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1
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Bo C, Liu X, Liu Y, Xu L, Huang Q. Resolvin D1 accelerates resolution of neuroinflammation by inhibiting microglia activation through the BDNF/TrkB signaling pathway. Eur J Med Res 2025; 30:189. [PMID: 40114280 PMCID: PMC11924792 DOI: 10.1186/s40001-025-02424-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 03/03/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Neuropathic pain is characterized by hyperalgesia, allodynia, and inflammation and it is often resistant to treatment. The formyl peptide receptor 2 (ALX/FPR2), a G-protein-coupled receptor, has been implicated in resolving inflammation, making its agonist, Resolvin D1 (RvD1), a potential therapeutic agent. Previous studies suggest that RvD1 alleviates neuropathic pain via anti-inflammatory effects, but its mechanisms remain unclear, particularly in relation to microglial activation and the brain-derived neurotrophic factor (BDNF)/TrkB signaling pathway. OBJECTIVE To investigate the analgesic effects of RvD1 in a spared nerve injury (SNI) model of neuropathic pain and explore its mechanisms through the regulation of neuroinflammation and the BDNF/TrkB signaling pathway. METHODS SNI mice received intrathecal RvD1 at varying doses (10-40 ng) to determine its efficacy in reducing mechanical allodynia and thermal sensitivity. The anti-inflammatory effects of RvD1 were assessed using ELISA, immunofluorescence, and western blotting to measure the expression of pro-inflammatory cytokines and BDNF. The involvement of ALX/FPR2 and TrkB receptors was further examined using antagonists Boc2 and K252a. RESULTS RvD1 significantly reduced mechanical and thermal allodynia in SNI mice in a dose-dependent manner. RvD1 also decreased microglial activation and expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and BDNF in both in vivo and in vitro models. These effects were reversed by Boc2 and K252a, confirming that the analgesic actions of RvD1 are mediated via the ALX/FPR2 receptor and inhibition of BDNF/TrkB signaling. CONCLUSION RvD1 alleviates neuropathic pain by reducing neuroinflammation through the ALX/FPR2 receptor and suppressing BDNF/TrkB signaling. These findings suggest RvD1 as a promising therapeutic agent for neuropathic pain management.
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Affiliation(s)
- Cunju Bo
- Department of Pain Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, Guangdong, China
| | - Xiaoming Liu
- Department of Pain Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, Guangdong, China
| | - Yongjian Liu
- Department of Pain Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, Guangdong, China
| | - Lingjun Xu
- Department of Pain Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, Guangdong, China
| | - Qiaodong Huang
- Department of Pain Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, Guangdong, China.
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2
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Antal M. Molecular Anatomy of Synaptic and Extrasynaptic Neurotransmission Between Nociceptive Primary Afferents and Spinal Dorsal Horn Neurons. Int J Mol Sci 2025; 26:2356. [PMID: 40076973 PMCID: PMC11900602 DOI: 10.3390/ijms26052356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/14/2025] Open
Abstract
Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals release glutamate into the synaptic cleft and stimulate postsynaptic spinal neurons by activating glutamate receptors located on the postsynaptic membrane. When overexcitation is evoked by peripheral inflammation, neuropathy or pruritogens, peptidergic nociceptive axon terminals may corelease various neuropeptides, neurotrophins and endomorphin, together with glutamate. However, in contrast to glutamate, neuropeptides, neurotrophins and endomorphin are released extrasynaptically. They diffuse from the site of release and modulate the function of spinal neurons via volume transmission, activating specific extrasynaptic receptors. Thus, the released neuropeptides, neurotrophins and endomorphin may evoke excitation, disinhibition or inhibition in various spinal neuronal populations, and together with glutamate, induce overall overexcitation, called central sensitization. In addition, the synaptic and extrasynaptic release of neurotransmitters is subjected to strong retrograde control mediated by various retrogradely acting transmitters, messengers, and their presynaptic receptors. Moreover, the composition of this complex chemical apparatus is heavily dependent on the actual patterns of nociceptive primary afferent activation in the periphery. This review provides an overview of the complexity of this signaling apparatus, how nociceptive primary afferents can activate secondary sensory spinal neurons via synaptic and volume transmission in the superficial spinal dorsal horn, and how these events can be controlled by presynaptic mechanisms.
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Affiliation(s)
- Miklós Antal
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
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3
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Antonijevic M, Dallemagne P, Rochais C. Indirect influence on the BDNF/TrkB receptor signaling pathway via GPCRs, an emerging strategy in the treatment of neurodegenerative disorders. Med Res Rev 2025; 45:274-310. [PMID: 39180386 DOI: 10.1002/med.22075] [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: 11/16/2021] [Revised: 12/06/2022] [Accepted: 08/04/2024] [Indexed: 08/26/2024]
Abstract
Neuronal survival depends on neurotrophins and their receptors. There are two types of neurotrophin receptors: a nonenzymatic, trans-membrane protein of the tumor necrosis factor receptor (TNFR) family-p75 receptor and the tyrosine kinase receptors (TrkR) A, B, and C. Activation of the TrkBR by brain-derived neurotrophic factor (BDNF) or neurotrophin 4/5 (NT-4/5) promotes neuronal survival, differentiation, and synaptic function. It is shown that in the pathogenesis of several neurodegenerative conditions (Alzheimer's disease, Parkinson's disease, Huntington's disease) the BDNF/TrkBR signaling pathway is impaired. Since it is known that GPCRs and TrkR are regulating several cell functions by interacting with each other and generating a cross-communication in this review we have focused on the interaction between different GPCRs and their ligands on BDNF/TrkBR signaling pathway.
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Hasani F, Masrour M, Khamaki S, Jazi K, Ghoodjani E, Teixeira AL. Brain-Derived Neurotrophic Factor (BDNF) as a Potential Biomarker in Brain Glioma: A Systematic Review and Meta-Analysis. Brain Behav 2025; 15:e70266. [PMID: 39789839 PMCID: PMC11726635 DOI: 10.1002/brb3.70266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/02/2024] [Accepted: 12/17/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND This systematic review and meta-analysis evaluates peripheral and CNS BDNF levels in glioma patients. METHODS Following PRISMA guidelines, we systematically searched databases for studies measuring BDNF in glioma patients and controls. After screening and data extraction, we conducted quality assessment, meta-analysis, and meta-regression. RESULTS Eight studies were included. Meta-analysis showed significantly reduced plasma BDNF levels in glioma patients versus controls (SMD: -1.0026; 95% CI: [-1.5284, -0.4769], p = 0.0002). High-grade gliomas had lower plasma BDNF (p = 0.0288). Tissue BDNF levels were higher in glioma patients (SMD: 1.9513; 95% CI: [0.7365, 3.1661], p = 0.0016) and correlated with tumor grade (p = 0.0122). Plasma BDNF levels negatively correlated with patient age (p = 0.0244) and positively with female percentage (p = 0.0007). CONCLUSION BDNF is a promising biomarker in glioma, showing significant changes in plasma and tissue levels correlating with tumor grade, patient age, and gender.
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Affiliation(s)
- Fatemeh Hasani
- Gastroenterology and Hepatology Research CenterGolestan University of Medical SciencesGorganIran
- Neuroscience Research CenterGolestan University of Medical SciencesGorganIran
| | - Mahdi Masrour
- School of MedicineTehran University of Medical SciencesTehranIran
| | - Sina Khamaki
- Gastroenterology and Hepatology Research CenterGolestan University of Medical SciencesGorganIran
- Neuroscience Research CenterGolestan University of Medical SciencesGorganIran
| | - Kimia Jazi
- Student Research Committee, Faculty of MedicineMedical University of QomQomIran
| | - Erfan Ghoodjani
- School of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Antonio L. Teixeira
- Biggs InstituteThe University of Texas Health Science Center at San AntonioSan AntonioTexasUSA
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Samaddar S, Redhwan MAM, Eraiah MM, Koneri R. Neurotrophins in Peripheral Neuropathy: Exploring Pathophysiological Mechanisms and Emerging Therapeutic Opportunities. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2025; 24:91-101. [PMID: 39238380 DOI: 10.2174/0118715273327121240820074049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/28/2024] [Accepted: 07/10/2024] [Indexed: 09/07/2024]
Abstract
Neuropathies, which encompass a wide array of peripheral nervous system disorders, present significant challenges due to their varied causes, such as metabolic diseases, toxic exposures, and genetic mutations. This review article, focused on the critical role of neurotrophins in peripheral neuropathy, highlights the intricate balance of neurotrophins necessary for nerve health and the pathophysiological consequences when this balance is disturbed. Neurotrophins, including Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT- 3), and Neurotrophin-4 (NT-4), are essential for neuronal survival, axonal growth, and synaptic plasticity. Their signaling pathways are crucial for maintaining peripheral nervous system integrity, primarily via the Tropomyosin receptor kinase (Trk) receptors and the p75 neurotrophin receptor p75(NTR). Dysregulation of neurotrophins is implicated in various neuropathies, such as diabetic neuropathy and chemotherapy-induced peripheral neuropathy, leading to impaired nerve function and regeneration. Understanding neurotrophin signaling intricacies and their alterations in neuropathic conditions is crucial for identifying novel therapeutic targets. Recent advancements illuminate neurotrophins' potential as therapeutic agents, promising disease-modifying treatments by promoting neuronal survival, enhancing axonal regeneration, and improving functional recovery post-nerve injury. However, translating these molecular insights into effective clinical applications faces challenges, including delivery methods, target specificity, and the instability of protein- based therapies.
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Affiliation(s)
- Suman Samaddar
- Research Institute, BGS Global Institute of Medical Sciences, Bengaluru, Karnataka, India
| | - Moqbel Ali Moqbel Redhwan
- Department of Pharmacology, KLE College of Pharmacy, Bengaluru, KLE Academy of Higher Education and Research, Belgavi, Karnataka, India
| | | | - Raju Koneri
- Research Institute, BGS Global Institute of Medical Sciences, Bengaluru, Karnataka, India
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6
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Naghshbandieh A, Naghshbandieh A, Barfi E, Abkhooie L. Assessment of the level of apoptosis in differentiated pseudo-neuronal cells derived from neural stem cells under the influence of various inducers. AMERICAN JOURNAL OF STEM CELLS 2024; 13:250-270. [PMID: 39850017 PMCID: PMC11751472 DOI: 10.62347/bptg6174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 10/23/2024] [Indexed: 01/25/2025]
Abstract
Development and maintenance of the nervous system are governed by a scheduled cell death mechanism known as apoptosis. Very much how neurons survive and function depends on the degree of death in differentiating pseudo-neuronal cells produced from neural stem cells. Different inducers can affect the degree of death in these cells: hormones, medicines, growth factors, and others. Developing inventive therapies for neurodegenerative illnesses depends on a knowledge of how these inducers impact mortality in differentiated pseudo-neuronal cells. Using flow cytometry, Western blotting, and fluorescence microscopy among other techniques, the degree of death in many pseudo-neuronal cells is evaluated. Flow cytometry generates dead cell counts from measurements of cell size, granularity, and DNA content. Whereas fluorescence microscopy visualizes dead cells using fluorescent dyes or antibodies, Western blotting detects caspases and Bcl-2 family proteins. This review attempts to offer a thorough investigation of present studies on death in differentiated pseudo-neuronal cells produced from neural stem cells under the effect of different inducers. Through investigating how these inducers influence death, the review aims to provide information that might direct the next studies and support treatment plans for neurodegenerative diseases. With an eye toward inducers like retinoic acid, selegiline, cytokines, valproic acid, and small compounds, we examined research to evaluate death rates. The findings offer important new perspectives on the molecular processes guiding death in these cells. There is still a complete lack of understanding of how different factors affect the molecular processes that lead to death, so understanding these processes can contribute to new therapeutic approaches to treat neurodegenerative diseases.
