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Forsell P, Parrado Fernández C, Nilsson B, Sandin J, Nordvall G, Segerdahl M. Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer's Disease. Pharmaceuticals (Basel) 2024; 17:997. [PMID: 39204102 PMCID: PMC11357672 DOI: 10.3390/ph17080997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/19/2024] [Accepted: 07/25/2024] [Indexed: 09/03/2024] Open
Abstract
Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer's disease has been described. Attempts to administer neurotrophins to patients have been reported, but the clinical trials have so far have been hampered by side effects or a lack of clear efficacy. Thus, much of the focus during recent years has been on identifying small molecules acting as agonists or positive allosteric modulators (PAMs) of Trk receptors. Two examples of successful discovery and development of PAMs are the TrkA-PAM E2511 and the pan-Trk PAM ACD856. E2511 has been reported to have disease-modifying effects in preclinical models, whereas ACD856 demonstrates both a symptomatic and a disease-modifying effect in preclinical models. Both molecules have reached the stage of clinical development and were reported to be safe and well tolerated in clinical phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging small molecules are interesting examples of possible novel symptomatic and disease-modifying treatments that could complement the existing anti-amyloid monoclonal antibodies for the treatment of Alzheimer's disease. This review aims to present the concept of positive allosteric modulators of the Trk receptors as a novel future treatment option for Alzheimer's disease and other neurodegenerative and cognitive disorders, and the current preclinical and clinical data supporting this new concept. Preclinical data indicate dual mechanisms, not only as cognitive enhancers, but also a tentative neurorestorative function.
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Affiliation(s)
- Pontus Forsell
- AlzeCure Pharma AB, Hälsovägen 7, 141 57 Huddinge, Sweden; (C.P.F.); (B.N.); (J.S.); (G.N.); (M.S.)
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Alfred Nobels allé 23, 141 52 Huddinge, Sweden
| | - Cristina Parrado Fernández
- AlzeCure Pharma AB, Hälsovägen 7, 141 57 Huddinge, Sweden; (C.P.F.); (B.N.); (J.S.); (G.N.); (M.S.)
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Alfred Nobels allé 23, 141 52 Huddinge, Sweden
| | - Boel Nilsson
- AlzeCure Pharma AB, Hälsovägen 7, 141 57 Huddinge, Sweden; (C.P.F.); (B.N.); (J.S.); (G.N.); (M.S.)
| | - Johan Sandin
- AlzeCure Pharma AB, Hälsovägen 7, 141 57 Huddinge, Sweden; (C.P.F.); (B.N.); (J.S.); (G.N.); (M.S.)
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Alfred Nobels allé 23, 141 52 Huddinge, Sweden
| | - Gunnar Nordvall
- AlzeCure Pharma AB, Hälsovägen 7, 141 57 Huddinge, Sweden; (C.P.F.); (B.N.); (J.S.); (G.N.); (M.S.)
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Alfred Nobels allé 23, 141 52 Huddinge, Sweden
| | - Märta Segerdahl
- AlzeCure Pharma AB, Hälsovägen 7, 141 57 Huddinge, Sweden; (C.P.F.); (B.N.); (J.S.); (G.N.); (M.S.)
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Alfred Nobels allé 23, 141 52 Huddinge, Sweden
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Yin T, Wang G, Wang L, Mudgal P, Wang E, Pan CC, Alexander PB, Wu H, Cao C, Liang Y, Tan L, Huang D, Chong M, Chen R, Lim BJW, Xiang K, Xue W, Wan L, Hu H, Loh YH, Wang XF, Li QJ. Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection. Nat Immunol 2024; 25:268-281. [PMID: 38195702 PMCID: PMC11377935 DOI: 10.1038/s41590-023-01723-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 11/29/2023] [Indexed: 01/11/2024]
Abstract
Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.
