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Liu Q, Han Z, Li T, Meng J, Zhu C, Wang J, Wang J, Zhang Z, Wu H. Microglial HO-1 aggravates neuronal ferroptosis via regulating iron metabolism and inflammation in the early stage after intracerebral hemorrhage. Int Immunopharmacol 2025; 147:113942. [PMID: 39740507 DOI: 10.1016/j.intimp.2024.113942] [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: 06/04/2024] [Revised: 12/09/2024] [Accepted: 12/22/2024] [Indexed: 01/02/2025]
Abstract
Heme oxygenase 1 (HO-1), an enzyme involved in heme catabolism, has been shown upregulated in microglia cells and plays a critical roles in neurological damages after intracerebral hemorrhage (ICH). However, the mechanisms by which HO-1 mediates the neuronal damages are still obscure. Here, our findings demonstrate that HO-1 over-expression exacerbates the pro-inflammatory response of microglia and induces neuronal ferroptosis through promoting intracellular iron deposition in the ICH model both in vitro and in vivo. Furthermore, in the co-cultured ICH model in vitro, we verify that HO-1 over-expression disrupts the balance of iron metabolism in microglia, which increases the iron efflux to the extracellular space and promotes iron ion uptake in neurons, leading to lipid peroxidation injury and further contributing to neuronal ferroptosis. Moreover, the specific ferroptosis inhibitor Ferrostatin-1 (Fer-1) treatment could mitigate the damages in the co-cultured HT22 cells that caused by HO-1 over-expression in microglia, and improve the neurological function in the ICH model in mice. By shedding light on the mechanisms of aggravating neuronal ferroptosis due to HO-1 overexpression in the early stages after ICH, our study provides insights into the potential therapy of targeting HO-1 to treat ICH.
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Affiliation(s)
- Qi Liu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Ziyi Han
- College of Medical Laboratory Technology, Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Tao Li
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Jincheng Meng
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Chenwei Zhu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Junmin Wang
- Department of Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Jian Wang
- Department of Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Zhen Zhang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
| | - He Wu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
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Wang S, Qin M, Fan X, Jiang C, Hou Q, Ye Z, Zhang X, Yang Y, Xiao J, Wallace K, Rastegar-Kashkooli Y, Peng Q, Jin D, Wang J, Wang M, Ding R, Tao J, Kim YT, Bhawal UK, Wang J, Chen X, Wang J. The role of metal ions in stroke: Current evidence and future perspectives. Ageing Res Rev 2024; 101:102498. [PMID: 39243890 DOI: 10.1016/j.arr.2024.102498] [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: 03/18/2024] [Revised: 07/24/2024] [Accepted: 09/04/2024] [Indexed: 09/09/2024]
Abstract
Metal ions play a pivotal role in maintaining optimal brain function within the human body. Nevertheless, the accumulation of these ions can result in irregularities that lead to brain damage and dysfunction. Disruptions of metal ion homeostasis can result in various pathologies, including inflammation, redox dysregulation, and blood-brain barrier disruption. While research on metal ions has chiefly focused on neurodegenerative diseases, little attention has been given to their involvement in the onset and progression of stroke. Recent studies have identified cuproptosis and confirmed ferroptosis as significant factors in stroke pathology, underscoring the importance of metal ions in stroke pathology, including abnormal ion transport, neurotoxicity, blood-brain barrier damage, and cell death. Additionally, it provides an overview of contemporary metal ion chelators and detection techniques, which may offer novel approaches to stroke treatment.
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Affiliation(s)
- Shaoshuai Wang
- Department of Pain Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; Non-commissioned Officer School of Army Medical University, Shijiazhuang, Hebei 050000, China
| | - Mengzhe Qin
- Department of Pain Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Xiaochong Fan
- Department of Pain Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Chao Jiang
- Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Qingchuan Hou
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Ziyi Ye
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Xinru Zhang
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Yunfan Yang
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jingyu Xiao
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Kevin Wallace
- College of Mathematical and Natural Sciences, University of Maryland, College Park, MD 20742, USA
| | - Yousef Rastegar-Kashkooli
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; School of International Education, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Qinfeng Peng
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Dongqi Jin
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Junyang Wang
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Menglu Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Ruoqi Ding
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jin Tao
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Yun Tai Kim
- Division of Functional Food Research, Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju-gun, Jeollabuk-do 55365, Republic of Korea; Department of Food Biotechnology, Korea University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Ujjal K Bhawal
- Center for Global Health Research, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 600077, India; Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Chiba 271-8587, Japan
| | - Junmin Wang
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
| | - Xuemei Chen
- Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
| | - Jian Wang
- Department of Pain Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China; Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China.
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Wang YY, Li K, Wang JJ, Hua W, Liu Q, Sun YL, Qi JP, Song YJ. Bone marrow-derived mesenchymal stem cell-derived exosome-loaded miR-129-5p targets high-mobility group box 1 attenuates neurological-impairment after diabetic cerebral hemorrhage. World J Diabetes 2024; 15:1979-2001. [PMID: 39280179 PMCID: PMC11372641 DOI: 10.4239/wjd.v15.i9.1979] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Diabetic intracerebral hemorrhage (ICH) is a serious complication of diabetes. The role and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-exo) in neuroinflammation post-ICH in patients with diabetes are unknown. In this study, we investigated the regulation of BMSC-exo on hyperglycemia-induced neuroinflammation. AIM To study the mechanism of BMSC-exo on nerve function damage after diabetes complicated with cerebral hemorrhage. METHODS BMSC-exo were isolated from mouse BMSC media. This was followed by transfection with microRNA-129-5p (miR-129-5p). BMSC-exo or miR-129-5p-overexpressing BMSC-exo were intravitreally injected into a diabetes mouse model with ICH for in vivo analyses and were cocultured with high glucose-affected BV2 cells for in vitro analyses. The dual luciferase test and RNA immunoprecipitation test verified the targeted binding relationship between miR-129-5p and high-mobility group box 1 (HMGB1). Quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to assess the levels of some inflammation factors, such as HMGB1, interleukin 6, interleukin 1β, toll-like receptor 4, and tumor necrosis factor α. Brain water content, neural function deficit score, and Evans blue were used to measure the neural function of mice. RESULTS Our findings indicated that BMSC-exo can promote neuroinflammation and functional recovery. MicroRNA chip analysis of BMSC-exo identified miR-129-5p as the specific microRNA with a protective role in neuroinflammation. Overexpression of miR-129-5p in BMSC-exo reduced the inflammatory response and neurological impairment in comorbid diabetes and ICH cases. Furthermore, we found that miR-129-5p had a targeted binding relationship with HMGB1 mRNA. CONCLUSION We demonstrated that BMSC-exo can reduce the inflammatory response after ICH with diabetes, thereby improving the neurological function of the brain.
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Affiliation(s)
- Yue-Ying Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ke Li
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jia-Jun Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wei Hua
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Qi Liu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Lan Sun
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ji-Ping Qi
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yue-Jia Song
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Wang YY, Li K, Wang JJ, Hua W, Liu Q, Sun YL, Qi JP, Song YJ. Bone marrow-derived mesenchymal stem cell-derived exosome-loaded miR-129-5p targets high-mobility group box 1 attenuates neurological-impairment after diabetic cerebral hemorrhage. World J Diabetes 2024; 15:1978-2000. [DOI: 10.4239/wjd.v15.i9.1978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/29/2024] [Accepted: 07/23/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Diabetic intracerebral hemorrhage (ICH) is a serious complication of diabetes. The role and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes (BMSC-exo) in neuroinflammation post-ICH in patients with diabetes are unknown. In this study, we investigated the regulation of BMSC-exo on hyperglycemia-induced neuroinflammation.
AIM To study the mechanism of BMSC-exo on nerve function damage after diabetes complicated with cerebral hemorrhage.
METHODS BMSC-exo were isolated from mouse BMSC media. This was followed by transfection with microRNA-129-5p (miR-129-5p). BMSC-exo or miR-129-5p-overexpressing BMSC-exo were intravitreally injected into a diabetes mouse model with ICH for in vivo analyses and were cocultured with high glucose-affected BV2 cells for in vitro analyses. The dual luciferase test and RNA immunoprecipitation test verified the targeted binding relationship between miR-129-5p and high-mobility group box 1 (HMGB1). Quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were conducted to assess the levels of some inflammation factors, such as HMGB1, interleukin 6, interleukin 1β, toll-like receptor 4, and tumor necrosis factor α. Brain water content, neural function deficit score, and Evans blue were used to measure the neural function of mice.
RESULTS Our findings indicated that BMSC-exo can promote neuroinflammation and functional recovery. MicroRNA chip analysis of BMSC-exo identified miR-129-5p as the specific microRNA with a protective role in neuroinflammation. Overexpression of miR-129-5p in BMSC-exo reduced the inflammatory response and neurological impairment in comorbid diabetes and ICH cases. Furthermore, we found that miR-129-5p had a targeted binding relationship with HMGB1 mRNA.
CONCLUSION We demonstrated that BMSC-exo can reduce the inflammatory response after ICH with diabetes, thereby improving the neurological function of the brain.
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Affiliation(s)
- Yue-Ying Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ke Li
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jia-Jun Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wei Hua
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Qi Liu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Lan Sun
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ji-Ping Qi
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yue-Jia Song
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Wang B, Tian L, Zhang Z, Liu Z, Li K, Zhang Q, Song Y, Qi J. CircTrim37 Ameliorates Intracerebral Hemorrhage Outcomes by Modulating Microglial Polarization via the miR-30c-5p/SOCS3 Axis. Mol Neurobiol 2024; 61:4038-4054. [PMID: 38055163 DOI: 10.1007/s12035-023-03776-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/03/2023] [Indexed: 12/07/2023]
Abstract
Circular RNAs (circRNAs) have been progressively recognized as critical regulators in the pathology and pathophysiology of central nervous system disease. However, the potential role of circRNAs in intracerebral hemorrhage (ICH) is still largely unclear. Here, we demonstrate that circTrim37 expression was significantly upregulated at 3 days after ICH by circular RNA microarray and qPCR assays. Overexpression of circTrim37 could significantly ameliorate brain injury volume, brain edema, neurologic deficits, and inflammation in vivo after ICH. CircTrim37 promotes M2 polarization while restrains M1 polarization in vitro. Furthermore, circTrim37 acts as an endogenous sponge for miR-30c-5p, thereby inhibiting miR-30c-5p activity, leading to the upregulation of SOCS3 and making the balance of microglial response towards an M2 phenotype. Taken together, our results indicate the participation of circTrim37 and its coupling mechanism in ICH and provide a novel therapeutic target for ICH.
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Affiliation(s)
- Benshuai Wang
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, 150001, China
| | - Lin Tian
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, 150001, China
| | - Zhen Zhang
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, 150001, China
| | - Zhiyi Liu
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, 150001, China
| | - Ke Li
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, 150001, China
| | - Qianqian Zhang
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, 150001, China
| | - Yuejia Song
- Department of Endocrinology, First Clinical Hospital, Harbin Medical University, Harbin, 150001, China.
| | - Jiping Qi
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, 150001, China.