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Affiliation(s)
- Adele Naghshbandieh
- Department of Anatomical Sciences, School of Medical Sciences, Tarbiat Modares UniversityTehran, Iran
| | - Atefe Naghshbandieh
- Department of Pharmaceutical Biotechnology and Department of Pharmaceutical and Bimolecular Science, University of MilanMilan, Italy
| | - Elahe Barfi
- Razi Herbal Medicines Research Center, Lorestan University of Medical SciencesKhorramabad, Iran
| | - Leila Abkhooie
- Razi Herbal Medicines Research Center, Lorestan University of Medical SciencesKhorramabad, Iran
- Department of Medical Biotechnology, School of Medicine, Lorestan University of Medical SciencesKhorramabad, Iran
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7
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Zhang B, Hu Y, Du H, Han S, Ren L, Cheng H, Wang Y, Gao X, Zheng S, Cui Q, Tian L, Liu T, Sun J, Chai R. Tissue engineering strategies for spiral ganglion neuron protection and regeneration. J Nanobiotechnology 2024; 22:458. [PMID: 39085923 PMCID: PMC11293049 DOI: 10.1186/s12951-024-02742-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/25/2024] [Indexed: 08/02/2024] Open
Abstract
Cochlear implants can directly activate the auditory system's primary sensory neurons, the spiral ganglion neurons (SGNs), via circumvention of defective cochlear hair cells. This bypass restores auditory input to the brainstem. SGN loss etiologies are complex, with limited mammalian regeneration. Protecting and revitalizing SGN is critical. Tissue engineering offers a novel therapeutic strategy, utilizing seed cells, biomolecules, and scaffold materials to create a cellular environment and regulate molecular cues. This review encapsulates the spectrum of both human and animal research, collating the factors contributing to SGN loss, the latest advancements in the utilization of exogenous stem cells for auditory nerve repair and preservation, the taxonomy and mechanism of action of standard biomolecules, and the architectural components of scaffold materials tailored for the inner ear. Furthermore, we delineate the potential and benefits of the biohybrid neural interface, an incipient technology in the realm of implantable devices. Nonetheless, tissue engineering requires refined cell selection and differentiation protocols for consistent SGN quality. In addition, strategies to improve stem cell survival, scaffold biocompatibility, and molecular cue timing are essential for biohybrid neural interface integration.
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Affiliation(s)
- Bin Zhang
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China
| | - Yangnan Hu
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
| | - Haoliang Du
- Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing University, Nanjing, 210008, China
| | - Shanying Han
- Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Lei Ren
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Hong Cheng
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Yusong Wang
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Xin Gao
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Shasha Zheng
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Qingyue Cui
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China
| | - Lei Tian
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
| | - Tingting Liu
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
| | - Jiaqiang Sun
- Department of Otolaryngology-Head and Neck Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, 230001, China.
| | - Renjie Chai
- State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Public Health, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
- Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
- Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
- Department of Neurology, Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
- Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China.
- Southeast University Shenzhen Research Institute, Shenzhen, 518063, China.
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8
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Kipp BT, Savage LM. Modulation of the p75NTR during Adolescent Alcohol Exposure Prevents Cholinergic Neuronal Atrophy and Associated Acetylcholine Activity and Behavioral Dysfunction. Int J Mol Sci 2024; 25:5792. [PMID: 38891978 PMCID: PMC11172149 DOI: 10.3390/ijms25115792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the nucleus basalis magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5 g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from postnatal day 25-57. A subset of these groups also received a protective dose of LM11A-31 (50 mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) and behaviorally relevant acetylcholine (ACh) activity was recorded in the PFC with a fluorescent indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, PFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together, these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration.
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Affiliation(s)
| | - Lisa M. Savage
- Department of Psychology, Binghamton University-State University of New York, Binghamton, NY 13902, USA;
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9
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Di Donato M, Giovannelli P, Migliaccio A, Castoria G. The nerve growth factor-delivered signals in prostate cancer and its associated microenvironment: when the dialogue replaces the monologue. Cell Biosci 2023; 13:60. [PMID: 36941697 PMCID: PMC10029315 DOI: 10.1186/s13578-023-01008-4] [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: 11/01/2022] [Accepted: 03/06/2023] [Indexed: 03/22/2023] Open
Abstract
Prostate cancer (PC) represents the most diagnosed and the second most lethal cancer in men worldwide. Its development and progression occur in concert with alterations in the surrounding tumor microenvironment (TME), made up of stromal cells and extracellular matrix (ECM) that dynamically interact with epithelial PC cells affecting their growth and invasiveness. PC cells, in turn, can functionally sculpt the TME through the secretion of various factors, including neurotrophins. Among them, the nerve growth factor (NGF) that is released by both epithelial PC cells and carcinoma-associated fibroblasts (CAFs) triggers the activation of various intracellular signaling cascades, thereby promoting the acquisition of a metastatic phenotype. After many years of investigation, it is indeed well established that aberrations and/or derangement of NGF signaling are involved not only in neurological disorders, but also in the pathogenesis of human proliferative diseases, including PC. Another key feature of cancer progression is the nerve outgrowth in TME and the concept of nerve dependence related to perineural invasion is currently emerging. NGF released by cancer cells can be a driver of tumor neurogenesis and nerves infiltrated in TME release neurotransmitters, which might stimulate the growth and sustainment of tumor cells.In this review, we aim to provide a snapshot of NGF action in the interactions between TME, nerves and PC cells. Understanding the molecular basis of this dialogue might expand the arsenal of therapeutic strategies against this widespread disease.
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Affiliation(s)
- Marzia Di Donato
- Department of Precision Medicine, University of Campania "L.Vanvitelli", 80138, Naples, Italy.
| | - Pia Giovannelli
- Department of Precision Medicine, University of Campania "L.Vanvitelli", 80138, Naples, Italy.
| | - Antimo Migliaccio
- Department of Precision Medicine, University of Campania "L.Vanvitelli", 80138, Naples, Italy
| | - Gabriella Castoria
- Department of Precision Medicine, University of Campania "L.Vanvitelli", 80138, Naples, Italy
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10
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Paoletti F, Covaceuszach S, Cassetta A, Calabrese AN, Novak U, Konarev P, Grdadolnik J, Lamba D, Golič Grdadolnik S. Distinct conformational changes occur within the intrinsically unstructured pro-domain of pro-Nerve Growth Factor in the presence of ATP and Mg 2. Protein Sci 2023; 32:e4563. [PMID: 36605018 PMCID: PMC9878617 DOI: 10.1002/pro.4563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/24/2022] [Accepted: 01/03/2023] [Indexed: 01/07/2023]
Abstract
Nerve growth factor (NGF), the prototypical neurotrophic factor, is involved in the maintenance and growth of specific neuronal populations, whereas its precursor, proNGF, is involved in neuronal apoptosis. Binding of NGF or proNGF to TrkA, p75NTR , and VP10p receptors triggers complex intracellular signaling pathways that can be modulated by endogenous small-molecule ligands. Here, we show by isothermal titration calorimetry and NMR that ATP binds to the intrinsically disordered pro-peptide of proNGF with a micromolar dissociation constant. We demonstrate that Mg2+ , known to play a physiological role in neurons, modulates the ATP/proNGF interaction. An integrative structural biophysics analysis by small angle X-ray scattering and hydrogen-deuterium exchange mass spectrometry unveils that ATP binding induces a conformational rearrangement of the flexible pro-peptide domain of proNGF. This suggests that ATP may act as an allosteric modulator of the overall proNGF conformation, whose likely distinct biological activity may ultimately affect its physiological homeostasis.
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Affiliation(s)
- Francesca Paoletti
- Laboratory for Molecular Structural Dynamics, Theory DepartmentNational Institute of ChemistryLjubljanaSlovenia
| | | | - Alberto Cassetta
- Institute of Crystallography—C.N.R.—Trieste OutstationTriesteItaly
| | - Antonio N. Calabrese
- School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular BiologyUniversity of LeedsLeedsUK
| | - Urban Novak
- Laboratory for Molecular Structural Dynamics, Theory DepartmentNational Institute of ChemistryLjubljanaSlovenia
| | - Petr Konarev
- A.V. Shubnikov Institute of Crystallography of Federal Scientific Research Centre “Crystallography and Photonics”Russian Academy of SciencesMoscowRussia
| | - Jože Grdadolnik
- Laboratory for Molecular Structural Dynamics, Theory DepartmentNational Institute of ChemistryLjubljanaSlovenia
| | - Doriano Lamba
- Institute of Crystallography—C.N.R.—Trieste OutstationTriesteItaly
- Interuniversity Consortium “Biostructures and Biosystems National Institute”RomeItaly
| | - Simona Golič Grdadolnik
- Laboratory for Molecular Structural Dynamics, Theory DepartmentNational Institute of ChemistryLjubljanaSlovenia
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Arutjunyan AV, Kerkeshko GO, Milyutina YP, Shcherbitskaia AD, Zalozniaia IV, Mikhel AV, Inozemtseva DB, Vasilev DS, Kovalenko AA, Kogan IY. Imbalance of Angiogenic and Growth Factors in Placenta in Maternal Hyperhomocysteinemia. BIOCHEMISTRY (MOSCOW) 2023; 88:262-279. [PMID: 37072327 DOI: 10.1134/s0006297923020098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
Numerous studies have shown that various adverse factors of different nature and action mechanisms have similar negative influence on placental angiogenesis, resulting in insufficiency of placental blood supply. One of the risk factors for pregnancy complications with placental etiology is an increased level of homocysteine in the blood of pregnant women. However, the effect of hyperhomocysteinemia (HHcy) on the development of the placenta and, in particular, on the formation of its vascular network is at present poorly understood. The aim of this work was to study the effect of maternal HHcy on the expression of angiogenic and growth factors (VEGF-A, MMP-2, VEGF-B, BDNF, NGF), as well as their receptors (VEGFR-2, TrkB, p75NTR), in the rat placenta. The effects of HHcy were studied in the morphologically and functionally different maternal and fetal parts of the placenta on the 14th and 20th day of pregnancy. The maternal HHcy caused increase in the levels of oxidative stress and apoptosis markers accompanied by an imbalance of the studied angiogenic and growth factors in the maternal and/or fetal part of the placenta. The influence of maternal HHcy in most cases manifested in a decrease in the protein content (VEGF-A), enzymatic activity (MMP-2), gene expression (VEGFB, NGF, TRKB), and accumulation of precursor form (proBDNF) of the investigated factors. In some cases, the effects of HHcy differed depending on the placental part and stage of development. The influence of maternal HHcy on signaling pathways and processes controlled by the studied angiogenic and growth factors could lead to incomplete development of the placental vasculature and decrease in the placental transport, resulting in fetal growth restriction and impaired fetal brain development.
