department of Neurosurgery, The 904th Hospital of PLA, Medical School of Anhui Medical University, Wuxi, Jiangsu 214044, China.
| | - Chun-Hua Hang
- Department of Neurosurgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210000, China.
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Ceprian M, Fulton D. Glial Cell AMPA Receptors in Nervous System Health, Injury and Disease. Int J Mol Sci 2019; 20:E2450. [PMID: 31108947 PMCID: PMC6566241 DOI: 10.3390/ijms20102450] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/11/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022] Open
Abstract
Glia form a central component of the nervous system whose varied activities sustain an environment that is optimised for healthy development and neuronal function. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)-type glutamate receptors (AMPAR) are a central mediator of glutamatergic excitatory synaptic transmission, yet they are also expressed in a wide range of glial cells where they influence a variety of important cellular functions. AMPAR enable glial cells to sense the activity of neighbouring axons and synapses, and as such many aspects of glial cell development and function are influenced by the activity of neural circuits. However, these AMPAR also render glia sensitive to elevations of the extracellular concentration of glutamate, which are associated with a broad range of pathological conditions. Excessive activation of AMPAR under these conditions may induce excitotoxic injury in glial cells, and trigger pathophysiological responses threatening other neural cells and amplifying ongoing disease processes. The aim of this review is to gather information on AMPAR function from across the broad diversity of glial cells, identify their contribution to pathophysiological processes, and highlight new areas of research whose progress may increase our understanding of nervous system dysfunction and disease.
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Affiliation(s)
- Maria Ceprian
- Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain.
- Departamento de Bioquímica y Biología Molecular, CIBERNED, IRICYS. Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Daniel Fulton
- Neuroscience and Ophthalmology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
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Fan P, Yu XY, Xie XH, Chen CH, Zhang P, Yang C, Peng X, Wang YT. Mitophagy is a protective response against oxidative damage in bone marrow mesenchymal stem cells. Life Sci 2019; 229:36-45. [PMID: 31085242 DOI: 10.1016/j.lfs.2019.05.027] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 01/26/2023]
Abstract
AIMS Bone marrow mesenchymal stem cells (BMSCs) show great potential in clinical applications such as in intervertebral disc degeneration. Nevertheless, environmental stress during the BMSC transplant or in the injured tissues is a catastrophic factor that causes cell toxicity and poor survival of BMSCs. Mitophagy plays a vital role in maintaining cellular homeostasis and defending against oxidative stress because this process could control mitochondrial quality and quantity by eliminating dysfunctional or damaged mitochondria that can cause cell death. However, the accurate mechanisms of mitophagy in protecting BMSCs against the harshness of oxidative stress remain largely unknown. MAIN METHODS BMSCs were treated with H2O2 for various time periods. Mitophagy response was evaluated through the expression levels of LC3-II, p62 and mitophagosomal formation by using Western blot and fluorescence analysis. Cell apoptosis was examined by flow cytometry and TUNEL assay. The interactions of mitophagy and apoptosis and the possible signalling pathways were investigated through the co-treatment of mitophagy inhibitor or mitophagy activator with H2O2. KEY FINDINGS Oxidative stress rapidly facilitated mitophagy through JNK at an early stage but decreased mitophagy and increased apoptosis at a late stage. Furthermore, mitophagy inhibition significantly enhanced the apoptosis in the cells treated by H2O2. SIGNIFICANCE Induced mitophagy may play pivotal roles in protecting cells against oxidative stress in BMSCs.
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Affiliation(s)
- Pan Fan
- Department of Spine Center, Zhongda Hospital, Medical School, Southeast University, China
| | - Xiao-Yu Yu
- Department of Gynaecology and Obstetrics, The Affiliated Jiangning Hospital of Nanjing Medical University, China
| | - Xing-Hui Xie
- Department of Spine Center, Zhongda Hospital, Medical School, Southeast University, China
| | - Chang-Hong Chen
- Department of Orthopaedic Surgery, Jiangyin Affiliated Hospital of Nanjing University of Chinese Medicine, China
| | - Po Zhang
- Department of Spine Center, Zhongda Hospital, Medical School, Southeast University, China
| | - Cheng Yang
- Department of Spine Center, Zhongda Hospital, Medical School, Southeast University, China
| | - Xin Peng
- Department of Spine Center, Zhongda Hospital, Medical School, Southeast University, China
| | - Yun-Tao Wang
- Department of Spine Center, Zhongda Hospital, Medical School, Southeast University, China.
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38
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Affiliation(s)
- Joseph M Bateman
- Maurice Wohl Clinical Neuroscience Institute, King's College London, UK
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39
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Koehler RC, Yang ZJ, Lee JK, Martin LJ. Perinatal hypoxic-ischemic brain injury in large animal models: Relevance to human neonatal encephalopathy. J Cereb Blood Flow Metab 2018; 38:2092-2111. [PMID: 30149778 PMCID: PMC6282216 DOI: 10.1177/0271678x18797328] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Perinatal hypoxia-ischemia resulting in death or lifelong disabilities remains a major clinical disorder. Neonatal models of hypoxia-ischemia in rodents have enhanced our understanding of cellular mechanisms of neural injury in developing brain, but have limitations in simulating the range, accuracy, and physiology of clinical hypoxia-ischemia and the relevant systems neuropathology that contribute to the human brain injury pattern. Large animal models of perinatal hypoxia-ischemia, such as partial or complete asphyxia at the time of delivery of fetal monkeys, umbilical cord occlusion and cerebral hypoperfusion at different stages of gestation in fetal sheep, and severe hypoxia and hypoperfusion in newborn piglets, have largely overcome these limitations. In monkey, complete asphyxia produces preferential injury to cerebellum and primary sensory nuclei in brainstem and thalamus, whereas partial asphyxia produces preferential injury to somatosensory and motor cortex, basal ganglia, and thalamus. Mid-gestational fetal sheep provide a valuable model for studying vulnerability of progenitor oligodendrocytes. Hypoxia followed by asphyxia in newborn piglets replicates the systems injury seen in term newborns. Efficacy of post-insult hypothermia in animal models led to the success of clinical trials in term human neonates. Large animal models are now being used to explore adjunct therapy to augment hypothermic neuroprotection.
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Affiliation(s)
- Raymond C Koehler
- 1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Zeng-Jin Yang
- 1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Jennifer K Lee
- 1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.,2 The Pathobiology Graduate Training Program, Johns Hopkins University, Baltimore, MD, USA
| | - Lee J Martin
- 2 The Pathobiology Graduate Training Program, Johns Hopkins University, Baltimore, MD, USA.,3 Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, MD, USA
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40
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BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk–Nox2–Drp1-mitochondrial fission pathways. Angiogenesis 2018; 21:599-615. [DOI: 10.1007/s10456-018-9611-z] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 04/03/2018] [Indexed: 12/22/2022]
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