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Fahrer J, Wittmann S, Wolf AC, Kostka T. Heme Oxygenase-1 and Its Role in Colorectal Cancer. Antioxidants (Basel) 2023; 12:1989. [PMID: 38001842 PMCID: PMC10669411 DOI: 10.3390/antiox12111989] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/03/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Heme oxygenase-1 (HO-1) is an enzyme located at the endoplasmic reticulum, which is responsible for the degradation of cellular heme into ferrous iron, carbon monoxide and biliverdin-IXa. In addition to this main function, the enzyme is involved in many other homeostatic, toxic and cancer-related mechanisms. In this review, we first summarize the importance of HO-1 in physiology and pathophysiology with a focus on the digestive system. We then detail its structure and function, followed by a section on the regulatory mechanisms that control HO-1 expression and activity. Moreover, HO-2 as important further HO isoform is discussed, highlighting the similarities and differences with regard to HO-1. Subsequently, we describe the direct and indirect cytoprotective functions of HO-1 and its breakdown products carbon monoxide and biliverdin-IXa, but also highlight possible pro-inflammatory effects. Finally, we address the role of HO-1 in cancer with a particular focus on colorectal cancer. Here, relevant pathways and mechanisms are presented, through which HO-1 impacts tumor induction and tumor progression. These include oxidative stress and DNA damage, ferroptosis, cell cycle progression and apoptosis as well as migration, proliferation, and epithelial-mesenchymal transition.
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Affiliation(s)
- Jörg Fahrer
- Division of Food Chemistry and Toxicology, Department of Chemistry, RPTU Kaiserslautern-Landau, Erwin-Schrödinger Strasse 52, D-67663 Kaiserslautern, Germany; (S.W.); (A.-C.W.)
| | | | | | - Tina Kostka
- Division of Food Chemistry and Toxicology, Department of Chemistry, RPTU Kaiserslautern-Landau, Erwin-Schrödinger Strasse 52, D-67663 Kaiserslautern, Germany; (S.W.); (A.-C.W.)
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Li D, Liu S, Yu T, Liu Z, Sun S, Bragin D, Shirokov A, Navolokin N, Bragina O, Hu Z, Kurths J, Fedosov I, Blokhina I, Dubrovski A, Khorovodov A, Terskov A, Tzoy M, Semyachkina-Glushkovskaya O, Zhu D. Photostimulation of brain lymphatics in male newborn and adult rodents for therapy of intraventricular hemorrhage. Nat Commun 2023; 14:6104. [PMID: 37775549 PMCID: PMC10541888 DOI: 10.1038/s41467-023-41710-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 09/15/2023] [Indexed: 10/01/2023] Open
Abstract
Intraventricular hemorrhage is one of the most fatal forms of brain injury that is a common complication of premature infants. However, the therapy of this type of hemorrhage is limited, and new strategies are needed to reduce hematoma expansion. Here we show that the meningeal lymphatics is a pathway to remove red blood cells from the brain's ventricular system of male human, adult and newborn rodents and is a target for non-invasive transcranial near infrared photobiomodulation. Our results uncover the clinical significance of phototherapy of intraventricular hemorrhage in 4-day old male rat pups that have the brain similar to a preterm human brain. The course of phototherapy in newborn rats provides fast recovery after intraventricular hemorrhage due to photo-improvements of lymphatic drainage and clearing functions. These findings shed light on the mechanisms of phototherapy of intraventricular hemorrhage that can be a clinically relevant technology for treatment of neonatal intracerebral bleedings.
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Affiliation(s)
- Dongyu Li
- Britton Chance Center for Biomedical Photonics - MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics - Advanced Biomedical Imaging Facility, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China
- School of Optical Electronic Information, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China
| | - Shaojun Liu
- Britton Chance Center for Biomedical Photonics - MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics - Advanced Biomedical Imaging Facility, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China
| | - Tingting Yu
- Britton Chance Center for Biomedical Photonics - MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics - Advanced Biomedical Imaging Facility, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China.
| | - Zhang Liu
- Britton Chance Center for Biomedical Photonics - MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics - Advanced Biomedical Imaging Facility, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China
| | - Silin Sun
- Britton Chance Center for Biomedical Photonics - MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics - Advanced Biomedical Imaging Facility, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China
| | - Denis Bragin
- Lovelace Biomedical Research Institute, Albuquerque, NM, 87108, USA
- Department of Neurology University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA
| | - Alexander Shirokov
- Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, Prospekt Entuziastov 13, Saratov, 410049, Russia
- Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia
| | - Nikita Navolokin
- Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia
- Saratov State Medical University, B. Kazachya str., 112, Saratov, 410012, Russia
| | - Olga Bragina
- Lovelace Biomedical Research Institute, Albuquerque, NM, 87108, USA
| | - Zhengwu Hu
- Britton Chance Center for Biomedical Photonics - MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics - Advanced Biomedical Imaging Facility, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China
- School of Optical Electronic Information, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China
| | - Jürgen Kurths
- Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia
- Physics Department, Humboldt University, Newtonstrasse 15, 12489, Berlin, Germany
- Potsdam Institute for Climate Impact Research, Telegrafenberg A31, 14473, Potsdam, Germany
- Sechenov First Moscow State Medical University, Bolshaya Pirogovskaya 2, building 4, 119435, Moscow, Russia
| | - Ivan Fedosov
- Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia
| | - Inna Blokhina
- Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia
| | | | | | - Andrey Terskov
- Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia
| | - Maria Tzoy
- Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia
| | - Oxana Semyachkina-Glushkovskaya
- Saratov State University, Astrakhanskaya str., 83, Saratov, 410012, Russia.
- Physics Department, Humboldt University, Newtonstrasse 15, 12489, Berlin, Germany.
| | - Dan Zhu
- Britton Chance Center for Biomedical Photonics - MoE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics - Advanced Biomedical Imaging Facility, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China.
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Sharkus R, Thakkar R, Kolson DL, Constantinescu CS. Dimethyl Fumarate as Potential Treatment for Alzheimer's Disease: Rationale and Clinical Trial Design. Biomedicines 2023; 11:1387. [PMID: 37239057 PMCID: PMC10216730 DOI: 10.3390/biomedicines11051387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/03/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Alzheimer's Disease (AD) is a debilitating disease that leads to severe cognitive impairment and functional decline. The role of tau hyperphosphorylation and amyloid plaque deposition in the pathophysiology of AD has been well described; however, neuroinflammation and oxidative stress related to sustained microglial activation is thought to play a significant role in the disease process as well. NRF-2 has been identified in modulating the effects of inflammation and oxidative stress in AD. Activation of NRF-2 leads to an increased production of antioxidant enzymes, including heme oxygenase, which has been shown to have protective effects in neurodegenerative disorders such as AD. Dimethyl fumarate and diroximel fumarate (DMF) have been approved for the use in relapsing-remitting multiple sclerosis. Research indicates that they can modulate the effects of neuroinflammation and oxidative stress through the NRF-2 pathway, and as such, could serve as a potential therapeutic option in AD. We propose a clinical trial design that could be used to assess DMF as a treatment option for AD.
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Affiliation(s)
- Robert Sharkus
- Department of Neurology, Cooper Neurological Institute, Cherry Hill, NJ 08002, USA; (R.S.); (R.T.)
| | - Richa Thakkar
- Department of Neurology, Cooper Neurological Institute, Cherry Hill, NJ 08002, USA; (R.S.); (R.T.)
| | - Dennis L. Kolson
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Cris S. Constantinescu
- Department of Neurology, Cooper Neurological Institute, Cherry Hill, NJ 08002, USA; (R.S.); (R.T.)
- Department of Neurology, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
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Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3948921. [PMID: 36164392 PMCID: PMC9509250 DOI: 10.1155/2022/3948921] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 08/17/2022] [Accepted: 09/03/2022] [Indexed: 02/07/2023]
Abstract
Acute intracerebral hemorrhage (ICH) is a devastating type of stroke worldwide. Neuronal destruction involved in the brain damage process caused by ICH includes a primary injury formed by the mass effect of the hematoma and a secondary injury induced by the degradation products of a blood clot. Additionally, factors in the coagulation cascade and complement activation process also contribute to secondary brain injury by promoting the disruption of the blood-brain barrier and neuronal cell degeneration by enhancing the inflammatory response, oxidative stress, etc. Although treatment options for direct damage are limited, various strategies have been proposed to treat secondary injury post-ICH. Perihematomal edema (PHE) is a potential surrogate marker for secondary injury and may contribute to poor outcomes after ICH. Therefore, it is essential to investigate the underlying pathological mechanism, evolution, and potential therapeutic strategies to treat PHE. Here, we review the pathophysiology and imaging characteristics of PHE at different stages after acute ICH. As illustrated in preclinical and clinical studies, we discussed the merits and limitations of varying PHE quantification protocols, including absolute PHE volume, relative PHE volume, and extension distance calculated with images and other techniques. Importantly, this review summarizes the factors that affect PHE by focusing on traditional variables, the cerebral venous drainage system, and the brain lymphatic drainage system. Finally, to facilitate translational research, we analyze why the relationship between PHE and the functional outcome of ICH is currently controversial. We also emphasize promising therapeutic approaches that modulate multiple targets to alleviate PHE and promote neurologic recovery after acute ICH.
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Sen RD, Nistal D, McGrath M, Barros G, Shenoy VS, Sekhar LN, Levitt MR, Kim LJ. De novo epilepsy after microsurgical resection of brain arteriovenous malformations. Neurosurg Focus 2022; 53:E6. [DOI: 10.3171/2022.4.focus2288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/12/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVE
Seizures are the second most common presenting symptom of brain arteriovenous malformations (bAVMs) after hemorrhage. Risk factors for preoperative seizures and subsequent seizure control outcomes have been well studied. There is a paucity of literature on postoperative, de novo seizures in initially seizure-naïve patients who undergo resection. Whereas this entity has been documented after craniotomy for a wide variety of neurosurgically treated pathologies including tumors, trauma, and aneurysms, de novo seizures after bAVM resection are poorly studied. Given the debilitating nature of epilepsy, the purpose of this study was to elucidate the incidence and risk factors associated with de novo epilepsy after bAVM resection.
METHODS
A retrospective review of patients who underwent resection of a bAVM over a 15-year period was performed. Patients who did not present with seizure were included, and the primary outcome was de novo epilepsy (i.e., a seizure disorder that only manifested after surgery). Demographic, clinical, and radiographic characteristics were compared between patients with and without postoperative epilepsy. Subgroup analysis was conducted on the ruptured bAVMs.
RESULTS
From a cohort of 198 patients who underwent resection of a bAVM during the study period, 111 supratentorial ruptured and unruptured bAVMs that did not present with seizure were included. Twenty-one patients (19%) developed de novo epilepsy. One-year cumulative rates of developing de novo epilepsy were 9% for the overall cohort and 8.5% for the cohort with ruptured bAVMs. There were no significant differences between the epilepsy and no-epilepsy groups overall; however, the de novo epilepsy group was younger in the cohort with ruptured bAVMs (28.7 ± 11.7 vs 35.1 ± 19.9 years; p = 0.04). The mean time between resection and first seizure was 26.0 ± 40.4 months, with the longest time being 14 years. Subgroup analysis of the ruptured and endovascular embolization cohorts did not reveal any significant differences. Of the patients who developed poorly controlled epilepsy (defined as Engel class III–IV), all had a history of hemorrhage and half had bAVMs located in the temporal lobe.
CONCLUSIONS
De novo epilepsy after bAVM resection occurs at an annual cumulative risk of 9%, with potentially long-term onset. Younger age may be a risk factor in patients who present with rupture. The development of poorly controlled epilepsy may be associated with temporal lobe location and a delay between hemorrhage and resection.