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Affiliation(s)
- Tao Yin
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Guoping Wang
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Liuyang Wang
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA
| | | | - Ergang Wang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Christopher C Pan
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | | | | | | | - Yaosi Liang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Lianmei Tan
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - De Huang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Mengyang Chong
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Rui Chen
- Hervor Therapeutics, Hangzhou, China
| | - Bryan Jian Wei Lim
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Kun Xiang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
| | - Wei Xue
- Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lixin Wan
- Department of Molecular Oncology and Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Hailan Hu
- Zhejiang University School of Brain Science and Brain Medicine, Hangzhou, China
| | - Yuin-Han Loh
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Xiao-Fan Wang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
| | - Qi-Jing Li
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA.
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
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Terracina S, Ferraguti G, Tarani L, Fanfarillo F, Tirassa P, Ralli M, Iannella G, Polimeni A, Lucarelli M, Greco A, Fiore M. Nerve Growth Factor and Autoimmune Diseases. Curr Issues Mol Biol 2023; 45:8950-8973. [PMID: 37998739 PMCID: PMC10670231 DOI: 10.3390/cimb45110562] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/06/2023] [Accepted: 11/08/2023] [Indexed: 11/25/2023] Open
Abstract
NGF plays a crucial immunomodulatory role and increased levels are found in numerous tissues during autoimmune states. NGF directly modulates innate and adaptive immune responses of B and T cells and causes the release of neuropeptides and neurotransmitters controlling the immune system activation in inflamed tissues. Evidence suggests that NGF is involved in the pathogenesis of numerous immune diseases including autoimmune thyroiditis, chronic arthritis, multiple sclerosis, systemic lupus erythematosus, mastocytosis, and chronic granulomatous disease. Furthermore, as NGF levels have been linked to disease severity, it could be considered an optimal early biomarker to identify therapeutic approach efficacy. In conclusion, by gaining insights into how these molecules function and which cells they interact with, future studies can devise targeted therapies to address various neurological, immunological, and other disorders more effectively. This knowledge may pave the way for innovative treatments based on NGF manipulation aimed at improving the quality of life for individuals affected by diseases involving neurotrophins.
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Affiliation(s)
- Sergio Terracina
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Luigi Tarani
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Francesca Fanfarillo
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Paola Tirassa
- Institute of Biochemistry and Cell Biology (IBBC-CNR), Department of Sensory Organs, Sapienza University of Rome, 00185 Rome, Italy
| | - Massimo Ralli
- Department of Sensory Organs, Sapienza University of Rome, 00185 Roma, Italy
| | - Giannicola Iannella
- Department of Sensory Organs, Sapienza University of Rome, 00185 Roma, Italy
| | - Antonella Polimeni
- Department of Odontostomatological and Maxillofacial Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Marco Lucarelli
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
- Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy
| | - Antonio Greco
- Department of Sensory Organs, Sapienza University of Rome, 00185 Roma, Italy
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology (IBBC-CNR), Department of Sensory Organs, Sapienza University of Rome, 00185 Rome, Italy
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Patra P, Rani A, Sharma N, Mukherjee C, Jha HC. Unraveling the Connection of Epstein-Barr Virus and Its Glycoprotein M 146-157 Peptide with Neurological Ailments. ACS Chem Neurosci 2023. [PMID: 37290090 DOI: 10.1021/acschemneuro.3c00231] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023] Open
Abstract
Epstein-Barr virus (EBV) is known to be associated with several cancers along with neurological modalities like Alzheimer's disease (AD) and multiple sclerosis (MS). Previous study from our group revealed that a 12 amino acid peptide fragment (146SYKHVFLSAFVY157) of EBV glycoprotein M (gM) exhibits amyloid-like self-aggregative properties. In the current study, we have investigated its effect on Aβ42 aggregation along with its effect on neural cell immunology and disease markers. EBV virion was also considered for the above-mentioned investigation. An increase in the aggregation of Aβ42 peptide was observed upon incubation with gM146-157. Further, the exposure of EBV and gM146-157 onto neuronal cells indicated the upregulation of inflammatory molecules like IL-1β, IL-6, TNF-α, and TGF-β that suggested neuroinflammation. Besides, host cell factors like mitochondrial potential and calcium ion signaling play a crucial role in cellular homeostasis and alterations in these factors aid in neurodegeneration. Changes in mitochondrial membrane potential manifested a decrease while elevation in the level of total Ca2+ ions was observed. Amelioration of Ca2+ ions triggers excitotoxicity in neurons. Subsequently, neurological disease-associated genes APP, ApoE4, and MBP were found to be increased at the protein level. Additionally, demyelination of neurons is a hallmark of MS and the myelin sheath consists of ∼70% of lipid/cholesterol-associated moieties. Hereby, genes associated with cholesterol metabolism indicated changes at the mRNA level. Enhanced expression of neurotropic factors like NGF and BDNF was discerned postexposure to EBV and gM146-157. Altogether, this study delineates a direct connection of EBV and its peptide gM146-157 with neurological illnesses.