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Affiliation(s)
- Alexander V Arutjunyan
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia.
| | - Gleb O Kerkeshko
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia
| | - Yulia P Milyutina
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia
- St. Petersburg State Pediatric Medical University, Russian Ministry of Health, St. Petersburg, 194100, Russia
| | - Anastasiia D Shcherbitskaia
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, 194223, Russia
| | - Irina V Zalozniaia
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia
| | - Anastasiia V Mikhel
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia
| | - Daria B Inozemtseva
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia
| | - Dmitrii S Vasilev
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, 194223, Russia
| | - Anna A Kovalenko
- I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, 194223, Russia
| | - Igor Yu Kogan
- D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, 199034, Russia
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12
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von Bohlen Und Halbach O. Neurotrophic Factors and Dendritic Spines. ADVANCES IN NEUROBIOLOGY 2023; 34:223-254. [PMID: 37962797 DOI: 10.1007/978-3-031-36159-3_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Dendritic spines are highly dynamic structures that play important roles in neuronal plasticity. The morphologies and the numbers of dendritic spines are highly variable, and this diversity is correlated with the different morphological and physiological features of this neuronal compartment. Dendritic spines can change their morphology and number rapidly, allowing them to adapt to plastic changes. Neurotrophic factors play important roles in the brain during development. However, these factors are also necessary for a variety of processes in the postnatal brain. Neurotrophic factors, especially members of the neurotrophin family and the ephrin family, are involved in the modulation of long-lasting effects induced by neuronal plasticity by acting on dendritic spines, either directly or indirectly. Thereby, the neurotrophic factors play important roles in processes attributed, for example, to learning and memory.
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13
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Stress-Induced Changes in Trophic Factor Expression in the Rodent Urinary Bladder: Possible Links With Angiogenesis. Int Neurourol J 2022; 26:299-307. [PMID: 36599338 PMCID: PMC9816446 DOI: 10.5213/inj.2244118.059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 12/12/2022] [Indexed: 12/30/2022] Open
Abstract
PURPOSE Substantive evidence supports a role of chronic stress in the development, maintenance, and even enhancement of functional bladder disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). Increased urinary frequency and bladder hyperalgesia have been reported in rodents exposed to a chronic stress paradigm. Here, we utilized a water avoidance stress (WAS) model in rodents to investigate the effect of chronic stress on vascular perfusion and angiogenesis. METHODS Female Wistar-Kyoto rats were exposed to WAS for 10 consecutive days. Bladder neck tissues were analyzed by western immunoblot for vascular endothelial growth factor (VEGF) and nerve growth factor precursor (proNGF). Vascular perfusion was assessed by fluorescent microangiography followed by Hypoxyprobe testing to identify regions of tissue hypoxia. RESULTS The expression of VEGF and proNGF in the bladder neck mucosa was significantly higher in the WAS rats than in the controls. There was a trend toward increased vascular perfusion, but without a statistically significant difference from the control group. The WAS rats displayed a 1.6-fold increase in perfusion. Additionally, a greater abundance of vessels was observed in the WAS rats, most notably in the microvasculature. CONCLUSION These findings show that chronic psychological stress induces factors that can lead to increased microvasculature formation, especially around the bladder neck, the region that contains most nociceptive bladder afferents. These findings may indicate a link between angiogenesis and other inflammatory factors that contribute to structural changes and pain in IC/BPS.
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14
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Hechtman JF. NTRK insights: best practices for pathologists. Mod Pathol 2022; 35:298-305. [PMID: 34531526 PMCID: PMC8860742 DOI: 10.1038/s41379-021-00913-8] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 11/21/2022]
Abstract
Since the discovery of an oncogenic tropomyosin-receptor kinase (TRK) fusion protein in the early 1980s, our understanding of neurotrophic tropomyosin-receptor kinase (NTRK) fusions, their unique patterns of frequency in different tumor types, and methods to detect them have grown in scope and depth. Identification of these molecular alterations in the management of patients with cancer has become increasingly important with the emergence of histology-agnostic, US Food and Drug Administration-approved, effective TRK protein inhibitors. Herein, we review the biology of TRK in normal and malignant tissues, as well as the prevalence and enrichment patterns of these fusions across tumor types. Testing methods currently used to identify NTRK1-3 fusions will be reviewed in detail, with attention to newer assays including RNA-based next-generation sequencing. Recently proposed algorithms for NTRK fusion testing will be compared, and practical insights provided on how testing can best be implemented and communicated within the multidisciplinary healthcare team.
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Affiliation(s)
- Jaclyn F Hechtman
- Molecular Pathologist, Neogenomics 9490 NeoGenomics Way, Fort Myers, FL, 33912, USA.
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Shmakova AA, Rysenkova KD, Ivashkina OI, Gruzdeva AM, Klimovich PS, Popov VS, Rubina KA, Anokhin KV, Tkachuk VA, Semina EV. Early Induction of Neurotrophin Receptor and miRNA Genes in Mouse Brain after Pentilenetetrazole-Induced Neuronal Activity. BIOCHEMISTRY. BIOKHIMIIA 2021; 86:1326-1341. [PMID: 34903157 DOI: 10.1134/s0006297921100138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 06/21/2021] [Accepted: 06/30/2021] [Indexed: 06/14/2023]
Abstract
Neurotrophin receptors regulate neuronal survival and network formation, as well as synaptic plasticity in the brain via interaction with their ligands. Here, we examined early changes in the expression of neurotrophin receptor genes Ntk1 (TrkA), Ntrk2 (TrkB), Ntrk3 (TrkC), Ngfr (p75NTR) and miRNAs that target theses gens in the mouse brain after induction of seizure activity by pentylenetetrazol. We found that expression of Ntrk3 and Ngfr was upregulated in the cortex and the hippocampus 1-3 hours after the seizures, while Ntrk2 expression increased after 3-6 hours in the anterior cortex and after 1 and 6 hours in the hippocampus. At the same time, the ratio of Bcl-2/Bax signaling proteins increased in the anterior and posterior cortex, but not in the hippocampus, suggesting the activation of anti-apoptotic signaling. Expression of miRNA-9 and miRNA-29a, which were predicted to target Ntrk3, was upregulated in the hippocampus 3 hours after pentylenetetrazol injection. Therefore, early cellular response to seizures in the brain includes induction of the Ntrk2, Ntrk3, Ngfr, miRNA-9, and miRNA-29a expression, as well as activation of Bcl-2 and Bax signaling pathways, which may characterize them as important mediators of neuronal adaptation and survival upon induction of the generalized brain activity.
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Affiliation(s)
- Anna A Shmakova
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
- Institute of Experimental Cardiology, National Cardiology Research Center of the Ministry of Health of the Russian Federation, Moscow, 121552, Russia
| | - Karina D Rysenkova
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
- Institute of Experimental Cardiology, National Cardiology Research Center of the Ministry of Health of the Russian Federation, Moscow, 121552, Russia
| | - Olga I Ivashkina
- Institute for Advanced Brain Studies, Lomonosov Moscow State University, Moscow, 119192, Russian Federation
- Anokhin Research Institute of Normal Physiology, Moscow, 125315, Russia
- Kurchatov Institute National Research Center, Moscow, 123182, Russia
| | - Anna M Gruzdeva
- Institute for Advanced Brain Studies, Lomonosov Moscow State University, Moscow, 119192, Russian Federation
| | - Polina S Klimovich
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
- Institute of Experimental Cardiology, National Cardiology Research Center of the Ministry of Health of the Russian Federation, Moscow, 121552, Russia
| | - Vladimir S Popov
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
| | - Kseniya A Rubina
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
| | - Konstantin V Anokhin
- Institute for Advanced Brain Studies, Lomonosov Moscow State University, Moscow, 119192, Russian Federation.
- Anokhin Research Institute of Normal Physiology, Moscow, 125315, Russia
| | - Vsevolod A Tkachuk
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
- Institute of Experimental Cardiology, National Cardiology Research Center of the Ministry of Health of the Russian Federation, Moscow, 121552, Russia
| | - Ekaterina V Semina
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia.
- Institute of Experimental Cardiology, National Cardiology Research Center of the Ministry of Health of the Russian Federation, Moscow, 121552, Russia
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16
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Hosoya M, Fujioka M, Murayama AY, Ozawa H, Okano H, Ogawa K. Neuronal development in the cochlea of a nonhuman primate model, the common marmoset. Dev Neurobiol 2021; 81:905-938. [PMID: 34545999 PMCID: PMC9298346 DOI: 10.1002/dneu.22850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/25/2021] [Accepted: 09/13/2021] [Indexed: 01/02/2023]
Abstract
Precise cochlear neuronal development is vital to hearing ability. Understanding the developmental process of the spiral ganglion is useful for studying hearing loss aimed at aging or regenerative therapy. Although interspecies differences have been reported between rodents and humans, to date, most of our knowledge about the development of cochlear neuronal development has been obtained from rodent models because of the difficulty in using human fetal samples in this field. In this study, we investigated cochlear neuronal development in a small New World monkey species, the common marmoset (Callithrix jacchus). We examined more than 25 genes involved in the neuronal development of the cochlea and described the critical developmental steps of these neurons. We also revealed similarities and differences between previously reported rodent models and this primate animal model. Our results clarified that this animal model of cochlear neuronal development is more similar to humans than rodents and is suitable as an alternative for the analysis of human cochlear development. The time course established in this report will be a useful tool for studying primate‐specific neuronal biology of the inner ear, which could eventually lead to new treatment strategies for human hearing loss.
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Affiliation(s)
- Makoto Hosoya
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masato Fujioka
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Ayako Y Murayama
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan.,Laboratory for Marmoset Neural Architecture, Center for Brain Science, RIKEN, Wako, Japan
| | - Hiroyuki Ozawa
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan.,Laboratory for Marmoset Neural Architecture, Center for Brain Science, RIKEN, Wako, Japan
| | - Kaoru Ogawa
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan
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17
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Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice. Int J Mol Sci 2021; 22:ijms22137002. [PMID: 34210092 PMCID: PMC8269163 DOI: 10.3390/ijms22137002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/10/2021] [Accepted: 06/17/2021] [Indexed: 12/19/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.
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18
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Evidence of p75 Neurotrophin Receptor Involvement in the Central Nervous System Pathogenesis of Classical Scrapie in Sheep and a Transgenic Mouse Model. Int J Mol Sci 2021; 22:ijms22052714. [PMID: 33800240 PMCID: PMC7962525 DOI: 10.3390/ijms22052714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/27/2021] [Accepted: 02/28/2021] [Indexed: 11/17/2022] Open
Abstract
Neurotrophins constitute a group of growth factor that exerts important functions in the nervous system of vertebrates. They act through two classes of transmembrane receptors: tyrosine-kinase receptors and the p75 neurotrophin receptor (p75NTR). The activation of p75NTR can favor cell survival or apoptosis depending on diverse factors. Several studies evidenced a link between p75NTR and the pathogenesis of prion diseases. In this study, we investigated the distribution of several neurotrophins and their receptors, including p75NTR, in the brain of naturally scrapie-affected sheep and experimentally infected ovinized transgenic mice and its correlation with other markers of prion disease. No evident changes in infected mice or sheep were observed regarding neurotrophins and their receptors except for the immunohistochemistry against p75NTR. Infected mice showed higher abundance of p75NTR immunostained cells than their non-infected counterparts. The astrocytic labeling correlated with other neuropathological alterations of prion disease. Confocal microscopy demonstrated the co-localization of p75NTR and the astrocytic marker GFAP, suggesting an involvement of astrocytes in p75NTR-mediated neurodegeneration. In contrast, p75NTR staining in sheep lacked astrocytic labeling. However, digital image analyses revealed increased labeling intensities in preclinical sheep compared with non-infected and terminal sheep in several brain nuclei. This suggests that this receptor is overexpressed in early stages of prion-related neurodegeneration in sheep. Our results confirm a role of p75NTR in the pathogenesis of classical ovine scrapie in both the natural host and in an experimental transgenic mouse model.