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Affiliation(s)
| | | | | | | | | | | | - Michael R. Levitt
- Departments of Neurological Surgery,
- Radiology, and
- Mechanical Engineering; and
- Stroke & Applied Neuroscience Center, University of Washington, Seattle, Washington
| | - Louis J. Kim
- Departments of Neurological Surgery,
- Radiology, and
- Stroke & Applied Neuroscience Center, University of Washington, Seattle, Washington
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11
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Shao L, Chen S, Ma L. Secondary Brain Injury by Oxidative Stress After Cerebral Hemorrhage: Recent Advances. Front Cell Neurosci 2022; 16:853589. [PMID: 35813506 PMCID: PMC9262401 DOI: 10.3389/fncel.2022.853589] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 05/16/2022] [Indexed: 11/25/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a clinical syndrome in which blood accumulates in the brain parenchyma because of a nontraumatic rupture of a blood vessel. Because of its high morbidity and mortality rate and the lack of effective therapy, the treatment of ICH has become a hot research topic. Meanwhile, Oxidative stress is one of the main causes of secondary brain injury(SBI) after ICH. Therefore, there is a need for an in-depth study of oxidative stress after ICH. This review will discuss the pathway and effects of oxidative stress after ICH and its relationship with inflammation and autophagy, as well as the current antioxidant therapy for ICH with a view to deriving better therapeutic tools or targets for ICH.
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Yu M, Tian T, Zhang J, Hu T. miR-141-3p protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by targeting ZEB2. J Clin Neurosci 2022; 99:253-260. [PMID: 35306455 DOI: 10.1016/j.jocn.2022.03.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/28/2022] [Accepted: 03/05/2022] [Indexed: 12/31/2022]
Abstract
MicroRNAs (miRNAs) participate in the diagnosis and treatment of intracerebral hemorrhage (ICH). miR-141-3p has been widely reported to regulate neurological disorders and cerebropathy. However, the specific role of miR-141-3p in ICH has not yet been revealed. The aim of this study was exploration of the biological functions and mechanism of miR-141-3p in ICH by establishing a collagenase-induced ICH mouse model. After ICH induction, miR-141-3p mimics or miR-NC were administered into the right striatum of the model mice followed by the performance of neurological tests. After euthanasia of the mice, the injury volume, brain water content, and injury to the blood-brain barrier (BBB) were evaluated. Evans blue (EB) was used to stain the brain slices, and EB extravasation was detected to evaluate the injury to BBB. miR-141-3p expression in perihematomal edema and hematoma areas after ICH was assessed by RT-qPCR. The levels of tight junction proteins in brain tissues and human brain microvascular endothelial cells (BMECs) were evaluated by western blotting. The FITC-dextran 20 method was used to assess BMEC permeability. The binding between miR-141-3p and zinc finger E-box-binding homeobox 2 (ZEB2) was verified with a luciferase reporter assay. In this study, miR-141-3p overexpression alleviated ICH-induced brain injury and protected BBB integrity in vivo. ZEB2 was a target gene of miR-141-3p. ZEB2 overexpression promoted BBB disruption, and miR-141-3p overexpression attenuated the promoting effect exerted by ZEB2. Overall, miR-141-3p protects against BBB disruption and attenuates brain injuries induced by ICH by targeting ZEB2.
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Affiliation(s)
- Miao Yu
- Department of Neurosurgery, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei, China
| | - Tian Tian
- Department of Neurosurgery, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei, China.
| | - Jiwei Zhang
- Department of Neurosurgery, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei, China
| | - Tiemin Hu
- Department of Neurosurgery, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei, China
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Liu L, Liu KJ, Cao JB, Yang J, Yu HL, He XX, He ZX, Zhu XJ. A Novel Netrin-1-Derived Peptide Enhances Protection against Neuronal Death and Mitigates of Intracerebral Hemorrhage in Mice. Int J Mol Sci 2021; 22:ijms22094829. [PMID: 34063230 PMCID: PMC8125294 DOI: 10.3390/ijms22094829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 04/25/2021] [Accepted: 04/29/2021] [Indexed: 12/22/2022] Open
Abstract
It has been reported that Netrin-1 is involved in neuroprotection following injury to the central nervous system. However, the minimal functional domain of Netrin-1 which can preserve the neuroprotection but avoid the major side effects of Netrin remains elusive. Here, we investigated the neuroprotective effect of a peptide E1 derived from Netrin-1′s EGF3 domain (residues 407–422). We found that it interacts with deleted colorectal carcinoma (DCC) to activate focal adhesion kinase phosphorylation exhibiting neuroprotection. The administration of the peptide E1 was able to improve functional recovery through reduced apoptosis in an experimental murine model of intracerebral hemorrhage (ICH). In summary, we reveal a functional sequence of Netrin-1 that is involved in the recovery process after ICH and identify a candidate peptide for the treatment of ICH.
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Zhang Z, Pang Y, Wang W, Zhu H, Jin S, Yu Z, Gu Y, Wu H. Neuroprotection of Heme Oxygenase-2 in Mice AfterIntracerebral Hemorrhage. J Neuropathol Exp Neurol 2021; 80:457-466. [PMID: 33870420 DOI: 10.1093/jnen/nlab025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
There are few effective preventive or therapeutic strategies to mitigate the effects of catastrophic intracerebral hemorrhage (ICH) in humans. Heme oxygenase is the rate-limiting enzyme in heme metabolism; heme oxygenase-2 (HO-2) is a constitutively expressed heme oxygenase. We explored the involvement of HO-2 in a collagenase-induced mouse model of ICH in C57BL/6 wild-type and HO-2 knockout mice. We assessed oxidative stress injury, blood-brain barrier permeability, neuronal damage, late-stage angiogenesis, and hematoma clearance using immunofluorescence, Western blot, MRI, and special staining methods. Our results show that HO-2 reduces brain injury volume and brain edema, alleviates cytotoxic injury, affects vascular function in the early stage of ICH, and improves hematoma absorbance and angiogenesis in the late stage of ICH in this model. Thus, we found that HO-2 has a protective effect on brain injury after ICH.
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Affiliation(s)
- Ze Zhang
- From the Department of Urology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yuxin Pang
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China
| | - Wei Wang
- Department of Magnetic Resonance Imaging, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hong Zhu
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China
| | - Sinan Jin
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China
| | - Zihan Yu
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China
| | - Yunhe Gu
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China
| | - He Wu
- Department of Pathology, First Clinical Hospital, Harbin Medical University, Harbin, China
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15
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Regional Brain Recovery from Acute Synaptic Injury in Simian Immunodeficiency Virus-Infected Rhesus Macaques Associates with Heme Oxygenase Isoform Expression. J Virol 2020; 94:JVI.01102-20. [PMID: 32669339 PMCID: PMC7495379 DOI: 10.1128/jvi.01102-20] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/10/2020] [Indexed: 12/21/2022] Open
Abstract
Brain injury induced by acute simian (or human) immunodeficiency virus infection may persist or spontaneously resolve in different brain regions. Identifying the host factor(s) that promotes spontaneous recovery from such injury may reveal targets for therapeutic drug strategies for promoting recovery from acute neuronal injury. The gradual recovery from such injury observed in many, but not all, brain regions in the rhesus macaque model is consistent with the possible existence of a therapeutic window of opportunity for intervening to promote recovery, even in those regions not showing spontaneous recovery. In persons living with human immunodeficiency virus infection, such neuroprotective treatments could ultimately be considered as adjuncts to the initiation of antiretroviral drug therapy. Brain injury occurs within days in simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) infection, and some recovery may occur within weeks. Inflammation and oxidative stress associate with such injury, but what drives recovery is unknown. Chronic HIV infection associates with reduced brain frontal cortex expression of the antioxidant/anti-inflammatory enzyme heme oxygenase-1 (HO-1) and increased neuroinflammation in individuals with cognitive impairment. We hypothesized that acute regional brain injury and recovery associate with differences in regional brain HO-1 expression. Using SIV-infected rhesus macaques, we analyzed multiple brain regions through acute and chronic infection (90 days postinfection [dpi]) and quantified viral (SIV gag RNA), synaptic (PSD-95; synaptophysin), axonal (neurofilament/neurofilament light chain [NFL]), inflammatory, and antioxidant (enzymes, including heme oxygenase isoforms [HO-1, HO-2]) markers. PSD-95 was reduced in the brainstem, basal ganglia, neocortex, and cerebellum within 13 dpi, indicating acute synaptic injury throughout the brain. All areas except the brainstem recovered. Unchanged NFL was consistent with no acute axonal injury. SIV RNA expression was highest in the brainstem throughout infection, and it associated with neuroinflammation. Surprisingly, during the synaptic injury and recovery phases, HO-2, and not HO-1, progressively decreased in the brainstem. Thus, acute SIV synaptic injury occurs throughout the brain, with spontaneous recovery in regions other than the brainstem. Within the brainstem, the high SIV load and inflammation, along with reduction of HO-2, may impair recovery. In other brain regions, stable HO-2 expression, with or without increasing HO-1, may promote recovery. Our data support roles for heme oxygenase isoforms in modulating recovery from synaptic injury in SIV infection and suggest their therapeutic targeting for promoting neuronal recovery. IMPORTANCE Brain injury induced by acute simian (or human) immunodeficiency virus infection may persist or spontaneously resolve in different brain regions. Identifying the host factor(s) that promotes spontaneous recovery from such injury may reveal targets for therapeutic drug strategies for promoting recovery from acute neuronal injury. The gradual recovery from such injury observed in many, but not all, brain regions in the rhesus macaque model is consistent with the possible existence of a therapeutic window of opportunity for intervening to promote recovery, even in those regions not showing spontaneous recovery. In persons living with human immunodeficiency virus infection, such neuroprotective treatments could ultimately be considered as adjuncts to the initiation of antiretroviral drug therapy.
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16
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Gruenewald AL, Garcia-Mesa Y, Gill AJ, Garza R, Gelman BB, Kolson DL. Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV. J Neurovirol 2020; 26:846-862. [PMID: 32910432 PMCID: PMC7716923 DOI: 10.1007/s13365-020-00902-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 08/17/2020] [Accepted: 08/24/2020] [Indexed: 12/14/2022]
Abstract
Previous studies showed that persons living with HIV (PLWH) demonstrate higher brain prefrontal cortex neuroinflammation and immunoproteasome expression compared to HIV-negative individuals; these associate positively with HIV levels. Lower expression of the antioxidant enzyme heme oxygenase 1 (HO-1) was observed in PLWH with HIV-associated neurocognitive impairment (HIV-NCI) compared to neurocognitively normal PLWH. We hypothesized that similar expression patterns occur throughout cortical, subcortical, and brainstem regions in PLWH, and that neuroinflammation and immunoproteasome expression associate with lower expression of neuronal markers. We analyzed autopsied brains (15 regions) from 9 PLWH without HIV-NCI and 7 matched HIV-negative individuals. Using Western blot and RT-qPCR, we quantified synaptic, inflammatory, immunoproteasome, endothelial, and antioxidant biomarkers, including HO-1 and its isoform heme oxygenase 2 (HO-2). In these PLWH without HIV-NCI, we observed higher expression of neuroinflammatory, endothelial, and immunoproteasome markers in multiple cortical and subcortical regions compared to HIV-negative individuals, suggesting a global brain inflammatory response to HIV. Several regions, including posterior cingulate cortex, globus pallidus, and cerebellum, showed a distinct pattern of higher type I interferon (IFN)-stimulated gene and immunoproteasome expression. PLWH without HIV-NCI also had (i) stable or higher HO-1 expression and positive associations between (ii) HO-1 and HIV levels (CSF, plasma) and (iii) HO-1 expression and neuroinflammation, in multiple cortical, subcortical, and brainstem regions. We observed no differences in synaptic marker expression, suggesting little, if any, associated neuronal injury. We speculate that this may reflect a neuroprotective effect of a concurrent HO-1 antioxidant response despite global neuroinflammation, which will require further investigation.