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Affiliation(s)
- Priyanka Patra
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore 453552, Madhya Pradesh, India
| | - Annu Rani
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore 453552, Madhya Pradesh, India
| | - Neha Sharma
- Department of Atomic Energy, Optical Coatings Laboratory, High Energy Lasers & Optics Section, Laser Technology Division, Laser Group, Raja Ramanna Centre for Advanced Technology, Indore 452013, Madhya Pradesh, India
| | - Chandrachur Mukherjee
- Department of Atomic Energy, Optical Coatings Laboratory, High Energy Lasers & Optics Section, Laser Technology Division, Laser Group, Raja Ramanna Centre for Advanced Technology, Indore 452013, Madhya Pradesh, India
| | - Hem Chandra Jha
- Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore 453552, Madhya Pradesh, India
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Freitas NL, Gomes YCP, Souza FDS, Torres RC, Echevarria-Lima J, Leite ACCB, Lima MASD, Araújo AQC, Silva MTT, Espíndola ODM. Lessons from the Cerebrospinal Fluid Analysis of HTLV-1-Infected Individuals: Biomarkers of Inflammation for HAM/TSP Development. Viruses 2022; 14:v14102146. [PMID: 36298702 PMCID: PMC9609689 DOI: 10.3390/v14102146] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 09/23/2022] [Accepted: 09/27/2022] [Indexed: 11/18/2022] Open
Abstract
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease that leads to motor impairment due to a chronic inflammatory process in the central nervous system (CNS). However, the HAM/TSP pathogenesis is not completely clear, and biomarkers to define the disease prognosis are still necessary. Thus, we aimed to identify biomarkers for HAM/TSP and potential mechanisms involved in disease development. To that end, the concentrations of VILIP-1, BDNF, VEGF, β-NGF, TGF-β1, fractalkine/CX3CL1, IL-6, IL-18, and TNF-α, and the soluble forms of TREM-1, TREM-2, and RAGE, were assessed using a multiplex bead-based immunoassay in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n = 20), asymptomatic HTLV-1 carriers (AC) (n = 13), and HTLV-1-seronegative individuals (n = 9), with the results analyzed according to the speed of HAM/TSP progression. HAM/TSP patients had elevated fractalkine in the serum but not in the CSF, particularly those with low neuroinflammatory activity (CSF/serum ratio of neopterin <1 and of CXCL10 < 2). HAM/TSP patients with normal CSF levels of neurofilament light chain (NfL) showed elevated β-NGF in serum, and serum BDNF levels were increased in HTLV-1-infected individuals, particularly in HTLV-1 AC. Both HTLV-1 AC and HAM/TSP patients had lower TGF-β1 levels in CSF compared to uninfected individuals, and HAM/TSP patients with active CNS inflammation showed higher CSF levels of IL-18, which correlated with markers of inflammation, neuronal death, and blood−brain-barrier permeability. Although none of the factors evaluated were associated with the speed of HAM/TSP progression, reduced TGF-β1 levels in CSF suggest that suppressive responses to control subclinical and/or active neurodegeneration are impaired, while increased CSF IL-18 indicates the involvement of inflammasome-mediated mechanisms in HAM/TSP development.