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Ozalp O, Cark O, Azbazdar Y, Haykir B, Cucun G, Kucukaylak I, Alkan-Yesilyurt G, Sezgin E, Ozhan G. Nradd Acts as a Negative Feedback Regulator of Wnt/β-Catenin Signaling and Promotes Apoptosis. Biomolecules 2021; 11:100. [PMID: 33466728 PMCID: PMC7828832 DOI: 10.3390/biom11010100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/05/2021] [Accepted: 01/11/2021] [Indexed: 12/16/2022] Open
Abstract
Wnt/β-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75NTR), as a negative regulator of Wnt/β-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/β-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/β-catenin signaling during development.
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Affiliation(s)
- Ozgun Ozalp
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey; (O.O.); (O.C.); (Y.A.); (B.H.); (G.C.); (I.K.); (G.A.-Y.)
- Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Inciralti-Balcova, 35340 Izmir, Turkey
| | - Ozge Cark
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey; (O.O.); (O.C.); (Y.A.); (B.H.); (G.C.); (I.K.); (G.A.-Y.)
- Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Inciralti-Balcova, 35340 Izmir, Turkey
| | - Yagmur Azbazdar
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey; (O.O.); (O.C.); (Y.A.); (B.H.); (G.C.); (I.K.); (G.A.-Y.)
- Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Inciralti-Balcova, 35340 Izmir, Turkey
| | - Betul Haykir
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey; (O.O.); (O.C.); (Y.A.); (B.H.); (G.C.); (I.K.); (G.A.-Y.)
- Institute of Physiology, Switzerland and National Center of Competence in Research NCCR Kidney, University of Zurich, CH-8057 Zurich, Switzerland
| | - Gokhan Cucun
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey; (O.O.); (O.C.); (Y.A.); (B.H.); (G.C.); (I.K.); (G.A.-Y.)
- Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Inciralti-Balcova, 35340 Izmir, Turkey
| | - Ismail Kucukaylak
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey; (O.O.); (O.C.); (Y.A.); (B.H.); (G.C.); (I.K.); (G.A.-Y.)
- Institute of Zoology-Developmental Biology, University of Cologne, 50674 Cologne, Germany
| | - Gozde Alkan-Yesilyurt
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey; (O.O.); (O.C.); (Y.A.); (B.H.); (G.C.); (I.K.); (G.A.-Y.)
| | - Erdinc Sezgin
- Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden;
- MRC Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, University of Oxford, Oxford OX39DS, UK
| | - Gunes Ozhan
- Izmir Biomedicine and Genome Center (IBG), Dokuz Eylul University Health Campus, Inciralti-Balcova, 35340 Izmir, Turkey; (O.O.); (O.C.); (Y.A.); (B.H.); (G.C.); (I.K.); (G.A.-Y.)
- Izmir International Biomedicine and Genome Institute (IBG-Izmir), Dokuz Eylul University, Inciralti-Balcova, 35340 Izmir, Turkey
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Nerve Growth Factor: The First Molecule of the Neurotrophin Family. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1331:3-10. [PMID: 34453288 DOI: 10.1007/978-3-030-74046-7_1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Neurotrophins (NTs) are molecules regulating differentiation, maintenance, and functional plasticity of vertebrate nervous systems. Nerve growth factor (NGF) was the first to be identified in the neurotrophin family. The long scientific history of NTs provided not only advancement in the neuroscience field but opened new scenarios involving different body districts in physiological and pathological conditions, which include the immune, endocrine, and skeletal system, vascular districts, inflammation, etc. To date, many biological aspects of NTs have been clarified, but the new discoveries are still opening new insights on molecular and cellular mechanisms and systemic effects, also affecting the possible therapeutic application of NTs. This short review summarizes the main aspects of NGF biology and biochemistry, including the role of the NGF precursor molecule, high- and low-affinity receptors and related intracellular pathways, and target cells.
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21
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Zou W, Hu X, Jiang L. Advances in Regulating Tumorigenicity and Metastasis of Cancer Through TrkB Signaling. Curr Cancer Drug Targets 2020; 20:779-788. [PMID: 32748747 DOI: 10.2174/1568009620999200730183631] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 06/27/2020] [Accepted: 06/29/2020] [Indexed: 01/12/2023]
Abstract
The clinical pathology of various human malignancies is supported by tropomyosin receptor kinase (Trk) B TrkB which is a specific binding receptor of the brain-derived neurotrophic factor (BDNF). TrkB and TrkB fusion proteins have been observed to be over-expressed in many cancer patients. Moreover, these proteins have been observed in multiple types of cells. A few signaling pathways can be modulated by the abnormal activation of the BDNF/TrkB pathway. These signaling pathways include PI3K/Akt pathway, transactivation of EGFR, phospholipase C-gamma (PLCγ) pathway, Ras-Raf-MEK-ERK pathway, Jak/STAT pathway, and nuclear factor kappalight- chain-enhancer of activated B cells (NF-kB) pathway. The BDNF/TrkB pathway, when overexpressed in tumors, is correlated with reduced clinical prognosis and short survival time of patients. Targeting the BDNF/TrkB pathway and the use of Trk inhibitors, such as entrectinib, larotrectinib, etc. are promising methods for targeted therapy of tumors. The present review provides an overview of the role of the TrkB pathway in the pathogenesis of cancer and its value as a potential therapeutic target.
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Affiliation(s)
- Wujun Zou
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
| | - Xiaoyan Hu
- Department of Pathogenic Biology, School of Basic Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Liang Jiang
- Department of Otorhinolaryngology, Head and Neck Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China
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22
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Zagrebelsky M, Tacke C, Korte M. BDNF signaling during the lifetime of dendritic spines. Cell Tissue Res 2020; 382:185-199. [PMID: 32537724 PMCID: PMC7529616 DOI: 10.1007/s00441-020-03226-5] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022]
Abstract
Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.
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Affiliation(s)
- Marta Zagrebelsky
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Spielmannstr 7, 38106, Braunschweig, Germany.
- Helmholtz Centre for Infection Research, AG NIND, Inhoffenstr. 7, D-38124, Braunschweig, Germany.
| | - Charlotte Tacke
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Spielmannstr 7, 38106, Braunschweig, Germany
| | - Martin Korte
- Division of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Spielmannstr 7, 38106, Braunschweig, Germany.
- Helmholtz Centre for Infection Research, AG NIND, Inhoffenstr. 7, D-38124, Braunschweig, Germany.
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Fang J, Wei Z, Zheng D, Ying T, Hong H, Hu D, Lin Y, Jiang X, Wu L, Lan T, Yang Z, Zhou X, Chen L. Recombinant Extracellular Domain (p75ECD) of the Neurotrophin Receptor p75 Attenuates Myocardial Ischemia-Reperfusion Injury by Inhibiting the p-JNK/Caspase-3 Signaling Pathway in Rat Microvascular Pericytes. J Am Heart Assoc 2020; 9:e016047. [PMID: 32567476 PMCID: PMC7670530 DOI: 10.1161/jaha.119.016047] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Background Pro-NTs (precursor of neurotrophins) and their receptor p75 are potential targets for preventing microvascular dysfunction induced by myocardial ischemia-reperfusion injury (IRI). p75ECD (ectodomain of neurotrophin receptor p75) may physiologically produce neurocytoprotective effects by scavenging pro-NTs. We therefore hypothesized that p75ECD may have a cardioprotective effect on IRI through microvascular mechanisms. Methods and Results Myocardial IRI was induced in Sprague-Dawley rats by occluding the left main coronary arteries for 45 minutes before a subsequent relaxation. Compared with the ischemia-reperfusion group, an intravenous injection of p75ECD (3 mg/kg) 5 minutes before reperfusion reduced the myocardial infarct area at 24 hours after reperfusion (by triphenyltetrazolium chloride, 44.9±3.9% versus 34.6±5.7%, P<0.05); improved the left ventricular ejection fraction (by echocardiography), with less myocardial fibrosis (by Masson's staining), and prevented microvascular dysfunction (by immunofluorescence) at 28 days after reperfusion; and reduced myocardial pro-NTs expression at 24 hours and 28 days after reperfusion (by Western blotting). A simulative IRI model using rat microvascular pericytes was established in vitro by hypoxia-reoxygenation (2/6 hours) combined with pro-NTs treatment (3 nmol/L) at R. p75ECD (3 μg/mL) given at R improved pericyte survival (by methyl thiazolyl tetrazolium assay) and attenuated apoptosis (by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling). In the reperfused hearts and hypoxia-reoxygenation +pro-NTs-injured pericytes, p75ECD inhibited the expression of p-JNK (phospho of c-Jun N-terminal kinase)/caspase-3 (by Western blotting). SP600125, an inhibitor of JNK, did not enhance the p75ECD-induced infarct-sparing effects and pericyte protection. Conclusions p75ECD may attenuate myocardial IRI via pro-NTs reduction-induced inhibition of p-JNK/caspase-3 pathway of microvascular pericytes in rats.
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Affiliation(s)
- Jun Fang
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
| | - ZhiXiong Wei
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
| | - DeDong Zheng
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
| | - Teng Ying
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
| | - HuaShan Hong
- Fujian Key Laboratory of Vascular Aging Department of Geriatrics Fujian Institute of Geriatrics Fujian Medical University Union Hospital Fuzhou P. R. China
| | - DanQing Hu
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
| | - YunLing Lin
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
| | - XiaoLiang Jiang
- Institute of Laboratory Animal Science Chinese Academy of Medical Sciences & Comparative Medicine Centre, Peking Union Medical Collage, and Beijing Collaborative Innovation Center for Cardiovascular Disorders Beijing P. R. China
| | - LingZhen Wu
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
| | - TingXiang Lan
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
| | - ZhiWei Yang
- Institute of Laboratory Animal Science Chinese Academy of Medical Sciences & Comparative Medicine Centre, Peking Union Medical Collage, and Beijing Collaborative Innovation Center for Cardiovascular Disorders Beijing P. R. China
| | - XinFu Zhou
- Neuroregeneration Laboratory Division of Health Sciences School of Pharmacy and Medical Sciences University of South Australia Adelaide South Australia Australia
| | - LiangLong Chen
- Department of Cardiology Fujian Heart Medical Center Fujian Institute of Coronary Heart Disease Fujian Medical University Union Hospital Fuzhou P. R. China
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Dravid A, Parittotokkaporn S, Aqrawe Z, O’Carroll SJ, Svirskis D. Determining Neurotrophin Gradients in Vitro To Direct Axonal Outgrowth Following Spinal Cord Injury. ACS Chem Neurosci 2020; 11:121-132. [PMID: 31825204 DOI: 10.1021/acschemneuro.9b00565] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
A spinal cord injury can damage neuronal connections required for both motor and sensory function. Barriers to regeneration within the central nervous system, including an absence of neurotrophic stimulation, impair the ability of injured neurons to reestablish their original circuitry. Exogenous neurotrophin administration has been shown to promote axonal regeneration and outgrowth following injury. The neurotrophins possess chemotrophic properties that guide axons toward the region of highest concentration. These growth factors have demonstrated potential to be used as a therapeutic intervention for orienting axonal growth beyond the injury lesion, toward denervated targets. However, the success of this approach is dependent on the appropriate spatiotemporal distribution of these molecules to ensure detection and navigation by the axonal growth cone. A number of in vitro gradient-based assays have been employed to investigate axonal response to neurotrophic gradients. Such platforms have helped elucidate the potential of applying a concentration gradient of neurotrophins to promote directed axonal regeneration toward a functionally significant target. Here, we review these techniques and the principles of gradient detection in axonal guidance, with particular focus on the use of neurotrophins to orient the trajectory of regenerating axons.