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Affiliation(s)
- Analise L Gruenewald
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 280 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA, 19104, USA
| | - Yoelvis Garcia-Mesa
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 280 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA, 19104, USA
| | - Alexander J Gill
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 280 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA, 19104, USA
| | - Rolando Garza
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 280 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA, 19104, USA
| | - Benjamin B Gelman
- Department of Pathology, University of Texas Medical Branch, 301 University Blvd., Keiller 3.118A, Route 0609, Galveston, TX, 77555, USA
| | - Dennis L Kolson
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 280 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA, 19104, USA.
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miR-183-5p alleviates early injury after intracerebral hemorrhage by inhibiting heme oxygenase-1 expression. Aging (Albany NY) 2020; 12:12869-12895. [PMID: 32602850 PMCID: PMC7377845 DOI: 10.18632/aging.103343] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 05/18/2020] [Indexed: 12/12/2022]
Abstract
Differences in microRNA (miRNA) expression after intracerebral hemorrhage (ICH) have been reported in human and animal models, and miRNAs are being investigated as a new treatment for inflammation and oxidative stress after ICH. In this study, we found that microRNA-183-5p expression was decreased in the mouse brain after ICH. To investigate the effect of miRNA-183-5p on injury and repair of brain tissue after ICH, saline, miRNA-183-5p agomir, or miRNA-183-5p antagomir were injected into the lateral ventricles of 8-week-old mice with collagenase-induced ICH. Three days after ICH, mice treated with exogenous miRNA-183-5p showed less brain edema, neurobehavioral defects, inflammation, oxidative stress, and ferrous deposition than control mice. In addition, by alternately treating mice with a heme oxygenase-1 (HO-1) inducer, a HO-1 inhibitor, a nuclear factor erythroid 2-related factor (Nrf2) activator, and Nrf2 knockout, we demonstrated an indirect, HO-1-dependent regulatory relationship between miRNA-183-5p and Nrf2. Our results indicate that miRNA-183-5p and HO-1 are promising therapeutic targets for controlling inflammation and oxidative damage after hemorrhagic stroke.
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18
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Hua W, Chen X, Wang J, Zang W, Jiang C, Ren H, Hong M, Wang J, Wu H, Wang J. Mechanisms and potential therapeutic targets for spontaneous intracerebral hemorrhage. BRAIN HEMORRHAGES 2020. [DOI: 10.1016/j.hest.2020.02.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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Wang S, Cui Y, Xu J, Gao H. miR-140-5p Attenuates Neuroinflammation and Brain Injury in Rats Following Intracerebral Hemorrhage by Targeting TLR4. Inflammation 2020; 42:1869-1877. [PMID: 31376096 DOI: 10.1007/s10753-019-01049-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The Toll-like receptor 4 (TLR4)-mediated neuroinflammation plays a key role in inducing secondary brain injury after intracerebral hemorrhage (ICH). However, how TLR4 is regulated during this pathological process is not well understood. In the present study, by taking advantage of a rat ICH model, we show that miR-140-5p is reversely correlated with TLR4 expression in the peri-hematomal striatum following ICH. In vitro, miR-140-5p directly targets TLR4 and suppresses its expression in a rat neuronal PC12 cell line. Moreover, an intracerebral ventricular injection of miR-140-5p mimics improves neurological function and reduces apoptotic cell death and limits the production of inflammatory cytokines following ICH, indicating that miR-140-5p attenuates brain injury and neuroinflammation in vivo. Furthermore, miR-140-5p suppresses TLR4 expression and inhibits the downstream MyD88/TRIF inflammatory pathway and NF-κB activity following ICH, suggesting that the inhibition of TLR4-mediated neuroinflammation at least in part accounts for the neuroprotective role of miR-140-5 against ICH-induced brain injury in rats. Collectively, these results identify miR-140-5 as a negative regulator of TLR4 and downstream inflammatory pathway following ICH, implicating that miR-140-5 might represent as a potential therapeutic target for alleviating ICH-induced brain injury.
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Affiliation(s)
- Shunda Wang
- Department of Rehabilitation Medicine, Shaanxi Provincial People's Hospital, Xi'an, 710068, Shaanxi, China
| | - Yujie Cui
- Rheumatology Department, The Fifth Affiliated Hospital Sun Yat-sen University, Zhuhai, 519000, China
| | - Jiaqi Xu
- Burn and Plastic Surgery, The Fifth Affiliated Hospital Sun Yat-sen University, Zhuhai, 519000, China
| | - Heng Gao
- Department Emergency Medicine, Shaanxi Provincial People's Hospital, No. 256 Friendship West Road, Xi'an, 710068, Shaanxi, China.
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Intracerebral Hemorrhage: Blood Components and Neurotoxicity. Brain Sci 2019; 9:brainsci9110316. [PMID: 31717522 PMCID: PMC6896063 DOI: 10.3390/brainsci9110316] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/30/2019] [Accepted: 11/07/2019] [Indexed: 12/13/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a subtype of stroke which is associated with the highest mortality and morbidity rates of all strokes. Although it is a major public health problem, there is no effective treatment for ICH. As a consequence of ICH, various blood components accumulate in the brain parenchyma and are responsible for much of the secondary brain damage and ICH-induced neurological deficits. Therefore, the strategies that could attenuate the blood component-induced neurotoxicity and improve hematoma resolution are highly needed. The present article provides an overview of blood-induced brain injury after ICH and emphasizes the need to conduct further studies elucidating the mechanisms of hematoma resolution after ICH.
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Heme Oxygenase-2 (HO-2) as a therapeutic target: Activators and inhibitors. Eur J Med Chem 2019; 183:111703. [PMID: 31550661 DOI: 10.1016/j.ejmech.2019.111703] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/13/2019] [Accepted: 09/14/2019] [Indexed: 12/24/2022]
Abstract
Heme oxygenase (HO) enzymes are involved in heme catabolism and several physiological functions. Among the different HO isoforms, HO-2 stands out for its neuroprotective properties and modulatory activity in male reproduction. However, unlike the HO-1 ligands, the potential therapeutic applications of HO-2 inhibitors/activators have not been extensively explored yet. Moreover, the physiological role of HO-2 is still unclear, mostly due to the lack of highly selective HO-2 chemical probes. To boost the interest on this intriguing target, the present review updates the knowledge on the structure-activity relationships of HO-2 inhibitors and activators, as well as their potential therapeutic applications. To the best of our knowledge, among HO-2 inhibitors, clemizole derivatives are the most selective HO-2 inhibitors reported so far (IC50 HO-1 >100 μM, IC50 HO-2 = 3.4 μM), while the HO-2 nonselective inhibitors described herein possess IC50 HO-2 values ≤ 10 μM. Furthermore, the development of HO-2 activators, such as menadione analogues, helped to understand the critical moieties required for HO-2 activation. Recent advances in the potential therapeutic applications of HO-2 inhibitors/activators cover the fields of neurodegenerative, cardiovascular, inflammatory, and reproductive diseases further stimulating the interest towards this target.
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Abstract
Haemoglobin is released into the CNS during the breakdown of red blood cells after intracranial bleeding. Extracellular free haemoglobin is directly neurotoxic. Haemoglobin scavenging mechanisms clear haemoglobin and reduce toxicity; these mechanisms include erythrophagocytosis, haptoglobin binding of haemoglobin, haemopexin binding of haem and haem oxygenase breakdown of haem. However, the capacity of these mechanisms is limited in the CNS, and they easily become overwhelmed. Targeting of haemoglobin toxicity and scavenging is, therefore, a rational therapeutic strategy. In this Review, we summarize the neurotoxic mechanisms of extracellular haemoglobin and the peculiarities of haemoglobin scavenging pathways in the brain. Evidence for a role of haemoglobin toxicity in neurological disorders is discussed, with a focus on subarachnoid haemorrhage and intracerebral haemorrhage, and emerging treatment strategies based on the molecular pathways involved are considered. By focusing on a fundamental biological commonality between diverse neurological conditions, we aim to encourage the application of knowledge of haemoglobin toxicity and scavenging across various conditions. We also hope that the principles highlighted will stimulate research to explore the potential of the pathways discussed. Finally, we present a consensus opinion on the research priorities that will help to bring about clinical benefits.
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Hua W, Yang X, Chen X, Ren H, Hong M, Wu H, Wang J. WITHDRAWN: Mechanisms and potential therapeutic targets for intracerebral hemorrhage. BRAIN HEMORRHAGES 2019. [DOI: 10.1016/j.hest.2019.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J. Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage. Prog Neurobiol 2019; 178:101610. [PMID: 30923023 DOI: 10.1016/j.pneurobio.2019.03.003] [Citation(s) in RCA: 212] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 03/07/2019] [Accepted: 03/16/2019] [Indexed: 12/18/2022]
Abstract
Intracerebral hemorrhage (ICH) is a common and severe cerebrovascular disease that has high mortality. Few survivors achieve self-care. Currently, patients receive only symptomatic treatment for ICH and benefit poorly from this regimen. Inflammatory cytokines are important participants in secondary injury after ICH. Increases in proinflammatory cytokines may aggravate the tissue injury, whereas increases in anti-inflammatory cytokines might be protective in the ICH brain. Inflammatory cytokines have been studied as therapeutic targets in a variety of acute and chronic brain diseases; however, studies on ICH are limited. This review summarizes the roles and functions of various pro- and anti-inflammatory cytokines in secondary brain injury after ICH and discusses pathogenic mechanisms and emerging therapeutic strategies and directions for treatment of ICH.
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Affiliation(s)
- Huimin Zhu
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, China
| | - Zhiqiang Wang
- Central laboratory, Linyi People's Hospital, Linyi, Shandong 276003, China
| | - Jixu Yu
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, China; Central laboratory, Linyi People's Hospital, Linyi, Shandong 276003, China; Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Xiuli Yang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Feng He
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, China
| | - Zhenchuan Liu
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, China.
| | - Fengyuan Che
- Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, China; Central laboratory, Linyi People's Hospital, Linyi, Shandong 276003, China.
| | - Xuemei Chen
- Department of Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, Henan, China
| | - Honglei Ren
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Michael Hong
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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Zhang X, Lu Y, Wu Q, Dai H, Li W, Lv S, Zhou X, Zhang X, Hang C, Wang J. Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll-like receptor 4 signaling pathway. FASEB J 2019; 33:722-737. [PMID: 30048156 DOI: 10.1096/fj.201800642rr] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/02/2018] [Indexed: 11/29/2024]
Abstract
Inflammation plays a key role in the progression of subarachnoid hemorrhage (SAH). Here, we examined the effects of astaxanthin (ATX) on the inflammatory response and secondary damage after SAH and the underlying mechanisms of action. In vivo, a prechiasmatic cistern injection model was established in rats and mice. In addition, neuron-microglia cocultures were exposed to oxyhemoglobin to mimic SAH in vitro. Western blotting revealed that protein expression of TLR4 was markedly increased in microglia at 24 h after SAH, with consequent increases in the downstream molecules myeloid differentiation factor 88 and NF-кB. Treatment with ATX significantly inhibited the TLR4 activation, increased sirtuin 1 expression, and inhibited the subsequent inflammatory response both in vivo and in vitro. ATX also significantly decreased high-mobility group box 1 nuclear translocation and secretion in neurons, an effect that was reversed by the sirtuin 1-specific inhibitor sirtinol. ATX administered 4 h after SAH ameliorated cerebral inflammation, brain edema, and neuronal death and improved neurologic function. ATX reduced neuronal death but did not improve neurologic function in TLR4 knockout mice. These results suggest that ATX reduces the proinflammatory response and secondary brain injury after SAH, primarily by increasing sirtuin 1 levels and inhibiting the TLR4 signaling pathway.-Zhang, X., Lu, Y., Wu, Q., Dai, H., Li, W., Lv, S., Zhou, X., Zhang, X., Hang, C., Wang, J. Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll-like receptor 4 signaling pathway.