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Affiliation(s)
- Nicole Lardini Freitas
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Yago Côrtes Pinheiro Gomes
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
- Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Flávia dos Santos Souza
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Rafael Carvalho Torres
- Instituto de Biofísica Carlos Chagas Filho (IBCCF), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil
- Instituto de Puericultura e Pediatria Martagão Gesteira, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-912, Brazil
| | - Juliana Echevarria-Lima
- Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil
| | | | | | - Abelardo Queiroz Campos Araújo
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Marcus Tulius Teixeira Silva
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
| | - Otávio de Melo Espíndola
- Instituto Nacional de Infectologia Evandro Chagas (INI), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro 21040-900, Brazil
- Correspondence:
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Functional tissue-engineered microtissue formed by self-aggregation of cells for peripheral nerve regeneration. Stem Cell Res Ther 2022; 13:3. [PMID: 35012663 PMCID: PMC8744299 DOI: 10.1186/s13287-021-02676-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/11/2021] [Indexed: 02/06/2023] Open
Abstract
Background Peripheral nerve injury (PNI) is one of the essential causes of physical disability with a high incidence rate. The traditional tissue engineering strategy, Top-Down strategy, has some limitations. A new tissue-engineered strategy, Bottom-Up strategy (tissue-engineered microtissue strategy), has emerged and made significant research progress in recent years. However, to the best of our knowledge, microtissues are rarely used in neural tissue engineering; thus, we intended to use microtissues to repair PNI.
Methods We used a low-adhesion cell culture plate to construct adipose-derived mesenchymal stem cells (ASCs) into microtissues in vitro, explored the physicochemical properties and microtissues components, compared the expression of cytokines related to nerve regeneration between microtissues and the same amount of two-dimension (2D)-cultured cells, co-cultured directly microtissues with dorsal root ganglion (DRG) or Schwann cells (SCs) to observe the interaction between them using immunocytochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA). We used grafts constructed by microtissues and polycaprolactone (PCL) nerve conduit to repair sciatic nerve defects in rats. Results The present study results indicated that compared with the same number of 2D-cultured cells, microtissue could secrete more nerve regeneration related cytokines to promote SCs proliferation and axons growth. Moreover, in the direct co-culture system of microtissue and DRG or SCs, axons of DRG grown in the direction of microtissue, and there seems to be a cytoplasmic exchange between SCs and ASCs around microtissue. Furthermore, microtissues could repair sciatic nerve defects in rat models more effectively than traditional 2D-cultured ASCs. Conclusion Tissue-engineered microtissue is an effective strategy for stem cell culture and therapy in nerve tissue engineering. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02676-0.
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Lin PH, Kuo LT, Luh HT. The Roles of Neurotrophins in Traumatic Brain Injury. LIFE (BASEL, SWITZERLAND) 2021; 12:life12010026. [PMID: 35054419 PMCID: PMC8780368 DOI: 10.3390/life12010026] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 02/08/2023]
Abstract
Neurotrophins are a collection of structurally and functionally related proteins. They play important roles in many aspects of neural development, survival, and plasticity. Traumatic brain injury (TBI) leads to different levels of central nervous tissue destruction and cellular repair through various compensatory mechanisms promoted by the injured brain. Many studies have shown that neurotrophins are key modulators of neuroinflammation, apoptosis, blood–brain barrier permeability, memory capacity, and neurite regeneration. The expression of neurotrophins following TBI is affected by the severity of injury, genetic polymorphism, and different post-traumatic time points. Emerging research is focused on the potential therapeutic applications of neurotrophins in managing TBI. We conducted a comprehensive review by organizing the studies that demonstrate the role of neurotrophins in the management of TBI.