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Affiliation(s)
- Anusha Dravid
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Sam Parittotokkaporn
- Department of Anatomy and Medical Imaging, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Zaid Aqrawe
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
- Department of Anatomy and Medical Imaging, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Simon J. O’Carroll
- Department of Anatomy and Medical Imaging, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
| | - Darren Svirskis
- School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand
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25
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Wu K, Huang D, Zhu C, Kasanga EA, Zhang Y, Yu E, Zhang H, Ni Z, Ye S, Zhang C, Hu J, Zhuge Q, Yang J. NT3 P75-2 gene-modified bone mesenchymal stem cells improve neurological function recovery in mouse TBI model. Stem Cell Res Ther 2019; 10:311. [PMID: 31651375 PMCID: PMC6814101 DOI: 10.1186/s13287-019-1428-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/07/2019] [Accepted: 09/24/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The attainment of extensive neurological function recovery remains the key challenge for the treatment of traumatic brain injury (TBI). Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has been shown to improve neurological function recovery after TBI. However, the survival of BMSCs after transplantation in early-stage TBI is limited, and much is unknown about the mechanisms mediating this neurological function recovery. Secretion of neurotrophic factors, including neurotrophin 3 (NT3), is one of the critical factors mediating BMSC neurological function recovery. Gene mutation of NT3 (NT3P75-2) has been shown to enhance the biological function of NT3 via the reduction of the activation of the P75 signal pathway. Thus, we investigated whether NT3P75-2 gene-modified BMSCs could enhance the survival of BMSCs and further improve neurological function recovery after TBI. METHODS The ability of NT3P75-2 induction to improve cell growth rate of NSC-34 and PC12 cells in vitro was first determined. BMSCs were then infected with three different lentiviruses (green fluorescent protein (GFP), GFP-NT3, or GFP-NT3P75-2), which stably express GFP, GFP-NT3, or GFP-NT3P75-2. At 24 h post-TBI induction in mice, GFP-labeled BMSCs were locally transplanted into the lesion site. Immunofluorescence and histopathology were performed at 1, 3, and/or 7 days after transplantation to evaluate the survival of BMSCs as well as the lesion volume. A modified neurological severity scoring system and the rotarod test were chosen to evaluate the functional recovery of the mice. Cell growth rate, glial activation, and signaling pathway analyses were performed to determine the potential mechanisms of NT3P75-2 in functional recovery after TBI. RESULTS Overall, NT3P75-2 improved cell growth rate of NSC-34 and PC12 cells in vitro. In addition, NT3P75-2 significantly improved the survival of transplanted BMSCs and neurological function recovery after TBI. Overexpression of NT3P75-2 led to a significant reduction in the activation of glial cells, brain water content, and brain lesion volume after TBI. This was associated with a reduced activation of the p75 neurotrophin receptor (P75NTR) and the c-Jun N-terminal kinase (JNK) signal pathway due to the low affinity of NT3P75-2 for the receptor. CONCLUSIONS Taken together, our results demonstrate that administration of NT3P75-2 gene-modified BMSCs dramatically improves neurological function recovery after TBI by increasing the survival of BMSCs and ameliorating the inflammatory environment, providing a new promising treatment strategy for TBI.
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Affiliation(s)
- Ke Wu
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Dongdong Huang
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Can Zhu
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Ella A Kasanga
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - Ying Zhang
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Enxing Yu
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Hengli Zhang
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhihui Ni
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Sheng Ye
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Chunli Zhang
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jiangnan Hu
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. .,Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
| | - Qichuan Zhuge
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
| | - Jianjing Yang
- Department of Neurosurgery, Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. .,Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
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Long-term Administration of Salicylate-induced Changes in BDNF Expression and CREB Phosphorylation in the Auditory Cortex of Rats. Otol Neurotol 2019; 39:e173-e180. [PMID: 29342042 PMCID: PMC5821486 DOI: 10.1097/mao.0000000000001717] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We investigated whether salicylate induces tinnitus through alteration of the expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, tyrosine kinase receptor B (TrkB), cAMP-responsive element-binding protein (CREB), and phosphorylated CREB (p-CREB) in the auditory cortex (AC).
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27
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Choucry AM, Al-Shorbagy MY, Attia AS, El-Abhar HS. Pharmacological Manipulation of Trk, p75NTR, and NGF Balance Restores Memory Deficit in Global Ischemia/Reperfusion Model in Rats. J Mol Neurosci 2019; 68:78-90. [PMID: 30863991 DOI: 10.1007/s12031-019-01284-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 02/21/2019] [Indexed: 01/17/2023]
Abstract
Long-term memory impairment is reported in more than 50% of cardiac arrest survivors. Monosialoganglioside (GM1) provided neuroprotection in experimental models of stroke but failed to replicate its promise clinically for unknown reasons. GM1 stimulates the release of nerve growth factor (NGF), which is synthesized as a precursor protein (pro-NGF) that either mediates apoptosis through the p75 neurotrophin receptor (p75NTR) or is cleaved by the protease furin (FUR) to yield mature NGF, the latter supporting survival through tropomyosin kinase receptor (Trk). The flavanol epicatechin (EPI) inhibits p75NTR-mediated signaling and apoptosis by pro-NGF. The aim of the current work is to test whether these two drugs affect, or communicate with, each other in the setting of CNS injuries. Using the two-vessel occlusion model of global ischemia/reperfusion (I/R), we tested if pharmacological modulation of Trk, p75NTR, and NGF balance with GM1, EPI, and their combination, can correct the memory deficit that follows this insult. Finally, we tested if FUR insufficiency and/or p75NTR-mediated apoptosis negatively affect the neurotherapeutic effect of GM1. Key proteins for Trk and p75NTR, FUR, and both forms of NGF were assessed. All treatment regiments successfully improved spatial memory retention and acquisition. A week after the insult, most Trk and p75NTR proteins were normal, but pro/mature NGF ratio remained sharply elevated and was associated with the poorest memory performance. Pharmacological correction of this balance was achieved by reinforcing Trk and p75NTR signaling. GM1 increased FUR levels, while concomitant administration of EPI weakened GM1 effect on pro-survival Trk and p75NTR mediators. GM1 neuroprotection is therefore not limited by FUR but could be dependent on p75NTR. Graphical Abstract "."
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Affiliation(s)
- Ali Mohamed Choucry
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., Cairo, 11562, Egypt.,Department of Biochemistry, Graduate School of Medicine and Pharmaceutical Sciences, Toyama University, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Muhammad Yusuf Al-Shorbagy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., Cairo, 11562, Egypt. .,School of Pharmacy, New Giza University, Giza, Egypt.
| | - Ahmed Sherif Attia
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El Aini St., Cairo, 11562, Egypt
| | - Hanan Salah El-Abhar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., Cairo, 11562, Egypt
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Montroull LE, Danelon V, Cragnolini AB, Mascó DH. Loss of TrkB Signaling Due to Status Epilepticus Induces a proBDNF-Dependent Cell Death. Front Cell Neurosci 2019; 13:4. [PMID: 30800056 PMCID: PMC6375841 DOI: 10.3389/fncel.2019.00004] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 01/08/2019] [Indexed: 01/25/2023] Open
Abstract
Neurotrophins (NTs) are secretory proteins that bind to target receptors and influence many cellular functions, such as cell survival and cell death in neurons. The mammalian NT brain-derived neurotrophic factor (matBDNF) is the C-terminal mature form released by cleavage from the proBDNF precursor. The binding of matBDNF to the tyrosine kinase receptor B (TrkB) activates different signaling cascades and leads to neuron survival and plasticity, while the interaction of proBDNF with the p75 NT receptor (p75NTR)/sortilin receptor complex has been highly involved in apoptosis. Many studies have demonstrated that prolonged seizures such as status epilepticus (SE) induce changes in the expression of NT, pro-NT, and their receptors. We have previously described that the blockage of both matBDNF and proBDNF signaling reduces neuronal death after SE in vivo (Unsain et al., 2008). We used an in vitro model as well as an in vivo model of SE to determine the specific role of TrkB and proBDNF signaling during neuronal cell death. We found that the matBDNF sequestering molecule TrkB-Fc induced an increase in neuronal death in both models of SE, and it also prevented a decrease in TrkB levels. Moreover, SE triggered the interaction between proBDNF and p75NTR, which was not altered by sequestering matBDNF. The intra-hippocampal administration of TrkB-Fc, combined with an antibody against proBDNF, prevented neuronal degeneration. In addition, we demonstrated that proBDNF binding to p75NTR exacerbates neuronal death when matBDNF signaling is impaired through TrkB. Our results indicated that both the mature and the precursor forms of BDNF may have opposite effects depending on the scenario in which they function and the signaling pathways they activate.
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Affiliation(s)
- Laura Ester Montroull
- Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba; Instituto de Investigaciones Biológicas y Tecnológicas (IIByT), CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Víctor Danelon
- Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba; Instituto de Investigaciones Biológicas y Tecnológicas (IIByT), CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Andrea Beatriz Cragnolini
- Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba; Instituto de Investigaciones Biológicas y Tecnológicas (IIByT), CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina
| | - Daniel Hugo Mascó
- Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba; Instituto de Investigaciones Biológicas y Tecnológicas (IIByT), CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina
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Zabbarova IV, Ikeda Y, Carder EJ, Wipf P, Wolf-Johnston AS, Birder LA, Yoshimura N, Getchell SE, Almansoori K, Tyagi P, Fry CH, Drake MJ, Kanai AJ. Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice. Neurourol Urodyn 2018; 37:2452-2461. [PMID: 29806700 DOI: 10.1002/nau.23722] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 05/09/2018] [Indexed: 01/23/2023]
Abstract
AIMS To determine the role of p75 neurotrophin receptor (p75NTR ) and the therapeutic effect of the selective small molecule p75NTR modulator, LM11A-31, in spinal cord injury (SCI) induced lower urinary tract dysfunction (LTUD) using a mouse model. METHODS Adult female T8 -T9 transected mice were gavaged daily with LM11A-31 (100 mg/kg) for up to 6 weeks, starting 1 day before, or 7 days following injury. Mice were evaluated in vivo using urine spot analysis, cystometrograms (CMGs), and external urethral sphincter (EUS) electromyograms (EMGs); and in vitro using histology, immunohistochemistry, and Western blot. RESULTS Our studies confirm highest expression of p75NTRs in the detrusor layer of the mouse bladder and lamina II region of the dorsal horn of the lumbar-sacral (L6 -S1 ) spinal cord which significantly decreased following SCI. LM11A-31 prevented or ameliorated the detrusor sphincter dyssynergia (DSD) and detrusor overactivity (DO) in SCI mice, significantly improving bladder compliance. Furthermore, LM11A-31 treatment blocked the SCI-related urothelial damage and bladder wall remodeling. CONCLUSION Drugs targeting p75NTRs can moderate DSD and DO in SCI mice, may identify pathophysiological mechanisms, and have therapeutic potential in SCI patients.