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Affiliation(s)
- Xiangsheng Zhang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yue Lu
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Qi Wu
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Haibin Dai
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Wei Li
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Shengyin Lv
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Xiaoming Zhou
- Department of Neurosurgery, Changzheng Hospital, School of Medicine, Second Military Medical University, Shanghai, China; and
| | - Xin Zhang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Chunhua Hang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Mohan S, Koller EJ, Fazal JA, De Oliveria G, Pawlowicz AI, Doré S. Genetic Deletion of PGF 2α-FP Receptor Exacerbates Brain Injury Following Experimental Intracerebral Hemorrhage. Front Neurosci 2018; 12:556. [PMID: 30233287 PMCID: PMC6134069 DOI: 10.3389/fnins.2018.00556] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 07/23/2018] [Indexed: 01/17/2023] Open
Abstract
Background: The release of inflammatory molecules such as prostaglandins (e.g., PGF2α) is associated with brain damage following an intracerebral hemorrhagic (ICH) stroke; however, the role of PGF2α and its cognate FP receptor in ICH remains unclear. This study focused on investigating the role of the FP receptor as a target for novel neuroprotective drugs in a preclinical model of ICH, aiming to investigate the contribution of the PGF2α-FP axis in modulating functional recovery and anatomical outcomes following ICH. Results: Neurological deficit scores in FP−/− mice were significantly higher compared to WT mice 72 h after ICH (6.1 ± 0.7 vs. 3.1 ± 0.8; P < 0.05). Assessing motor skills, the total time mice stayed on the rotating rod was significantly less in FP−/−mice compared to WT mice 24 h after ICH (27.0 ± 7.5 vs. 52.4 ± 11.2 s; P < 0.05). Using grip strength to quantify forepaw strength, results showed that the FP−/− mice had significantly less strength compared to WT mice 72 h after ICH (96.4 ± 17.0 vs. 129.6 ± 5.9 g; P < 0.01). In addition to the behavioral outcomes, histopathological measurements were made. In Cresyl violet stained brain sections, the FP−/− mice showed a significantly larger lesion volume compared to the WT (15.0 ± 2.2 vs. 3.2 ± 1.7 mm3; P < 0.05 mice.) To estimate the presence of ferric iron in the peri-hematoma area, Perls' staining was performed, which revealed that FP−/− mice had significantly greater staining than the WT mice (186.3 ± 34.4% vs. 86.9 ± 13.0% total positive pixel counts, P < 0.05). Immunoreactivity experiments on brain sections from FP−/− and WT mice post-ICH were performed to monitor changes in microgliosis and astrogliosis using antibodies against Iba1 and GFAP respectively. These experiments showed that FP−/− mice had a trend toward greater astrogliosis than WT mice post-ICH. Conclusion: We showed that deletion of the PGF2α FP receptor exacerbates behavioral impairments and increases lesion volumes following ICH compared to WT-matched controls.Detailed mechanisms responsible for these novel results are actively being pursued.
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Affiliation(s)
- Shekher Mohan
- Department of Pharmaceutical Sciences, Manchester University, College of Pharmacy, Natural and Health Sciences, Fort Wayne, IN, United States
| | - Emily J Koller
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, FL, United States
| | - Jawad A Fazal
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, FL, United States
| | - Gabriela De Oliveria
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, FL, United States
| | - Anna I Pawlowicz
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, FL, United States
| | - Sylvain Doré
- Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, FL, United States.,Departments of Neurology, Psychiatry, Psychology, Pharmaceutics and Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, FL, United States
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Zhang X, Wu Q, Lu Y, Wan J, Dai H, Zhou X, Lv S, Chen X, Zhang X, Hang C, Wang J. Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways. Free Radic Biol Med 2018; 124:504-516. [PMID: 29966698 PMCID: PMC6286712 DOI: 10.1016/j.freeradbiomed.2018.06.035] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 01/19/2023]
Abstract
Salvianolic acid B (SalB), a natural polyphenolic compound extracted from the herb of Salvia miltiorrhiza, possesses antioxidant and neuroprotective properties and has been shown to be beneficial for diseases that affect vasculature and cognitive function. Here we investigated the protective effects of SalB against subarachnoid hemorrhage (SAH)-induced oxidative damage, and the involvement of underlying molecular mechanisms. In a rat model of SAH, SalB inhibited SAH-induced oxidative damage. The reduction in oxidative damage was associated with suppressed reactive oxygen species generation; decreased lipid peroxidation; and increased glutathione peroxidase, glutathione, and superoxide dismutase activities. Concomitant with the suppressed oxidative stress, SalB significantly reduced neurologic impairment, brain edema, and neural cell apoptosis after SAH. Moreover, SalB dramatically induced nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and increased expression of heme oxygenase-1 and NADPH: quinine oxidoreductase-1. In a mouse model of SAH, Nrf2 knockout significantly reversed the antioxidant effects of SalB against SAH. Additionally, SalB activated sirtuin 1 (SIRT1) expression, whereas SIRT1-specific inhibitor sirtinol pretreatment significantly suppressed SalB-induced SIRT1 activation and Nrf2 expression. Sirtinol pretreatment also reversed the antioxidant and neuroprotective effects of SalB. In primary cultured cortical neurons, SalB suppressed oxidative damage, alleviated neuronal degeneration, and improved cell viability. These beneficial effects were associated with activation of the SIRT1 and Nrf2 signaling pathway and were reversed by sirtinol treatment. Taken together, these in vivo and in vitro findings suggest that SalB provides protection against SAH-triggered oxidative damage by upregulating the Nrf2 antioxidant signaling pathway, which may be modulated by SIRT1 activation.
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Affiliation(s)
- Xiangsheng Zhang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China; Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Qi Wu
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Yue Lu
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Jieru Wan
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Haibin Dai
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Xiaoming Zhou
- Department of Neurosurgery, Changzheng Hospital, School of Medicine, Second Military Medical University, Shanghai, China
| | - Shengyin Lv
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Xuemei Chen
- Department of Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xin Zhang
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
| | - Chunhua Hang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China.
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Marconi VC, Duncan MS, So-Armah K, Re VL, Lim JK, Butt AA, Goetz MB, Rodriguez-Barradas MC, Alcorn CW, Lennox J, Beckman JA, Justice A, Freiberg M. Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV-Positive and HIV-Negative Individuals in VACS (Veterans Aging Cohort Study). J Am Heart Assoc 2018; 7:JAHA.117.007792. [PMID: 29720501 PMCID: PMC6015337 DOI: 10.1161/jaha.117.007792] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Background Bilirubin may protect against cardiovascular disease (CVD) by reducing oxidative stress. Whether elevated bilirubin reduces the risk of CVD events among HIV+ individuals and if this differs from uninfected individuals remain unclear. We assessed whether bilirubin independently predicted the risk of CVD events among HIV+ and uninfected participants in VACS (Veterans Aging Cohort Study). Methods and Results We conducted a prospective cohort study using VACS participants free of baseline CVD. Total bilirubin was categorized by quartiles. CVD as well as acute myocardial infarction, heart failure, and ischemic stroke events were assessed. Cox regression was used to evaluate hazard ratios of outcomes associated with quartiles of total bilirubin in HIV+ and uninfected people after adjusting for multiple risk factors. There were 96 381 participants (30 427 HIV+); mean age was 48 years, 48% were black, and 97% were men. There were 6603 total incident CVD events over a mean of 5.7 years. In adjusted models, increasing quartiles of baseline total bilirubin were associated with decreased hazards of all outcomes (hazard ratio, 0.86; 95% confidence interval, 0.80–0.91). Among HIV+ participants, results persisted for heart failure, ischemic stroke, and total CVD, but nonsignificant associations were observed for acute myocardial infarction. Conclusions VACS participants (regardless of HIV status) with elevated bilirubin levels had a lower risk of incident total CVD, acute myocardial infarction, heart failure, and ischemic stroke events after adjusting for known risk factors. Future studies should investigate how this apparently protective effect of elevated bilirubin could be harnessed to reduce CVD risk or improve risk estimation among HIV+ individuals.
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Affiliation(s)
- Vincent C Marconi
- Atlanta VA Medical Center, Atlanta, GA
- Emory University School of Medicine, Atlanta, GA
- Emory University Rollins School of Public Health, Atlanta, GA
| | - Meredith S Duncan
- Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN
| | | | - Vincent Lo Re
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Joseph K Lim
- Yale University School of Medicine, New Haven, CT
| | - Adeel A Butt
- Weill Cornell Medical College, Mars, PA
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA
| | - Matthew Bidwell Goetz
- Veterans Affairs Greater Los Angeles Health Care System, Los Angeles, CA
- David Geffen School of Medicine at UCLA, Los Angeles, CA
| | | | - Charles W Alcorn
- University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA
| | | | - Joshua A Beckman
- Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN
| | - Amy Justice
- Yale University School of Medicine, New Haven, CT
- Veterans Affairs Connecticut Healthcare System, West Haven, CT
| | - Matthew Freiberg
- Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN
- Tennessee Valley Health Care System Nashville VA, Nashville, TN
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Chen-Roetling J, Regan RF. Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage. Curr Pharm Des 2018; 23:2226-2237. [PMID: 27799046 DOI: 10.2174/1381612822666161027150616] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 10/16/2016] [Accepted: 10/22/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND Injury to cells adjacent to an intracerebral hemorrhage (ICH) is likely mediated at least in part by toxins released from the hematoma that initiate complex and interacting injury cascades. Pharmacotherapies targeting a single toxin or pathway, even if consistently effective in controlled experimental models, have a high likelihood of failure in a variable clinical setting. Nuclear factor erythroid-2 related factor 2 (Nrf2) regulates the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and antiinflammatory effects, and may be a target of interest after ICH. METHODS Studies that tested the effect of HO and Nrf2 in models relevant to ICH are summarized, with an effort to reconcile conflicting data by consideration of methodological limitations. RESULTS In vitro studies demonstrated that Nrf2 activators rapidly increased HO-1 expression in astrocytes, and reduced their vulnerability to hemoglobin or hemin. Modulating HO-1 expression via genetic approaches yielded similar results. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss and neurological deficits. These effects were mimicked by selective astrocyte HO-1 overexpression in transgenic mice. CONCLUSION Systemic treatment with Nrf2 activators after ICH is protective in rodents. Two compounds, dimethyl fumarate and hemin, are currently approved for treatment of multiple sclerosis and acute porphyria, respectively, and have acceptable safety profiles over years of clinical use. Further development of these drugs as ICH therapeutics seems warranted.
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Affiliation(s)
- Jing Chen-Roetling
- Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107, United States
| | - Raymond F Regan
- Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107, United States
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30
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Barzegar M, Shaygannejad V, Mirmosayyeb O, Valipour S, Akbari R, Vesal S, Ashtar F, Dehghani L, Mohammadi A, Esmaeil N. Serum Bilirubin Level Changes in Multiple Sclerosis Patients. CASPIAN JOURNAL OF NEUROLOGICAL SCIENCES 2018. [DOI: 10.29252/nirp.cjns.4.12.30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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31
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Babadjouni RM, Radwanski RE, Walcott BP, Patel A, Durazo R, Hodis DM, Emanuel BA, Mack WJ. Neuroprotective strategies following intraparenchymal hemorrhage. J Neurointerv Surg 2017; 9:1202-1207. [PMID: 28710084 DOI: 10.1136/neurintsurg-2017-013197] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 06/20/2017] [Accepted: 06/23/2017] [Indexed: 12/23/2022]
Abstract
Intracerebral hemorrhage and, more specifically, intraparenchymal hemorrhage, are devastating disease processes with poor clinical outcomes. Primary injury to the brain results from initial hematoma expansion while secondary hemorrhagic injury occurs from blood-derived products such as hemoglobin, heme, iron, and coagulation factors that overwhelm the brains natural defenses. Novel neuroprotective treatments have emerged that target primary and secondary mechanisms of injury. Nonetheless, translational application of neuroprotectants from preclinical to clinical studies has yet to show beneficial clinical outcomes. This review summarizes therapeutic agents and neuroprotectants in ongoing clinical trials aimed at targeting primary and secondary mechanisms of injury after intraparenchymal hemorrhage.