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Affiliation(s)
- Ping-Hung Lin
- Department of Medical Education, School of Medicine, National Taiwan University, Taipei 100, Taiwan;
| | - Lu-Ting Kuo
- Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan;
| | - Hui-Tzung Luh
- Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
- Taipei Neuroscience Institute, Taipei Medical University, New Taipei City 235, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan
- Correspondence: ; Tel.: +886-956279587
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Gonzalez Osorio C, Guduru P, Osier N. The Female Impact in the World of Neurodegeneration. Front Integr Neurosci 2021; 15:750603. [PMID: 34690712 PMCID: PMC8526548 DOI: 10.3389/fnint.2021.750603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/09/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
| | - Pragnya Guduru
- College of Natural Sciences, University of Texas at Austin, Austin, TX, United States
| | - Nico Osier
- University of Texas at Austin School of Nursing, Austin, TX, United States
- Department of Neurology Austin, Dell Medical School, Austin, TX, United States
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Brandi R, Fabiano M, Giorgi C, Arisi I, La Regina F, Malerba F, Turturro S, Storti AE, Ricevuti F, Amadio S, Volontè C, Capsoni S, Scardigli R, D’Onofrio M, Cattaneo A. Nerve Growth Factor Neutralization Promotes Oligodendrogenesis by Increasing miR-219a-5p Levels. Cells 2021; 10:cells10020405. [PMID: 33669304 PMCID: PMC7920049 DOI: 10.3390/cells10020405] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 12/11/2022] Open
Abstract
In the brain, the neurotrophin Nerve growth factor (NGF) regulates not only neuronal survival and differentiation, but also glial and microglial functions and neuroinflammation. NGF is known to regulate oligodendrogenesis, reducing myelination in the central nervous system (CNS). In this study, we found that NGF controls oligodendrogenesis by modulating the levels of miR-219a-5p, a well-known positive regulator of oligodendrocyte differentiation. We exploited an NGF-deprivation mouse model, the AD11 mice, in which the postnatal expression of an anti-NGF antibody leads to NGF neutralization and progressive neurodegeneration. Notably, we found that these mice also display increased myelination. A microRNA profiling of AD11 brain samples and qRT-PCR analyses revealed that NGF deprivation leads to an increase of miR-219a-5p levels in hippocampus and cortex and a corresponding down-regulation of its predicted targets. Neurospheres isolated from the hippocampus of AD11 mice give rise to more oligodendrocytes and this process is dependent on miR-219a-5p, as shown by decoy-mediated inhibition of this microRNA. Moreover, treatment of AD11 neurospheres with NGF inhibits miR-219a-5p up-regulation and, consequently, oligodendrocyte differentiation, while anti-NGF treatment of wild type (WT) oligodendrocyte progenitors increases miR-219a-5p expression and the number of mature cells. Overall, this study indicates that NGF inhibits oligodendrogenesis and myelination by down-regulating miR-219a-5p levels, suggesting a novel molecular circuitry that can be exploited for the discovery of new effectors for remyelination in human demyelinating diseases, such as Multiple Sclerosis.
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Affiliation(s)
- Rossella Brandi
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
| | - Marietta Fabiano
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
| | - Corinna Giorgi
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
- CNR, Institute of Molecular Biology and Pathology (IBPM), P.le Aldo Moro, 5, 00185 Rome, Italy
| | - Ivan Arisi
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
- CNR, Institute of Translational Pharmacology (IFT), Via del Fosso del Cavaliere 100, 00131 Rome, Italy
| | - Federico La Regina
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
| | - Francesca Malerba
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
| | - Sabrina Turturro
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
| | - Andrea Ennio Storti
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
| | - Flavia Ricevuti
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
| | - Susanna Amadio
- IRCCS Fondazione Santa Lucia, Preclinical Neuroscience, Via del Fosso di Fiorano 65, 00143 Rome, Italy; (S.A.); (C.V.)
| | - Cinzia Volontè
- IRCCS Fondazione Santa Lucia, Preclinical Neuroscience, Via del Fosso di Fiorano 65, 00143 Rome, Italy; (S.A.); (C.V.)
- CNR, Institute for Systems Analysis and Computer Science, Via Dei Taurini 19, 00185 Rome, Italy
| | - Simona Capsoni
- Bio@SNS, Scuola Normale Superiore, 56124 Pisa, Italy;
- Institute of Physiology, Department of Neuroscience and Rehabilitation University of Ferrara, 44121 Ferrara, Italy
| | - Raffaella Scardigli
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
- CNR, Institute of Translational Pharmacology (IFT), Via del Fosso del Cavaliere 100, 00131 Rome, Italy
- Correspondence: (R.S.); (M.D.); (A.C.)
| | - Mara D’Onofrio
- European Brain Research Institute (EBRI) “Rita Levi-Montalcini”, Viale Regina Elena, 295, 00161 Rome, Italy; (R.B.); (M.F.); (C.G.); (I.A.); (F.L.R.); (F.M.); (S.T.); (A.E.S.); (F.R.)