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Affiliation(s)
- Irina V Zabbarova
- Department of Medicine, University of Pittsburgh, Renal-Electrolyte Division, Pittsburgh, Pennsylvania
| | - Youko Ikeda
- Department of Medicine, University of Pittsburgh, Renal-Electrolyte Division, Pittsburgh, Pennsylvania
| | - Evan J Carder
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Peter Wipf
- Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Amanda S Wolf-Johnston
- Department of Medicine, University of Pittsburgh, Renal-Electrolyte Division, Pittsburgh, Pennsylvania
| | - Lori A Birder
- Department of Medicine, University of Pittsburgh, Renal-Electrolyte Division, Pittsburgh, Pennsylvania.,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Naoki Yoshimura
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Samuel E Getchell
- Department of Medicine, University of Pittsburgh, Renal-Electrolyte Division, Pittsburgh, Pennsylvania
| | - Khalifa Almansoori
- Department of Medicine, University of Pittsburgh, Renal-Electrolyte Division, Pittsburgh, Pennsylvania
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Christopher H Fry
- School of Physiology Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Marcus J Drake
- School of Physiology Pharmacology and Neuroscience, University of Bristol, Bristol, UK
| | - Anthony J Kanai
- Department of Medicine, University of Pittsburgh, Renal-Electrolyte Division, Pittsburgh, Pennsylvania.,Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Abstract
There are several forms of brain-derived neurotrophic factor (BDNF), the precursor of BDNF, mature BDNF, and BDNF propeptide. They exert different effects through different transmembrane receptor signaling systems. Precursor of BDNF is enzymatically cleaved, either by intracellular or by extracellular proteases, to generate mature BDNF and its propeptide (BDNF propeptide). The aim of this study was to evaluate the potential molecular mechanisms that underlie the inhibition of glioma cell growth by the BDNF propeptide. To achieve this, we examined the expression of BDNF propeptide in C6 glioma cells. The 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and the apoptosis assay were used to assess the effects of the BDNF propeptide on the growth and apoptosis of glioma cells. We found that the BDNF propeptide promoted C6 glioma cell apoptosis and decreased in-vitro cell growth. We also found using western blot that cleaved caspase3 and B cell lymphoma 2 (Bcl2)-associated X protein abundances increased, whereas Bcl2 abundance decreased. Our data suggest that the BDNF propeptide may have an inhibitory effect on glioma through activation of the caspase3 pathway.
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Wang J, Bains H, Anastasia A, Bracken C. NMR backbone resonance assignments of the prodomain variants of BDNF in the urea denatured state. BIOMOLECULAR NMR ASSIGNMENTS 2018; 12:43-45. [PMID: 28933046 PMCID: PMC6865803 DOI: 10.1007/s12104-017-9777-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 09/13/2017] [Indexed: 06/07/2023]
Abstract
Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family of proteins which plays a central role in neuronal survival, growth, plasticity and memory. A single Val66Met variant has been identified in the prodomain of human BDNF that is associated with anxiety, depression and memory disorders. The structural differences within the full-length prodomain Val66 and Met66 isoforms could shed light on the mechanism of action of the Met66 and its impact on the development of neuropsychiatric-associated disorders. In the present study, we report the backbone 1H, 13C, and 15N NMR assignments of both full-length Val66 and Met66 prodomains in the presence of 2 M urea. These conditions were utilized to suppress residual structure and aid subsequent native state structural investigations aimed at mapping and identifying variant-dependent conformational differences under native-state conditions.
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Affiliation(s)
- Jing Wang
- Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, Box 63, New York, NY, 10065, USA
| | - Henrietta Bains
- Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, Box 63, New York, NY, 10065, USA
| | - Agustin Anastasia
- Instituto Ferreyra (INIMEC-CONICET-Universidad Nacional de Córdoba), Córdoba, Argentina
| | - Clay Bracken
- Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, Box 63, New York, NY, 10065, USA.
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33
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Ryu JC, Tooke K, Malley SE, Soulas A, Weiss T, Ganesh N, Saidi N, Daugherty S, Saragovi U, Ikeda Y, Zabbarova I, Kanai AJ, Yoshiyama M, Farhadi HF, de Groat WC, Vizzard MA, Yoon SO. Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest 2018; 128:1772-1786. [PMID: 29584618 DOI: 10.1172/jci97837] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 02/08/2018] [Indexed: 12/15/2022] Open
Abstract
Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro-nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase-positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.
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Affiliation(s)
- Jae Cheon Ryu
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Katharine Tooke
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Susan E Malley
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Anastasia Soulas
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Tirzah Weiss
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Nisha Ganesh
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Nabila Saidi
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
| | - Stephanie Daugherty
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Uri Saragovi
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Youko Ikeda
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Irina Zabbarova
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Anthony J Kanai
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Mitsuharu Yoshiyama
- Department of Urology, University of Yamanashi Graduate School of Medical Science, Chuo, Japan
| | - H Francis Farhadi
- Department of Neurological Surgery, Ohio State University, Columbus, Ohio, USA
| | - William C de Groat
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Margaret A Vizzard
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont, USA
| | - Sung Ok Yoon
- Department of Biological Chemistry and Pharmacology, Ohio State University, Columbus, Ohio, USA
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Mysona BA, Zhao J, Smith S, Bollinger KE. Relationship between Sigma-1 receptor and BDNF in the visual system. Exp Eye Res 2018; 167:25-30. [PMID: 29031856 PMCID: PMC5757370 DOI: 10.1016/j.exer.2017.10.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 10/10/2017] [Accepted: 10/11/2017] [Indexed: 12/27/2022]
Abstract
Glaucoma is an incurable optic neuropathy characterized by dysfunction and death of retinal ganglion cells (RGCs). Brain derived neurotrophic factor (BDNF) is an essential neurotrophin that supports RGC function and survival. Despite BDNF's importance, our knowledge of molecular mechanisms that modulate BDNF processing and secretion is incomplete. Sigma-1 receptor (S1R) is associated with increased BDNF in hippocampus and with BDNF secretion by brain-derived astrocytes and neuronal cell lines. Much less is known about the relationship between S1R and BDNF in the visual system. Here, we examine how S1R activation and deletion alter expression of mature BDNF (mBDNF) and proBDNF in retina and cultured optic nerve head (ONH) astrocytes. For S1R activation, the S1R agonist (+)-pentazocine (PTZ, 0.5 mg/kg) was administered by intraperitoneal injection to C57BL/6J mice, 3 times per week, for 5 weeks. Expression of proBDNF and mBDNF was also examined in S1R knockout and age-matched C57BL/6J mice. In vitro, cultured ONH astrocytes were treated with 3 μM PTZ for 24 h followed by collection of media and ONH astrocyte lysates. Results showed that treatment with (+)-PTZ increased mBDNF protein in both retina and hippocampus. In contrast, S1R deletion was associated with retinal mBDNF deficits. In ONH astrocytes S1R agonist (+)-PTZ significantly increased levels of secreted BDNF and proBDNF in cell lysates. These findings support a role for S1R in the modulation of BDNF levels within the retina and optic nerve head. Treatment with S1R agonists might provide benefit in diseases such as glaucoma by increasing BDNF levels from endogenous sources.
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Affiliation(s)
- Barbara A Mysona
- James and Jean Culver Vision Discovery Institute, Augusta, GA, 30912, United States; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States; Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States
| | - Jing Zhao
- James and Jean Culver Vision Discovery Institute, Augusta, GA, 30912, United States; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States; Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States
| | - Sylvia Smith
- James and Jean Culver Vision Discovery Institute, Augusta, GA, 30912, United States; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States; Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States
| | - Kathryn E Bollinger
- James and Jean Culver Vision Discovery Institute, Augusta, GA, 30912, United States; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States; Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, United States.
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Wehner AB, Abdesselem H, Dickendesher TL, Imai F, Yoshida Y, Giger RJ, Pierchala BA. Semaphorin 3A is a retrograde cell death signal in developing sympathetic neurons. Development 2017; 143:1560-70. [PMID: 27143756 DOI: 10.1242/dev.134627] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 02/29/2016] [Indexed: 12/30/2022]
Abstract
During development of the peripheral nervous system, excess neurons are generated, most of which will be lost by programmed cell death due to a limited supply of neurotrophic factors from their targets. Other environmental factors, such as 'competition factors' produced by neurons themselves, and axon guidance molecules have also been implicated in developmental cell death. Semaphorin 3A (Sema3A), in addition to its function as a chemorepulsive guidance cue, can also induce death of sensory neurons in vitro The extent to which Sema3A regulates developmental cell death in vivo, however, is debated. We show that in compartmentalized cultures of rat sympathetic neurons, a Sema3A-initiated apoptosis signal is retrogradely transported from axon terminals to cell bodies to induce cell death. Sema3A-mediated apoptosis utilizes the extrinsic pathway and requires both neuropilin 1 and plexin A3. Sema3A is not retrogradely transported in older, survival factor-independent sympathetic neurons, and is much less effective at inducing apoptosis in these neurons. Importantly, deletion of either neuropilin 1 or plexin A3 significantly reduces developmental cell death in the superior cervical ganglia. Taken together, a Sema3A-initiated apoptotic signaling complex regulates the apoptosis of sympathetic neurons during the period of naturally occurring cell death.
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Affiliation(s)
- Amanda B Wehner
- Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA Neuroscience Program, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Houari Abdesselem
- Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
| | - Travis L Dickendesher
- Neuroscience Program, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Fumiyasu Imai
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45299, USA
| | - Yutaka Yoshida
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45299, USA
| | - Roman J Giger
- Neuroscience Program, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
| | - Brian A Pierchala
- Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA Neuroscience Program, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
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Yu X, Liu Z, Hou R, Nie Y, Chen R. Nerve growth factor and its receptors on onset and diagnosis of ovarian cancer. Oncol Lett 2017; 14:2864-2868. [PMID: 28928825 PMCID: PMC5588143 DOI: 10.3892/ol.2017.6527] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 03/10/2017] [Indexed: 12/27/2022] Open
Abstract
The effect of nerve growth factor (NGF) and its receptors on the onset and diagnosis of ovarian cancer was investigated. A total of 35 patients with ovarian tumor admitted in the First Affiliated Hospital of Nanchang University from July 2014 to July 2015 were selected as study subjects and were divided into an observation group (including 21 patients with benign ovarian tumor, and 14 patients with malignant ovarian tumor), and a control group (21 healthy women). The quantity of expression of mRNA in NGF and its receptors (TrkA and p75NTR) was detected using fluorescent quantitative PCR. The protein expression of NGF, TrkA and p75NTR in different study samples was detected using ELISA and western blot analysis. The location of expression was determined using immunohistochemistry. The positive cell rate in different samples was analyzed. Compared with healthy women, the quantity of expression of mRNA in NGF, TrkA and p75NTR in patients with ovarian cancer was increased significantly. The results of ELISA showed that the quantity of protein expression of NGF, TrkA and p75NTR was 0.98±0.12, 1.23±0.14 and 0.76±0.07 µg/l in healthy women, and was 3.21±0.16, 5.28±0.25 and 2.97±0.13 µg/l, respectively, in women with ovarian tumor, and there were statistically significant differences (P<0.05), and the level of expression in patients with malignant ovarian tumor was significantly higher than that in patients with benign ovarian cancer. Western blot analysis also showed that the quantity of expression of NGF, TrkA and p75NTR gene in women with ovarian cancer was significantly higher than that in healthy women. Immunohistochemical results showed that the number of positive cells of NGF, TrkA and p75NTR gene in the tissue of patients with ovarian cancer (89.5, 93.4 and 82.5%, respectively) was significantly higher than those in healthy ovarian tissue (9.4, 10.3 and 7.9%, respectively). In conclusion, NGF and its receptor can contribute to the occurrence of ovarian cancer, and the onset condition of ovarian cancer can be diagnosed through the detection of high or low expression of NGF and its receptors.