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Affiliation(s)
- Robin Moshe Babadjouni
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Ryan E Radwanski
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Brian P Walcott
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Arati Patel
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Ramon Durazo
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Drew M Hodis
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Benjamin A Emanuel
- Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - William J Mack
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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32
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Zhang Z, Song Y, Zhang Z, Li D, Zhu H, Liang R, Gu Y, Pang Y, Qi J, Wu H, Wang J. Distinct role of heme oxygenase-1 in early- and late-stage intracerebral hemorrhage in 12-month-old mice. J Cereb Blood Flow Metab 2017; 37:25-38. [PMID: 27317654 PMCID: PMC5363754 DOI: 10.1177/0271678x16655814] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Revised: 05/12/2016] [Accepted: 05/25/2016] [Indexed: 12/22/2022]
Abstract
Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. Heme oxygenase-1 (HO-1), the key enzyme in heme degradation, is highly expressed after ICH, but its role is still unclear. In this study, we used an HO-1 inducer and inhibitor to test the role of HO-1 in different stages of ICH in vivo and in vitro. In the early stage of ICH, high HO-1 expression worsened the outcomes of mice subjected to the collagenase-induced ICH model. HO-1 increased brain edema, white matter damage, neuronal death, and neurobehavioral deficits. Furthermore, elevated HO-1 increased inflammation, oxidative stress, matrix metalloproteinase-9/2 activity, and iron deposition. In the later stage of ICH, long-term induction of HO-1 increased hematoma absorption, angiogenesis, and recovery of neurologic function. We conclude that HO-1 activation mediates early brain damage after ICH but promotes neurologic function recovery in the later stage of ICH.
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Affiliation(s)
- Zhen Zhang
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Yuejia Song
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Ze Zhang
- Department of Urology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Danyang Li
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Hong Zhu
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Rui Liang
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Yunhe Gu
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Yuxin Pang
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Jiping Qi
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - He Wu
- Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, PR China
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
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Karuppagounder SS, Alim I, Khim SJ, Bourassa MW, Sleiman SF, John R, Thinnes CC, Yeh TL, Demetriades M, Neitemeier S, Cruz D, Gazaryan I, Killilea DW, Morgenstern L, Xi G, Keep RF, Schallert T, Tappero RV, Zhong J, Cho S, Maxfield FR, Holman TR, Culmsee C, Fong GH, Su Y, Ming GL, Song H, Cave JW, Schofield CJ, Colbourne F, Coppola G, Ratan RR. Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models. Sci Transl Med 2016; 8:328ra29. [PMID: 26936506 DOI: 10.1126/scitranslmed.aac6008] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.
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Affiliation(s)
- Saravanan S Karuppagounder
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Ishraq Alim
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Soah J Khim
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Megan W Bourassa
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Sama F Sleiman
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Roseleen John
- Department of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada
| | | | - Tzu-Lan Yeh
- Department of Chemistry, University of Oxford, OX1 3TA Oxford, UK
| | | | - Sandra Neitemeier
- Institut fuer Pharmakologie and Klinische Pharmazie, Phillips-Universitaet Marburg, D 35032 Marburg, Germany
| | - Dana Cruz
- Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Irina Gazaryan
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | | | - Lewis Morgenstern
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Guohua Xi
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Richard F Keep
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Timothy Schallert
- Department of Psychology, University of Texas at Austin, Austin, TX 78712, USA
| | - Ryan V Tappero
- Photon Sciences Directorate, Brookhaven National Laboratory, Upton, NY 11973, USA
| | - Jian Zhong
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Sunghee Cho
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Frederick R Maxfield
- Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Theodore R Holman
- Chemistry and Biochemistry, Department, University of California at Santa Cruz, Santa Cruz, CA 95064, USA
| | - Carsten Culmsee
- Institut fuer Pharmakologie and Klinische Pharmazie, Phillips-Universitaet Marburg, D 35032 Marburg, Germany
| | - Guo-Hua Fong
- Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Yijing Su
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Guo-li Ming
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Hongjun Song
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - John W Cave
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA
| | | | - Frederick Colbourne
- Department of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada
| | - Giovanni Coppola
- Department of Psychiatry, University of California at Los Angeles, CA 90095, USA
| | - Rajiv R Ratan
- Sperling Center for Hemorrhagic Stroke Recovery, Burke Medical Research Institute, White Plains, NY 10605, USA. Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
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Li Y, Xu XL, Zhao D, Pan LN, Huang CW, Guo LJ, Lu Q, Wang J. TLR3 ligand Poly IC Attenuates Reactive Astrogliosis and Improves Recovery of Rats after Focal Cerebral Ischemia. CNS Neurosci Ther 2016; 21:905-13. [PMID: 26494128 DOI: 10.1111/cns.12469] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 09/06/2015] [Accepted: 09/13/2015] [Indexed: 01/08/2023] Open
Abstract
AIMS Brain ischemia activates astrocytes in a process known as astrogliosis. Although this process has beneficial effects, excessive astrogliosis can impair neuronal recovery. Polyinosinic-polycytidylic acid (Poly IC) has shown neuroprotection against cerebral ischemia-reperfusion injury, but whether it regulates reactive astrogliosis and glial scar formation is not clear. METHODS We exposed cultured astrocytes to oxygen-glucose deprivation/reoxygenation (OGD/R) and used a rat middle cerebral artery occlusion (MCAO)/reperfusion model to investigate the effects of Poly IC. Astrocyte proliferation and proliferation-related molecules were evaluated by immunostaining and Western blotting. Neurological deficit scores, infarct volumes and neuroplasticity were evaluated in rats after transient MCAO. RESULTS In vitro, Poly IC inhibited astrocyte proliferation, upregulated Toll-like receptor 3 (TLR3) expression, upregulated interferon-β, and downregulated interleukin-6 production. These changes were blocked by a neutralizing antibody against TLR3, suggesting that Poly IC function is TLR3-dependent. Moreover, in the MCAO model, Poly IC attenuated reactive astrogliosis, reduced brain infarction volume, and improved neurological function. In addition, Poly IC prevented MCAO-induced reductions in soma size, dendrite length, and number of dendritic bifurcations in cortical neurons of the infarct penumbra. CONCLUSIONS By ameliorating astrogliosis-related damage, Poly IC is a potential therapeutic agent for attenuating neuronal damage and promoting recovery after brain ischemia.
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Affiliation(s)
- Yang Li
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xu-Lin Xu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Dan Zhao
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lin-Na Pan
- Medical Department of Neurology, The Second Hospital of Nanchang, Nanchang, China
| | - Chun-Wei Huang
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lian-Jun Guo
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Qing Lu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA
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Han X, Lan X, Li Q, Gao Y, Zhu W, Cheng T, Maruyama T, Wang J. Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury. J Cereb Blood Flow Metab 2016; 36:1059-74. [PMID: 26661165 PMCID: PMC4908617 DOI: 10.1177/0271678x15606462] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 07/27/2015] [Indexed: 11/16/2022]
Abstract
Prostaglandin E2 EP3 receptor is the only prostaglandin E2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68(+) microglia, but increased the number of Ym-1(+) M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase-mediated cytotoxicity and proinflammatory responses.
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Affiliation(s)
- Xiaoning Han
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xi Lan
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Qiang Li
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yufeng Gao
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Wei Zhu
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tian Cheng
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Takayuki Maruyama
- Project Management, Discovery and Research, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, Japan
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Intracerebral Hemorrhage, Oxidative Stress, and Antioxidant Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:1203285. [PMID: 27190572 PMCID: PMC4848452 DOI: 10.1155/2016/1203285] [Citation(s) in RCA: 209] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 11/20/2015] [Accepted: 03/28/2016] [Indexed: 12/20/2022]
Abstract
Hemorrhagic stroke is a common and severe neurological disorder and is associated with high rates of mortality and morbidity, especially for intracerebral hemorrhage (ICH). Increasing evidence demonstrates that oxidative stress responses participate in the pathophysiological processes of secondary brain injury (SBI) following ICH. The mechanisms involved in interoperable systems include endoplasmic reticulum (ER) stress, neuronal apoptosis and necrosis, inflammation, and autophagy. In this review, we summarized some promising advances in the field of oxidative stress and ICH, including contained animal and human investigations. We also discussed the role of oxidative stress, systemic oxidative stress responses, and some research of potential therapeutic options aimed at reducing oxidative stress to protect the neuronal function after ICH, focusing on the challenges of translation between preclinical and clinical studies, and potential post-ICH antioxidative therapeutic approaches.
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Microglial Polarization and Inflammatory Mediators After Intracerebral Hemorrhage. Mol Neurobiol 2016; 54:1874-1886. [PMID: 26894396 DOI: 10.1007/s12035-016-9785-6] [Citation(s) in RCA: 203] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Accepted: 02/08/2016] [Indexed: 12/21/2022]
Abstract
Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity. When a diseased artery within the brain bursts, expansion and absorption of the resulting hematoma trigger a series of reactions that cause primary and secondary brain injury. Microglia are extremely important for removing the hematoma and clearing debris, but they are also a source of ongoing inflammation. This article discusses the role of microglial activation/polarization and related inflammatory mediators, such as Toll-like receptor 4, matrix metalloproteinases, high-mobility group protein box-1, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron, in secondary injury after ICH and highlights the potential targets for ICH treatment.
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Righy C, Bozza MT, Oliveira MF, Bozza FA. Molecular, Cellular and Clinical Aspects of Intracerebral Hemorrhage: Are the Enemies Within? Curr Neuropharmacol 2016; 14:392-402. [PMID: 26714583 PMCID: PMC4876594 DOI: 10.2174/1570159x14666151230110058] [Citation(s) in RCA: 45] [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: 01/28/2015] [Revised: 11/28/2015] [Accepted: 12/29/2015] [Indexed: 12/13/2022] Open
Abstract
Hemorrhagic stroke is a disease with high incidence and mortality rates. In addition to the mass lesions that result from hemorrhagic stroke, substances such as the blood-derived products (BDP) (hemoglobin (Hb), heme and iron) induce a potent inflammatory response and exert direct toxic effects on neurons, astrocytes, and microglia. In the present review, we discuss the mechanisms of brain injury secondary to hemorrhagic stroke, focusing on the involvement of BDP as major players of cellular redox imbalance, inflammation, and glutamate excitotoxicity. Potential natural mechanisms of protection against free Hb and heme such as haptoglobin and hemopexin, respectively, are highlighted. We finally discuss the experimental and clinical trials targeting free iron and heme scavenging as well as inflammation, as potential new therapies to minimize the devastating effects of hemorrhagic stroke on brain structure and function.
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Affiliation(s)
- Cássia Righy
- Avenida Brasil 4.365, Manguinhos, Rio de Janeiro-RJ, CEP 21.040-900, Pavilhão Gaspar Viana.
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Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice. Brain Behav Immun 2015; 46:293-310. [PMID: 25697396 PMCID: PMC4422065 DOI: 10.1016/j.bbi.2015.02.011] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 01/28/2015] [Accepted: 02/08/2015] [Indexed: 02/07/2023] Open
Abstract
Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH.