- CNR, Institute of Translational Pharmacology (IFT), Via del Fosso del Cavaliere 100, 00131 Rome, Italy
- Correspondence: (R.S.); (M.D.); (A.C.)
| | - Antonino Cattaneo
- Bio@SNS, Scuola Normale Superiore, 56124 Pisa, Italy;
- Correspondence: (R.S.); (M.D.); (A.C.)
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10
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Nowack L, Teschers CS, Albrecht S, Gilmour R. Oligodendroglial glycolipids in (Re)myelination: implications for multiple sclerosis research. Nat Prod Rep 2021; 38:890-904. [PMID: 33575689 DOI: 10.1039/d0np00093k] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Covering: up to 2020 This short review surveys aspects of glycolipid-based natural products and their biological relevance in multiple sclerosis (MS). The role of isolated gangliosides in disease models is discussed together with an overview of ganglioside-inspired small molecule drugs and imaging probes. The discussion is extended to neurodegeneration in a more general context and addresses the need for more efficient synthetic methods to generate (glyco)structures that are of therapeutic relevance.
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Affiliation(s)
- Luise Nowack
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany. and Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany.
| | - Charlotte S Teschers
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany.
| | - Stefanie Albrecht
- Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149 Münster, Germany.
| | - Ryan Gilmour
- Institute for Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 36, 48149 Münster, Germany.
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11
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Dhein S. Different Effects of Cannabis Abuse on Adolescent and Adult Brain. Pharmacology 2020; 105:609-617. [PMID: 32629444 DOI: 10.1159/000509377] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 06/11/2020] [Indexed: 11/19/2022]
Abstract
Cannabis abuse is a common phenomenon among adolescents. The dominant psychoactive substance in Cannabis sativa is tetrahydrocannabinol (THC). However, in the past 40 years the content of the psychoactive ingredient THC in most of the preparations is not constant but has increased due to other breeding and culturing conditions. THC acts as the endocannabinoids at CB1 and CB2 receptors but pharmacologically can be described as a partial (not a pure) agonist. Recent evidence shows that activation of the CB1 receptor by THC can diminish the production of neuronal growth factor in neurons and affect other signalling cascades involved in synapsis formation. Since these factors play an important role in the brain development and in the neuronal conversion processes during puberty, it seems reasonable that THC can affect the adolescent brain in another manner than the adult brain. Accordingly, in adolescent cannabis users structural changes were observed with loss of grey matter in certain brain areas. Moreover, recent studies show different effects of THC on adolescent and adult brains and on behaviour. These studies indicate that early THC abuse can result in neuropsychological deficits. This review gives an overview over the present knowledge in this field.
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Affiliation(s)
- Stefan Dhein
- Institute f. Pharmacology, University Leipzig, Leipzig, Germany, .,Fachdienst Gesundheit, Altenburg, Germany,
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12
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Houlton J, Abumaria N, Hinkley SFR, Clarkson AN. Therapeutic Potential of Neurotrophins for Repair After Brain Injury: A Helping Hand From Biomaterials. Front Neurosci 2019; 13:790. [PMID: 31427916 PMCID: PMC6688532 DOI: 10.3389/fnins.2019.00790] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/15/2019] [Indexed: 12/17/2022] Open
Abstract
Stroke remains the leading cause of long-term disability with limited options available to aid in recovery. Significant effort has been made to try and minimize neuronal damage following stroke with use of neuroprotective agents, however, these treatments have yet to show clinical efficacy. Regenerative interventions have since become of huge interest as they provide the potential to restore damaged neural tissue without being limited by a narrow therapeutic window. Neurotrophins, such as brain-derived neurotrophic factor (BDNF), and their high affinity receptors are actively produced throughout the brain and are involved in regulating neuronal activity and normal day-to-day function. Furthermore, neurotrophins are known to play a significant role in both protection and recovery of function following neurodegenerative diseases such as stroke and traumatic brain injury (TBI). Unfortunately, exogenous administration of these neurotrophins is limited by a lack of blood-brain-barrier (BBB) permeability, poor half-life, and rapid degradation. Therefore, we have focused this review on approaches that provide a direct and sustained neurotrophic support using pharmacological therapies and mimetics, physical activity, and potential drug delivery systems, including discussion around advantages and limitations for use of each of these systems. Finally, we discuss future directions of biomaterial drug-delivery systems, including the incorporation of heparan sulfate (HS) in conjunction with neurotrophin-based interventions.