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Affiliation(s)
- Xiaolin Yu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhaoxia Liu
- Department of Obstetrics and Gynecology, Nanshan Hospital, Shenzhen, Guangdong 518052, P.R. China
| | - Rui Hou
- Graduate School of Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yijun Nie
- Department of Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Rensheng Chen
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Uegaki K, Kumanogoh H, Mizui T, Hirokawa T, Ishikawa Y, Kojima M. BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction. Int J Mol Sci 2017; 18:ijms18051042. [PMID: 28498321 PMCID: PMC5454954 DOI: 10.3390/ijms18051042] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 05/06/2017] [Accepted: 05/08/2017] [Indexed: 02/03/2023] Open
Abstract
Most growth factors are initially synthesized as precursors then cleaved into bioactive mature domains and pro-domains, but the biological roles of pro-domains are poorly understood. In the present study, we investigated the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which promotes neuronal survival, differentiation and synaptic plasticity. The BDNF pro-peptide is a post-processing product of the precursor BDNF. Using surface plasmon resonance and biochemical experiments, we first demonstrated that the BDNF pro-peptide binds to mature BDNF with high affinity, but not other neurotrophins. This interaction was more enhanced at acidic pH than at neutral pH, suggesting that the binding is significant in intracellular compartments such as trafficking vesicles rather than the extracellular space. The common Val66Met BDNF polymorphism results in a valine instead of a methionine in the pro-domain, which affects human brain functions and the activity-dependent secretion of BDNF. We investigated the influence of this variation on the interaction between BDNF and the pro-peptide. Interestingly, the Val66Met polymorphism stabilized the heterodimeric complex of BDNF and its pro-peptide. Furthermore, compared with the Val-containing pro-peptide, the complex with the Met-type pro-peptide was more stable at both acidic and neutral pH, suggesting that the Val66Met BDNF polymorphism forms a more stable complex. A computational modeling provided an interpretation to the role of the Val66Met mutation in the interaction of BDNF and its pro-peptide. Lastly, we performed electrophysiological experiments, which indicated that the BDNF pro-peptide, when pre-incubated with BDNF, attenuated the ability of BDNF to inhibit hippocampal long-term depression (LTD), suggesting a possibility that the BDNF pro-peptide may interact directly with BDNF and thereby inhibit its availability. It was previously reported that the BDNF pro-domain exerts a chaperone-like function and assists the folding of the BDNF protein. However, our results suggest a new role for the BDNF pro-domain (or pro-peptide) following proteolytic cleave of precursor BDNF, and provide insight into the Val66Met polymorphism.
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Affiliation(s)
- Koichi Uegaki
- Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan.
- Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
| | - Haruko Kumanogoh
- Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan.
- Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
| | - Toshiyuki Mizui
- Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan.
- Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
| | - Takatsugu Hirokawa
- Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
- Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan.
- Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan.
| | - Yasuyuki Ishikawa
- Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
- Department of Systems Life Engineering, Maebashi Institute of Technology 460-1, Kamisadori, Maebashi 370-0816, Japan.
| | - Masami Kojima
- Biomedical Research Institute (BMD), National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31 Midorioka, Ikeda, Osaka 563-8577, Japan.
- Core Research for Evolutional Science and Technology (CREST), Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
- Graduate School of Frontier Bioscience, Osaka University, Suita 565-0871, Japan.
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Mysona BA, Zhao J, Bollinger KE. Role of BDNF/TrkB pathway in the visual system: Therapeutic implications for glaucoma. EXPERT REVIEW OF OPHTHALMOLOGY 2016; 12:69-81. [PMID: 28751923 DOI: 10.1080/17469899.2017.1259566] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Neuroprotective therapeutics are needed to treat glaucoma, an optic neuropathy that results in death of retinal ganglion cells (RGCs). AREAS COVERED The BDNF/TrkB pathway is important for RGC survival. Temporal and spatial alterations in the BDNF/TrkB pathway occur in development and in response to acute optic nerve injury and to glaucoma. In animal models, BDNF supplementation is successful at slowing RGC death after acute optic nerve injury and in glaucoma, however, the BDNF/TrkB signaling is not the only pathway supporting long term RGC survival. EXPERT COMMENTARY Much remains to be discovered about the interaction between retrograde, anterograde, and retinal BDNF/TrkB signaling pathways in both neurons and glia. An ideal therapeutic agent for glaucoma likely has several modes of action that target multiple mechanisms of neurodegeneration including the BDNF/TrkB pathway.
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Affiliation(s)
- B A Mysona
- Augusta University Department of Cellular Biology and Anatomy, James and Jean Culver Vision Discovery Institute. Address: Augusta University Department of Cellular Biology and Anatomy, Health Sciences Campus, 1120 15th Street, Augusta, GA 30912, USA,
| | - J Zhao
- Medical College of Georgia, Department of Ophthalmology at Augusta University, James and Jean Culver Vision Discovery Institute. Address: Medical College of Georgia, Department of Ophthalmology at Augusta University, 1120 15th Street, Augusta, GA 30912, USA,
| | - K E Bollinger
- Medical College of Georgia, Department of Ophthalmology at Augusta University, Augusta University Department of Cellular Biology and Anatomy, James and Jean Culver Vision Discovery Institute. Address: Medical College of Georgia, Department of Ophthalmology at Augusta University, 1120 15th Street, Augusta, GA 30912, USA,
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Al-Qudah MA, Al-Dwairi A. Mechanisms and regulation of neurotrophin synthesis and secretion. NEUROSCIENCES (RIYADH, SAUDI ARABIA) 2016; 21:306-313. [PMID: 27744458 PMCID: PMC5224427 DOI: 10.17712/nsj.2016.4.20160080] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Neurotrophins are secreted proteins that are synthesized as pre-pro-neurotrophins on the rough endoplasmic reticulum, which are subsequently processed and then secreted as mature proteins. During synthesis, neurotrophins are sorted in the trans-Golgi apparatus into 2 pathways of secretion; the constitutive and the regulated pathways. Neurotrophins in the constitutive pathway are secreted cautiously without any trigger, while in the regulated pathway of secretion an external stimulus elevates the calcium concentration intracellularly leading to neurotrophin release. The regulation of sorting and secretion of neurotrophins is critical for several processes in the body, such as synaptic plasticity, neurodegenerative disorders, demyelination disease, and inflammation. The purpose of this review is to summarize the current mechanisms of neurotrophin sorting and secretion.
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Affiliation(s)
- Mohammad A Al-Qudah
- Department of Physiology, Jordan University of Science and Technology, Irbid, Jordan. E-mail:
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Dincheva I, Lynch NB, Lee FS. The Role of BDNF in the Development of Fear Learning. Depress Anxiety 2016; 33:907-916. [PMID: 27699937 PMCID: PMC5089164 DOI: 10.1002/da.22497] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 02/22/2016] [Indexed: 01/15/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a growth factor that is dynamically expressed in the brain across postnatal development, regulating neuronal differentiation and synaptic plasticity. The neurotrophic hypothesis of psychiatric mood disorders postulates that in the adult brain, decreased BDNF levels leads to altered neural plasticity, contributing to disease. Although BDNF has been established as a key factor regulating the critical period plasticity in the developing visual system, it has recently been shown to also play a role in fear circuitry maturation, which has implications for the emergence of fear-related mood disorders. This review provides a detailed overview of developmental changes in expression of BDNF isoforms, as well as their receptors across postnatal life. In addition, recent developmental studies utilizing a genetic BDNF single nucleotide polymorphism (Val66Met) knock-in mouse highlight the impact of BDNF on fear learning during a sensitive period spanning the transition into adolescent time frame. We hypothesize that BDNF in the developing brain regulates fear circuit plasticity during a sensitive period in early adolescence, and alterations in BDNF expression (genetic or environmental) have a persistent impact on fear behavior and fear-related disorders.
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Affiliation(s)
- Iva Dincheva
- Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, New York.
| | - Niccola B. Lynch
- Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, New York
| | - Francis S. Lee
- Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, New York,Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York,Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College of Cornell University, New York, New York
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Guo J, Ji Y, Ding Y, Jiang W, Sun Y, Lu B, Nagappan G. BDNF pro-peptide regulates dendritic spines via caspase-3. Cell Death Dis 2016; 7:e2264. [PMID: 27310873 PMCID: PMC5143394 DOI: 10.1038/cddis.2016.166] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 04/11/2016] [Accepted: 05/05/2016] [Indexed: 01/18/2023]
Abstract
The precursor of brain-derived neurotrophic factor (BDNF) (proBDNF) is enzymatically cleaved, by either intracellular (furin/PC1) or extracellular proteases (tPA/plasmin/MMP), to generate mature BDNF (mBDNF) and its pro-peptide (BDNF pro-peptide). Little is known about the function of BDNF pro-peptide. We have developed an antibody that specifically detects cleaved BDNF pro-peptide, but not proBDNF or mBDNF. Neuronal depolarization elicited a marked increase in extracellular BDNF pro-peptide, suggesting activity-dependent regulation of its extracellular levels. Exposure of BDNF pro-peptide to mature hippocampal neurons in culture dramatically reduced dendritic spine density. This effect was mediated by caspase-3, as revealed by studies with pharmacological inhibitors and genetic knockdown. BDNF pro-peptide also increased the number of ‘elongated' mitochondria and cytosolic cytochrome c, suggesting the involvement of mitochondrial-caspase-3 pathway. These results, along with BDNF pro-peptide effects recently reported on growth cones and long-term depression (LTD), suggest that BDNF pro-peptide is a negative regulator of neuronal structure and function.
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Affiliation(s)
- J Guo
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Y Ji
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China
| | - Y Ding
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China
| | - W Jiang
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China
| | - Y Sun
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - B Lu
- School of Medicine, Tsinghua University, Beijing 100084, China
| | - G Nagappan
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China
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Gardner RT, Ripplinger CM, Myles RC, Habecker BA. Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias. Circ Arrhythm Electrophysiol 2016; 9:e001359. [PMID: 26810594 DOI: 10.1161/circep.115.001359] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Ryan T Gardner
- From the Department of Physiology and Pharmacology and Knight Cardiovascular Institute, Oregon Health and Science University, Portland (R.T.G., B.A.H.); Department of Pharmacology, School of Medicine, University of California, Davis (C.M.R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.C.M.)
| | - Crystal M Ripplinger
- From the Department of Physiology and Pharmacology and Knight Cardiovascular Institute, Oregon Health and Science University, Portland (R.T.G., B.A.H.); Department of Pharmacology, School of Medicine, University of California, Davis (C.M.R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.C.M.)
| | - Rachel C Myles
- From the Department of Physiology and Pharmacology and Knight Cardiovascular Institute, Oregon Health and Science University, Portland (R.T.G., B.A.H.); Department of Pharmacology, School of Medicine, University of California, Davis (C.M.R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.C.M.)
| | - Beth A Habecker
- From the Department of Physiology and Pharmacology and Knight Cardiovascular Institute, Oregon Health and Science University, Portland (R.T.G., B.A.H.); Department of Pharmacology, School of Medicine, University of California, Davis (C.M.R.); and Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.C.M.).
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Cheng E, Hansen MR. Schwannomas provide insight into the role of p75(NTR) and merlin in Schwann cells following nerve injury and during regeneration. Neural Regen Res 2016; 11:73-4. [PMID: 26981085 PMCID: PMC4774233 DOI: 10.4103/1673-5374.175045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Elise Cheng
- Department of Otolaryngology - Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Marlan R Hansen
- Department of Otolaryngology - Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA; Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
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Gaub P, de Léon A, Gibon J, Soubannier V, Dorval G, Séguéla P, Barker PA. HBpF-proBDNF: A New Tool for the Analysis of Pro-Brain Derived Neurotrophic Factor Receptor Signaling and Cell Biology. PLoS One 2016; 11:e0150601. [PMID: 26950209 PMCID: PMC4780767 DOI: 10.1371/journal.pone.0150601] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 02/17/2016] [Indexed: 01/12/2023] Open
Abstract
Neurotrophins activate intracellular signaling pathways necessary for neuronal survival, growth and apoptosis. The most abundant neurotrophin in the adult brain, brain-derived neurotrophic factor (BDNF), is first synthesized as a proBDNF precursor and recent studies have demonstrated that proBDNF can be secreted and that it functions as a ligand for a receptor complex containing p75NTR and sortilin. Activation of proBDNF receptors mediates growth cone collapse, reduces synaptic activity, and facilitates developmental apoptosis of motoneurons but the precise signaling cascades have been difficult to discern. To address this, we have engineered, expressed and purified HBpF-proBDNF, an expression construct containing a 6X-HIS tag, a biotin acceptor peptide (BAP) sequence, a PreScission™ Protease cleavage site and a FLAG-tag attached to the N-terminal part of murine proBDNF. Intact HBpF-proBDNF has activities indistinguishable from its wild-type counterpart and can be used to purify proBDNF signaling complexes or to monitor proBDNF endocytosis and retrograde transport. HBpF-proBDNF will be useful for characterizing proBDNF signaling complexes and for deciphering the role of proBDNF in neuronal development, synapse function and neurodegenerative disease.