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Chen-Roetling J, Song W, Schipper HM, Regan CS, Regan RF. Astrocyte overexpression of heme oxygenase-1 improves outcome after intracerebral hemorrhage. Stroke 2015; 46:1093-8. [PMID: 25690543 DOI: 10.1161/strokeaha.115.008686] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND PURPOSE Heme oxygenase-1 (HO-1) catalyzes the rate-limiting reaction of heme breakdown and may have both antioxidant and pro-oxidant effects. In previous studies, HO-1 overexpression protected astrocytes from heme-mediated injury in vitro. In the present study, we tested the hypothesis that selective astrocyte overexpression of HO-1 improves outcome after intracerebral hemorrhage. METHODS Male and female transgenic mice overexpressing human HO-1 driven by the GFAP promoter (GFAP.HMOX1) and wild-type controls received striatal injections of autologous blood (25 μL). Blood-brain barrier disruption was assessed by Evans blue assay and striatal cell viability by methylthiazolyldiphenyl-tetrazolium bromide assay. Neurological deficits were quantified by digital analysis of spontaneous cage activity, adhesive removal, and elevated body swing tests. RESULTS Mortality rate for wild-type mice was 34.8% and was similar for males and females; all GFAP.HMOX1 mice survived. Striatal Evans blue leakage at 24 hours was 23.4±3.2 ng in surviving wild-type mice, compared with 10.9±1.8 ng in transgenics. Perihematomal cell viability was reduced to 61±4% of contralateral at 3 days in wild-type mice, versus 80±4% in transgenics. Focal neurological deficits were significantly reduced and spontaneous cage activity was increased in GFAP.HMOX1 mice. CONCLUSIONS Selective HO-1 overexpression in astrocytes reduces mortality, blood-brain barrier disruption, perihematomal cell injury, and neurological deficits in an autologous blood injection intracerebral hemorrhage model. Genetic or pharmacological therapies that acutely increase astrocyte HO-1 may be beneficial after intracerebral hemorrhage.
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Affiliation(s)
- Jing Chen-Roetling
- From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.)
| | - Wei Song
- From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.)
| | - Hyman M Schipper
- From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.)
| | - Christopher S Regan
- From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.)
| | - Raymond F Regan
- From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.).
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Chen-Roetling J, Lu X, Regan RF. Targeting heme oxygenase after intracerebral hemorrhage. ACTA ACUST UNITED AC 2015; 2. [PMID: 25642455 DOI: 10.14800/ttnd.474] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Intracerebral hemorrhage (ICH) is the primary event in approximately 10% of strokes, and has higher rates of morbidity and mortality than ischemic stroke. Experimental evidence suggests that the toxicity of hemoglobin and its degradation products contributes to secondary injury that may be amenable to therapeutic intervention. Hemin, the oxidized form of heme, accumulates in intracranial hematomas to cytotoxic levels. The rate limiting step of its breakdown is catalyzed by the heme oxygenase (HO) enzymes, which consist of inducible HO-1 and constitutively-expressed HO-2. The effect of these enzymes on perihematomal injury and neurological outcome has been investigated in ICH models using both genetic and pharmacological approaches to alter their expression, with variable results reported. These findings are summarized and reconciled in this review; therapeutic strategies that may optimize HO expression and activity after ICH are described.
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Affiliation(s)
- Jing Chen-Roetling
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Xiangping Lu
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Raymond F Regan
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA
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Mohan S, Narumiya S, Doré S. Neuroprotective role of prostaglandin PGE2 EP2 receptor in hemin-mediated toxicity. Neurotoxicology 2015; 46:53-9. [PMID: 25451967 PMCID: PMC4681391 DOI: 10.1016/j.neuro.2014.10.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 10/18/2014] [Accepted: 10/23/2014] [Indexed: 01/01/2023]
Abstract
Heme (Fe(2+) protoporphyrin IX) and hemin (Fe(3+)), the prosthetic group of hemoprotein, are cytotoxic due to their ability to contribute to the production of reactive oxygen species, increased intracellular calcium levels, and stimulate glutamate-mediated excitotoxicity. Previous work by our group showed that blockade of the prostaglandin E2 (PGE2)-EP1 receptor reduced hemin-induced cytotoxicity in primary cortical neuronal cultures. However, the role of the prostaglandin E2 (PGE2)-EP2 receptor in hemin neurotoxicity remains unclear. Activation of the EP2 receptor in neurons results in increased cyclic AMP (cAMP) and protein kinase A signaling; therefore, we hypothesized that the activation of the EP2 receptor decreases hemin neurotoxicity. Using postnatal primary cortical neurons cultured from wildtype-control (WT) and EP2(-/-) mice, we investigated the role of the EP2 receptor in hemin neurotoxicity by monitoring cell survival with the Calcein-AM live-cell and lactate dehydrogenase assays. MitoTracker staining was also performed to determine how mitochondria were affected by hemin. Hemin neurotoxicity in EP2(-/-) neurons was 37.2 ± 17.0% greater compared to WT neurons. Of interest, cotreatment with the EP2 receptor agonist, butaprost (1 and 10 μM), significantly attenuated hemin neurotoxicity by 55.7 ± 21.1% and 60.1 ± 14.8%, respectively. To further investigate signaling mechanisms related to EP2 receptor mediating cytoprotection, neurons were cotreated with hemin and activators/inhibitors of both the cAMP-protein kinase A/exchange protein directly activated by cAMP (Epac) pathways. Forskolin, a cAMP activator, and 8-pCPT-cAMP, an Epac activator, both attenuated hemin neurotoxicity by 78.8 ± 22.2% and 58.4 ± 9.8%, respectively, as measured using the lactate dehydrogenase assay. Together, the results reveal that activation of the EP2 receptor is protective against hemin neurotoxicity in vitro and these findings suggest that neuroprotection occurs through the cAMP-Epac pathway in neuronal cultures. Therefore, activation of the EP2 receptor could be used to minimize neuronal damage following exposure to supraphysiological levels of hemin.
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MESH Headings
- Adjuvants, Immunologic/pharmacology
- Alprostadil/analogs & derivatives
- Alprostadil/pharmacology
- Analysis of Variance
- Animals
- Animals, Newborn
- Cell Survival/drug effects
- Cerebral Cortex/cytology
- Colforsin/pharmacology
- Cyclic AMP/analogs & derivatives
- Cyclic AMP/pharmacology
- Dose-Response Relationship, Drug
- Excitatory Amino Acid Agonists/pharmacology
- Glutamic Acid/pharmacology
- Hemin/toxicity
- L-Lactate Dehydrogenase/metabolism
- Mice
- Mice, Knockout
- Neurons/drug effects
- Neuroprotective Agents/pharmacology
- Receptors, Prostaglandin E, EP2 Subtype/agonists
- Receptors, Prostaglandin E, EP2 Subtype/genetics
- Receptors, Prostaglandin E, EP2 Subtype/metabolism
- Thionucleotides/pharmacology
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Affiliation(s)
- Shekher Mohan
- Department of Anesthesiology, University of Florida, Gainesville, FL, USA
| | - Shuh Narumiya
- Department of Pharmacology, Kyoto University, Kyoto, Japan
| | - Sylvain Doré
- Department of Anesthesiology, University of Florida, Gainesville, FL, USA; Departments of Neurology, Psychiatry, and Neuroscience, University of Florida, Gainesville, FL, USA.
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Neuroprotective effect of heme oxygenase-2 knockout in the blood injection model of intracerebral hemorrhage. BMC Res Notes 2014; 7:561. [PMID: 25149897 PMCID: PMC4147166 DOI: 10.1186/1756-0500-7-561] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 07/31/2014] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND The toxicity of heme breakdown products may contribute to the pathogenesis of intracerebral hemorrhage (ICH). Heme catabolism is catalyzed by the heme oxygenase enzymes. We have previously reported that heme oxygenase-2 (HO-2), the constitutive isoform, protects neurons from hemin in vitro and reduces oxidative stress after striatal blood injection. In order to further evaluate HO-2 as a therapeutic target, we tested the hypothesis that HO-2 gene deletion protects neurons and attenuates behavioral deficits after ICH. FINDINGS Injection of 20 μl blood into the right striatum of HO-2 wild-type mice resulted in loss of approximately one third of striatal neurons 4-8 days later. Neuronal survival was significantly increased in HO-2 knockout mice at both time points. This was associated with reduced motor deficit as detected by the corner test; however, no differences were detected in spontaneous activity or the adhesive removal or elevated body swing tests. CONCLUSION HO-2 knockout attenuates perihematomal neuron loss in the blood injection ICH model, but has a weak and variable effect on neurological outcome.
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Muñoz-Sánchez J, Chánez-Cárdenas ME. A review on hemeoxygenase-2: focus on cellular protection and oxygen response. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:604981. [PMID: 25136403 PMCID: PMC4127239 DOI: 10.1155/2014/604981] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 04/30/2014] [Indexed: 12/13/2022]
Abstract
Hemeoxygenase (HO) system is responsible for cellular heme degradation to biliverdin, iron, and carbon monoxide. Two isoforms have been reported to date. Homologous HO-1 and HO-2 are microsomal proteins with more than 45% residue identity, share a similar fold and catalyze the same reaction. However, important differences between isoforms also exist. HO-1 isoform has been extensively studied mainly by its ability to respond to cellular stresses such as hemin, nitric oxide donors, oxidative damage, hypoxia, hyperthermia, and heavy metals, between others. On the contrary, due to its apparently constitutive nature, HO-2 has been less studied. Nevertheless, its abundance in tissues such as testis, endothelial cells, and particularly in brain, has pointed the relevance of HO-2 function. HO-2 presents particular characteristics that made it a unique protein in the HO system. Since attractive results on HO-2 have been arisen in later years, we focused this review in the second isoform. We summarize information on gene description, protein structure, and catalytic activity of HO-2 and particular facts such as its cellular impact and activity regulation. Finally, we call attention on the role of HO-2 in oxygen sensing, discussing proposed hypothesis on heme binding motifs and redox/thiol switches that participate in oxygen sensing as well as evidences of HO-2 response to hypoxia.
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Affiliation(s)
- Jorge Muñoz-Sánchez
- Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, 14269 Delegación Tlalpan, DF, Mexico
| | - María Elena Chánez-Cárdenas
- Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, 14269 Delegación Tlalpan, DF, Mexico
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Pan LN, Zhu W, Li Y, Xu XL, Guo LJ, Lu Q, Wang J. Astrocytic Toll-like receptor 3 is associated with ischemic preconditioning-induced protection against brain ischemia in rodents. PLoS One 2014; 9:e99526. [PMID: 24914679 PMCID: PMC4051824 DOI: 10.1371/journal.pone.0099526] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 05/15/2014] [Indexed: 11/18/2022] Open
Abstract
Background Cerebral ischemic preconditioning (IPC) protects brain against ischemic injury. Activation of Toll-like receptor 3 (TLR3) signaling can induce neuroprotective mediators, but whether astrocytic TLR3 signaling is involved in IPC-induced ischemic tolerance is not known. Methods IPC was modeled in mice with three brief episodes of bilateral carotid occlusion. In vitro, IPC was modeled in astrocytes by 1-h oxygen-glucose deprivation (OGD). Injury and components of the TLR3 signaling pathway were measured after a subsequent protracted ischemic event. A neutralizing antibody against TLR3 was used to evaluate the role of TLR3 signaling in ischemic tolerance. Results IPC in vivo reduced brain damage from permanent middle cerebral artery occlusion in mice and increased expression of TLR3 in cortical astrocytes. IPC also reduced damage in isolated astrocytes after 12-h OGD. In astrocytes, IPC or 12-h OGD alone increased TLR3 expression, and 12-h OGD alone increased expression of phosphorylated NFκB (pNFκB). However, IPC or 12-h OGD alone did not alter the expression of Toll/interleukin receptor domain-containing adaptor-inducing IFNβ (TRIF) or phosphorylated interferon regulatory factor 3 (pIRF3). Exposure to IPC before OGD increased TRIF and pIRF3 expression but decreased pNFκB expression. Analysis of cytokines showed that 12-h OGD alone increased IFNβ and IL-6 secretion; 12-h OGD preceded by IPC further increased IFNβ secretion but decreased IL-6 secretion. Preconditioning with TLR3 ligand Poly I:C increased pIRF3 expression and protected astrocytes against ischemic injury; however, cells treated with a neutralizing antibody against TLR3 lacked the IPC- and Poly I:C-induced ischemic protection and augmentation of IFNβ. Conclusions The results suggest that IPC-induced ischemic tolerance is mediated by astrocytic TLR3 signaling. This reprogramming of TLR3 signaling by IPC in astrocytes may play an important role in suppression of the post-ischemic inflammatory response and thereby protect against ischemic damage. The mechanism may be via activation of the TLR3/TRIF/IRF3 signaling pathway.