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Affiliation(s)
- Josh Houlton
- Brain Health Research Centre, Department of Anatomy, University of Otago, Dunedin, New Zealand
| | - Nashat Abumaria
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai, China
- Department of Laboratory Animal Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Simon F. R. Hinkley
- The Ferrier Research Institute, Victoria University of Wellington, Petone, New Zealand
| | - Andrew N. Clarkson
- Brain Health Research Centre, Department of Anatomy, University of Otago, Dunedin, New Zealand
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13
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Yan XB, Zhao YF, Yang YM, Wang N, He BZ, Qiu XT. Impact of astrocyte and lymphocyte interactions on the blood-brain barrier in multiple sclerosis. Rev Neurol (Paris) 2019; 175:396-402. [PMID: 31027862 DOI: 10.1016/j.neurol.2018.12.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/12/2018] [Accepted: 12/28/2018] [Indexed: 11/25/2022]
Abstract
OBJECTIVE This study was designed to investigate the impact of astrocyte and lymphocyte (LC) interactions in the blood-brain barrier (BBB) on the pathogenesis of multiple sclerosis (MS). METHODS Primary rat brain microvascular endothelial cells (rBMECs) and astrocytes isolated from Sprague-Dawley rats were used to establish in vitro BBB models. Transendothelial electrical resistance (TEER) and permeability were compared between rBMEC monocultures and rBMEC/astrocyte co-cultures to evaluate the validity of each as a BBB cell model. rBMEC/LC co-cultures and rBMEC/astrocyte/LC tri-cultures were established to evaluate inflammatory responses in MS by measuring the gene expression levels of nerve growth factor (NGF), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), interleukin 17 (IL-17), interferon γ (IFN-γ), and forkhead box P3 (Foxp3). RESULTS The rBMEC/astrocyte co-cultures exhibited higher TEER values and lower lymphocyte permeabilities than those of rBMEC monocultures. Compared to the rBMEC mono-cultures, the rBMEC/astrocyte/LC tri-cultures showed significantly decreased NGF, IL-17, and IFN-γ and increased MMP-2 and Foxp3 expression. Furthermore, the tri-cultures exhibited decreased NGF, IL-17, and IFN-γ expression compared to the rBMEC/astrocyte co-cultures, and increased MMP-2 expression compared to that shown by the rBMEC/LC co-cultures. MMP-9 expression did not vary significantly between the four established BBB cell models. CONCLUSION These results suggest that the synergistic effect between astrocytes and LCs may increase the expression of MMP-2 and decrease that of IL-17 and IFN-γ at the BBB. Furthermore, the use of rBMEC/astrocytes/LC tri-cultures enabled us to test the synergistic effect between astrocytes and LCs and their roles in MS pathogenesis.
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Affiliation(s)
- X-B Yan
- Department of Neurology, The Second Clinical Hospital of Harbin Medical University, 150086 Harbin, China.