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Affiliation(s)
- Perrine Gaub
- Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Andrès de Léon
- Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Julien Gibon
- Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Vincent Soubannier
- Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Geneviève Dorval
- Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Philippe Séguéla
- Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4, Canada
| | - Philip A. Barker
- Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, H3A 2B4, Canada
- * E-mail:
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Gibon J, Barker PA, Séguéla P. Opposing presynaptic roles of BDNF and ProBDNF in the regulation of persistent activity in the entorhinal cortex. Mol Brain 2016; 9:23. [PMID: 26932787 PMCID: PMC4774087 DOI: 10.1186/s13041-016-0203-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 02/25/2016] [Indexed: 11/15/2022] Open
Abstract
Background Sustained, persistent firing (PF) of cortical pyramidal neurons following a short depolarization is a crucial cellular mechanism required for spatial and working memory. Pyramidal neurons in the superficial and deep layers of the medial and lateral entorhinal cortex (EC) display this property of prolonged firing activity. Here, we focused on the regulation of this activity in EC neurons by mature brain derived neurotrophic factor (BDNF) and its precursor proBDNF. Results Using patch clamp electrophysiology in acute mouse cortical slices, we observed that BDNF facilitates cholinergic PF in pyramidal neurons in layer V of the medial EC. Inhibition of TrkB with K252a blocks the potentiating effect of BDNF whereas inhibition of p75NTR with function-blocking antibodies does not. By recording spontaneous excitatory post-synaptic currents (sEPSC), we find that BDNF acts pre-synaptically via TrkB to increase glutamate release whereas proBDNF acting via p75NTR acts to reduce it. MPEP abolished the facilitating effect of BDNF on PF, demonstrating that the metabotropic glutamate receptor mGluR5 plays a critical role in the BDNF effect. In contrast, paired pulse ratio and EPSC measurements indicated that proBDNF, via presynaptic p75NTR, is a negative regulator of glutamate release in the EC. Conclusions Taken together, our findings demonstrate that the BDNF/TrkB pathway facilitates persistent activity whereas the proBDNF/p75NTR pathway inhibits this mnemonic property of entorhinal pyramidal neurons.
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Affiliation(s)
- Julien Gibon
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Suite 778, Montreal, Quebec, H3A 2B4, Canada.
| | - Philip A Barker
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Suite 778, Montreal, Quebec, H3A 2B4, Canada.
| | - Philippe Séguéla
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Suite 778, Montreal, Quebec, H3A 2B4, Canada.
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Akil H, Perraud A, Jauberteau MO, Mathonnet M. Tropomyosin-related kinase B/brain derived-neurotrophic factor signaling pathway as a potential therapeutic target for colorectal cancer. World J Gastroenterol 2016; 22:490-500. [PMID: 26811602 PMCID: PMC4716054 DOI: 10.3748/wjg.v22.i2.490] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 09/25/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related death in western countries. Approximately one-quarter of newly diagnosed patients for CRC have metastases, and a further 40%-50% experience disease recurrence or develop metastases after all standard therapies. Therefore, understanding the molecular mechanisms involved in the progression of CRC and subsequently developing novel therapeutic targets is crucial to improve management of CRC and patients’ long-term survival. Several tyrosine kinase receptors have been implicated in CRC development, progression and metastasis, including epidermal growth factor receptor (EGFR) and vascular EGFR. Recently, tropomyosin-related kinase B (TrkB), a tyrosine kinase receptor, has been reported in CRC and found to clearly exert several biological and clinical features, such as tumor cell growth and survival in vitro and in vivo, metastasis formation and poor prognosis. Here we review the significance of TrkB and its ligand brain derived-neurotrophic factor in CRC. We focus on their expression in CRC tumor samples, and their functional roles in CRC cell lines and in in vivo models. Finally we discuss therapeutic approaches that can lead to the development of novel therapeutic agents for treating TrkB-expressing CRC tumors.
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Dubanet L, Bentayeb H, Petit B, Olivrie A, Saada S, de la Cruz-Morcillo MA, Lalloué F, Gourin MP, Bordessoule D, Faumont N, Delage-Corre M, Fauchais AL, Jauberteau MO, Troutaud D. Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas. Br J Cancer 2015; 113:934-44. [PMID: 26284337 PMCID: PMC4578080 DOI: 10.1038/bjc.2015.274] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 06/11/2015] [Accepted: 06/22/2015] [Indexed: 12/22/2022] Open
Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines. Methods: We analysed expression of NGF, BDNF, and their receptors (Trk, p75NTR) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75NTR axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies. Results: A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75NTR, TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75NTR was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model. Conclusions: This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups.
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Affiliation(s)
- Lydie Dubanet
- EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France
| | - Hafidha Bentayeb
- EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France
| | - Barbara Petit
- Laboratoire d'Anatomie-Pathologique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France
| | - Agnès Olivrie
- Structure Régionale de Référence des Lymphomes du Limousin, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.,Service d'Hématologie Clinique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France
| | - Sofiane Saada
- EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France
| | - Miguel A de la Cruz-Morcillo
- EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France
| | - Fabrice Lalloué
- EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France
| | - Marie-Pierre Gourin
- Structure Régionale de Référence des Lymphomes du Limousin, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.,Service d'Hématologie Clinique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France
| | - Dominique Bordessoule
- Structure Régionale de Référence des Lymphomes du Limousin, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.,Service d'Hématologie Clinique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France.,UMR CNRS 7276, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland 87025, Limoges Cedex, France
| | - Nathalie Faumont
- UMR CNRS 7276, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland 87025, Limoges Cedex, France
| | - Manuela Delage-Corre
- Laboratoire d'Anatomie-Pathologique, CHU de Limoges, 2 Avenue Martin Luther King, 87000 Limoges Cedex, France
| | - Anne-Laure Fauchais
- EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France
| | - Marie-Odile Jauberteau
- EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France
| | - Danielle Troutaud
- EA3842, Facultés de Médecine et de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France
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Coucha M, Elshaer SL, Eldahshan WS, Mysona BA, El-Remessy AB. Molecular mechanisms of diabetic retinopathy: potential therapeutic targets. Middle East Afr J Ophthalmol 2015; 22:135-44. [PMID: 25949069 PMCID: PMC4411608 DOI: 10.4103/0974-9233.154386] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in United States. Research indicates an association between oxidative stress and the development of diabetes complications. However, clinical trials with general antioxidants have failed to prove effective in diabetic patients. Mounting evidence from experimental studies that continue to elucidate the damaging effects of oxidative stress and inflammation in both vascular and neural retina suggest its critical role in the pathogenesis of DR. This review will outline the current management of DR as well as present potential experimental therapeutic interventions, focusing on molecules that link oxidative stress to inflammation to provide potential therapeutic targets for treatment or prevention of DR. Understanding the biochemical changes and the molecular events under diabetic conditions could provide new effective therapeutic tools to combat the disease.
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Affiliation(s)
- Maha Coucha
- Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, University of Georgia, Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University, Georgia, USA ; Research Service, Charlie Norwood VA Medical Center, Augusta 30912, Georgia, USA
| | - Sally L Elshaer
- Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, University of Georgia, Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University, Georgia, USA ; Research Service, Charlie Norwood VA Medical Center, Augusta 30912, Georgia, USA
| | - Wael S Eldahshan
- Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, University of Georgia, Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University, Georgia, USA ; Research Service, Charlie Norwood VA Medical Center, Augusta 30912, Georgia, USA
| | - Barbara A Mysona
- Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, University of Georgia, Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University, Georgia, USA ; Research Service, Charlie Norwood VA Medical Center, Augusta 30912, Georgia, USA
| | - Azza B El-Remessy
- Department of Clinical Pharmacy, Program in Clinical and Experimental Therapeutics, University of Georgia, Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University, Georgia, USA ; Research Service, Charlie Norwood VA Medical Center, Augusta 30912, Georgia, USA
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The Acquisition of Target Dependence by Developing Rat Retinal Ganglion Cells. eNeuro 2015; 2:eN-NWR-0044-14. [PMID: 26464991 PMCID: PMC4586937 DOI: 10.1523/eneuro.0044-14.2015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 06/22/2015] [Accepted: 06/23/2015] [Indexed: 11/23/2022] Open
Abstract
Similar to neurons in the peripheral nervous system, immature CNS-derived RGCs become dependent on target-derived neurotrophic support as their axons reach termination sites in the brain. To study the factors that influence this developmental transition we took advantage of the fact that rat RGCs are born, and target innervation occurs, over a protracted period of time. Early-born RGCs have axons in the SC by birth (P0), whereas axons from late-born RGCs do not innervate the SC until P4-P5. Birth dating RGCs using EdU allowed us to identify RGCs (1) with axons still growing toward targets, (2) transitioning to target dependence, and (3) entirely dependent on target-derived support. Using laser-capture microdissection we isolated ∼34,000 EdU+ RGCs and analyzed transcript expression by custom qPCR array. Statistical analyses revealed a difference in gene expression profiles in actively growing RGCs compared with target-dependent RGCs, as well as in transitional versus target-dependent RGCs. Prior to innervation RGCs expressed high levels of BDNF and CNTFR α but lower levels of neurexin 1 mRNA. Analysis also revealed greater expression of transcripts for signaling molecules such as MAPK, Akt, CREB, and STAT. In a supporting in vitro study, purified birth-dated P1 RGCs were cultured for 24-48 h with or without BDNF; lack of BDNF resulted in significant loss of early-born but not late-born RGCs. In summary, we identified several important changes in RGC signaling that may form the basis for the switch from target independence to dependence.
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Abstract
Neurotrophins (NTs) belong to a family of trophic factors that regulate the survival, growth and programmed cell death of neurons. In mammals, there are four structurally and functionally related NT proteins, viz. nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 and neurotrophin 4. Most research on NTs to date has focussed on the effects of NGF and BDNF signalling via their respective cognate high affinity neurotrophic tyrosine kinase viz TrkA and TrkB receptors. Apart from the key physiologic roles of NGF and BDNF in peripheral and central nervous system function, NGF and BDNF signalling via TrkA and TrkB receptors respectively have been implicated in mechanisms underpinning neuropathic pain. Additionally, NGF and BDNF signalling via the low-affinity pan neurotrophin receptor at 75 kDa (p75NTR) may also contribute to the pathobiology of neuropathic pain. In this review, we critically assess the role of neurotrophins signalling via their cognate high affinity receptors as well as the low affinity p75NTR in the pathophysiology of peripheral neuropathic and central neuropathic pain. We also identify knowledge gaps to guide future research aimed at generating novel insight on how to optimally modulate NT signalling for discovery of novel therapeutics to improve neuropathic pain relief.
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