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Affiliation(s)
- Lin-na Pan
- Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
- Medical Department of Neurology, The Second Hospital of Nanchang, Nanchang, Jiangxi, People's Republic of China
| | - Wei Zhu
- Department of Emergency Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America
| | - Yang Li
- Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Xu-lin Xu
- Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
- The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Hubei Province, Wuhan, Hubei, People's Republic of China
| | - Lian-jun Guo
- Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
- The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Hubei Province, Wuhan, Hubei, People's Republic of China
| | - Qing Lu
- Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
- The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Hubei Province, Wuhan, Hubei, People's Republic of China
- * E-mail:
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America
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Zhu W, Gao Y, Chang CF, Wan JR, Zhu SS, Wang J. Mouse models of intracerebral hemorrhage in ventricle, cortex, and hippocampus by injections of autologous blood or collagenase. PLoS One 2014; 9:e97423. [PMID: 24831292 PMCID: PMC4022524 DOI: 10.1371/journal.pone.0097423] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Accepted: 04/17/2014] [Indexed: 01/08/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is a devastating condition. Existing preclinical ICH models focus largely on striatum but neglect other brain areas such as ventricle, cortex, and hippocampus. Clinically, however, hemorrhagic strokes do occur in these other brain regions. In this study, we established mouse hemorrhagic models that utilize stereotactic injections of autologous whole blood or collagenase to produce ventricular, cortical, and hippocampal injury. We validated and characterized these models by histology, immunohistochemistry, and neurobehavioral tests. In the intraventricular hemorrhage (IVH) model, C57BL/6 mice that received unilateral ventricular injections of whole blood demonstrated bilateral ventricular hematomas, ventricular enlargement, and brain edema in the ipsilateral cortex and basal ganglia at 72 h. Unilateral injections of collagenase (150 U/ml) caused reproducible hematomas and brain edema in the frontal cortex in the cortical ICH (c-ICH) model and in the hippocampus in the hippocampal ICH (h-ICH) model. Immunostaining revealed cellular inflammation and neuronal death in the periventricular regions in the IVH brain and in the perihematomal regions in the c-ICH and h-ICH brains. Locomotor abnormalities measured with a 24-point scoring system were present in all three models, especially on days 1, 3, and 7 post-ICH. Locomotor deficits measured by the wire-hanging test were present in models of IVH and c-ICH, but not h-ICH. Interestingly, mice in the c-ICH model demonstrated emotional abnormality, as measured by the tail suspension test and forced swim test, whereas h-ICH mice exhibited memory abnormality, as measured by the novel object recognition test. All three ICH models generated reproducible brain damage, brain edema, inflammation, and consistent locomotor deficits. Additionally, the c-ICH model produced emotional deficits and the h-ICH model produced cognitive deficits. These three models closely mimic human ICH and should be useful for investigating the pathophysiology of ICH in ventricle, cortex, and hippocampus and for evaluating potential therapeutic strategies.
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Affiliation(s)
- Wei Zhu
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America
| | - Yufeng Gao
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America
| | - Che-Feng Chang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America
| | - Jie-ru Wan
- Department of Biological Sciences, Illinois Institute of Technology, College of Science, Chicago, Illinois, United States of America
| | - Shan-shan Zhu
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America
| | - Jian Wang
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America
- * E-mail:
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Heinemann SH, Hoshi T, Westerhausen M, Schiller A. Carbon monoxide--physiology, detection and controlled release. Chem Commun (Camb) 2014; 50:3644-60. [PMID: 24556640 PMCID: PMC4072318 DOI: 10.1039/c3cc49196j] [Citation(s) in RCA: 299] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Carbon monoxide (CO) is increasingly recognized as a cell-signalling molecule akin to nitric oxide (NO). CO has attracted particular attention as a potential therapeutic agent because of its reported anti-hypertensive, anti-inflammatory and cell-protective effects. We discuss recent progress in identifying new effector systems and elucidating the mechanisms of action of CO on, e.g., ion channels, as well as the design of novel methods to monitor CO in cellular environments. We also report on recent developments in the area of CO-releasing molecules (CORMs) and materials for controlled CO application. Novel triggers for CO release, metal carbonyls and degradation mechanisms of CORMs are highlighted. In addition, potential formulations of CORMs for targeted CO release are discussed.
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Affiliation(s)
- Stefan H. Heinemann
- Center for Molecular Biomedicine (CMB), Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital, Hans-Knöll-Straße 2, D-07745 Jena, Germany
| | - Toshinori Hoshi
- Department of Physiology, University of Pennsylvania, 415 Curie Boulevard, 605 CRB, Philadelphia, PA 19104-6085, USA
| | - Matthias Westerhausen
- Institute for Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstr. 8, D-07743 Jena, Germany
| | - Alexander Schiller
- Institute for Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstr. 8, D-07743 Jena, Germany
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Abstract
Hemin accumulates in intracerebral hematomas and may contribute to cell injury in adjacent tissue. Despite its relevance to hemorrhagic CNS insults, very little is known about hemin trafficking by neural cells. In the present study, hemin uptake and release were quantified in primary murine cortical cultures, and the effect of the hemin-binding compound deferoxamine (DFO) was assessed. Net uptake of (55)Fe-hemin was similar in mixed neuron-glia, neuron, and glia cultures, but was 2.6-3.6-fold greater in microglia cultures. After washout, 40-60% of the isotope signal was released by mixed neuron-glia cultures into albumin-containing medium within 24 h. Inhibiting hemin breakdown with tin protoporphyrin IX (SnPPIX) had minimal effect, while release of the fluorescent hemin analog zinc mesoporphyrin was quantitatively similar to that of (55)Fe-hemin. Isotope was released most rapidly by neurons (52.2 ± 7.2% at 2 h), compared with glia (15.6 ± 1.3%) and microglia (17.6 ± 0.54%). DFO did not alter (55)Fe-hemin uptake, but significantly increased its release. Mixed cultures treated with 10 μM hemin for 24 h sustained widespread neuronal loss that was attenuated by DFO. Concomitant treatment with SnPPIX had no effect on either enhancement of isotope release by DFO or neuroprotection. These results suggest that in the presence of a physiologic albumin concentration, hemin uptake by neural cells is followed by considerable extracellular release. Enhancement of this release by DFO may contribute to its protective effect against hemin toxicity.
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Affiliation(s)
- J Chen-Roetling
- Department of Emergency Medicine, Thomas Jefferson University , Philadelphia, PA , USA
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Role of PGE₂ EP1 receptor in intracerebral hemorrhage-induced brain injury. Neurotox Res 2013; 24:549-59. [PMID: 23824501 DOI: 10.1007/s12640-013-9410-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 06/18/2013] [Accepted: 06/21/2013] [Indexed: 01/02/2023]
Abstract
Prostaglandin E₂ (PGE₂) has been described to exert beneficial and detrimental effects in various neurologic disorders. These conflicting roles of PGE₂ could be attributed to its diverse receptor subtypes, EP1-EP4. At present, the precise role of EP1 in intracerebral hemorrhage (ICH) is unknown. Therefore, to elucidate its possible role in ICH, intrastriatal injection of collagenase was given in randomized groups of adult male wildtype (WT) and EP1 receptor knockout (EP1⁻/⁻)C57BL/6 mice. Functional outcomes including neurologic deficits, rotarod performance, open field activity, and adhesive removal performance were evaluated at 24, 48, and 72 h post-ICH. Lesion volume, cell survival and death, were assessed using Cresyl Violet, and Fluoro-Jade staining, respectively. Microglial activation and phagocytosis were estimated using Iba1 immunoreactivity and fluorescently-labeled microspheres. Following 72 h post-ICH, EP1⁻/⁻ mice showed deteriorated outcomes compared to the WT control mice. These outcomes were demonstrated by elevated neurological deficits, exacerbated lesion volume, and significantly worsened sensorimotor functions. Fluoro-Jade staining showed significantly increased numbers of degenerating neurons and reduced neuronal survival in EP1⁻/⁻ compared to WT mice. To assess in vivo phagocytosis, the number of microspheres phagocytosed by Iba1-positive cells was 145.4 ± 15.4 % greater in WT compared to EP1⁻/⁻ mice. These data demonstrate that EP1 deletion exacerbates neuro-behavioral impairments following ICH, potentially by slowing down/impairing microglial phagocytosis. A better understanding of this EP1 mechanism could lead to improved intervention strategies for hemorrhagic stroke.
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Chen-Roetling J, Lu X, Regan KA, Regan RF. A rapid fluorescent method to quantify neuronal loss after experimental intracerebral hemorrhage. J Neurosci Methods 2013; 216:128-36. [PMID: 23583700 PMCID: PMC3679307 DOI: 10.1016/j.jneumeth.2013.03.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 03/22/2013] [Accepted: 03/24/2013] [Indexed: 10/26/2022]
Abstract
Neuronal loss in tissue surrounding an intracerebral hemorrhage (ICH) is usually quantified by labor-intensive histological methods that are subject to bias. Fluorescent protein expression has been successfully used as a marker of cell viability in vitro and in retinal studies in vivo, but not in any ICH model to date. The potential of this approach was investigated using transgenic mice that constitutively express the red fluorescent protein variant dTomato in central neurons under the control of the Thy1 promoter. Breeding and growth of these mice were similar to their wild-type counterparts; behavioral phenotyping by digital analysis of home cage video recordings detected no differences. Bright fluorescence was evident in fresh brain samples with minimal background fluorescence, and was reduced in tissue surrounding the hematoma. In order to assess fluorescence loss as an injury marker in a planned study, these mice were crossed with heme oxygenase (HO)-2 knockouts and wild-type controls; striatal hemorrhage was induced by stereotactic injection of collagenase. Fluorescence in hemorrhagic striata was reduced to 86.4±3.9%, 62.2±5.1%, and 58.3±3.0% of contra-lateral on days 1, 4 and 8, respectively, and correlated closely with reduction in striatal cell viability as quantified by MTT assay. HO-2 knockout and wild-type values did not differ significantly. Similar results were observed with stereological cell counts of striatal neurons identified by NeuN immunoreactivity. These results suggest that loss of constitutive dTomato fluorescence is an accurate and efficient marker of neuronal loss in tissue surrounding a striatal hematoma.
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Affiliation(s)
- Jing Chen-Roetling
- Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107
| | - Xiangping Lu
- Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107
| | - Kathleen A. Regan
- Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107
| | - Raymond F. Regan
- Department of Emergency Medicine, Thomas Jefferson University, 1025 Walnut Street, College Building Room 813, Philadelphia, PA 19107
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