| | - Y-F Zhao
- Department of Neurology, The Second Clinical Hospital of Harbin Medical University, 150086 Harbin, China
| | - Y-M Yang
- Department of Neurology, The Second Clinical Hospital of Harbin Medical University, 150086 Harbin, China
| | - N Wang
- Department of Neurology, The Second Clinical Hospital of Harbin Medical University, 150086 Harbin, China
| | - B-Z He
- The University of New South Wales, 2033 Kensington, Australia
| | - X-T Qiu
- Department of Neurology, The Second Clinical Hospital of Harbin Medical University, 150086 Harbin, China
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14
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NGF and Its Receptors in the Regulation of Inflammatory Response. Int J Mol Sci 2017; 18:ijms18051028. [PMID: 28492466 PMCID: PMC5454940 DOI: 10.3390/ijms18051028] [Citation(s) in RCA: 204] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 03/31/2017] [Accepted: 05/03/2017] [Indexed: 12/28/2022] Open
Abstract
There is growing interest in the complex relationship between the nervous and immune systems and how its alteration can affect homeostasis and result in the development of inflammatory diseases. A key mediator in cross-talk between the two systems is nerve growth factor (NGF), which can influence both neuronal cell function and immune cell activity. The up-regulation of NGF described in inflamed tissues of many diseases can regulate innervation and neuronal activity of peripheral neurons, inducing the release of immune-active neuropeptides and neurotransmitters, but can also directly influence innate and adaptive immune responses. Expression of the NGF receptors tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR) is dynamically regulated in immune cells, suggesting a varying requirement for NGF depending on their state of differentiation and functional activity. NGF has a variety of effects that can be either pro-inflammatory or anti-inflammatory. This apparent contradiction can be explained by considering NGF as part of an endogenous mechanism that, while activating immune responses, also activates pathways necessary to dampen the inflammatory response and limit tissue damage. Decreases in TrkA expression, such as that recently demonstrated in immune cells of arthritis patients, might prevent the activation by NGF of regulatory feed-back mechanisms, thus contributing to the development and maintenance of chronic inflammation.
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15
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Skaper SD. Nerve growth factor: a neuroimmune crosstalk mediator for all seasons. Immunology 2017; 151:1-15. [PMID: 28112808 PMCID: PMC5382350 DOI: 10.1111/imm.12717] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/16/2017] [Accepted: 01/18/2017] [Indexed: 12/13/2022] Open
Abstract
Neurotrophic factors comprise a broad family of biomolecules - most of which are peptides or small proteins - that support the growth, survival and differentiation of both developing and mature neurons. The prototypical example and best-characterized neurotrophic factor is nerve growth factor (NGF), which is widely recognized as a target-derived factor responsible for the survival and maintenance of the phenotype of specific subsets of peripheral neurons and basal forebrain cholinergic nuclei during development and maturation. In addition to being active in a wide array of non-nervous system cells, NGF is also synthesized by a range of cell types not considered as classical targets for innervation by NGF-dependent neurons; these include cells of the immune-haematopoietic lineage and populations in the brain involved in neuroendocrine functions. NGF concentrations are elevated in numerous inflammatory and autoimmune states such as multiple sclerosis, chronic arthritis, systemic lupus erythematosus and mastocytosis, in conjunction with increased accumulation of mast cells. Intriguingly, NGF seems to be linked also with diabetic pathology and insulin homeostasis. Mast cells and NGF appear involved in neuroimmune interactions and tissue inflammation. As mast cells are capable of producing and responding to NGF, this suggests that alterations in mast cell behaviour could provoke maladaptive neuroimmune tissue responses, including those of an autoimmune nature. Moreover, NGF exerts a modulatory role on sensory nociceptive nerve physiology in the adult, which appears to correlate with hyperalgesic phenomena occurring in tissue inflammation. NGF can therefore be viewed as a multifactorial modulator of neuro-immune-endocrine functions.
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Affiliation(s)
- Stephen D. Skaper
- Department of Pharmaceutical and Pharmacological SciencesUniversity of PaduaPaduaItaly
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16
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Varma AV, McBride L, Marble M, Tilton A. Congenital insensitivity to pain and anhidrosis: Case report and review of findings along neuro-immune axis in the disorder. J Neurol Sci 2016; 370:201-210. [PMID: 27772759 DOI: 10.1016/j.jns.2016.09.037] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/30/2016] [Accepted: 09/20/2016] [Indexed: 12/19/2022]
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17
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Blandini F, Rinaldi L, Tassorelli C, Sances G, Motta M, Samuele A, Fancellu R, Nappi G, Leon A. Peripheral Levels of BDNF and NGF in Primary Headaches. Cephalalgia 2016; 26:136-42. [PMID: 16426267 DOI: 10.1111/j.1468-2982.2005.01006.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), have been implicated in the generation and modulation of pain. To investigate whether alterations in neurotrophin levels can be detected in subjects suffering from nociceptive disorders, such as primary headaches, we determined the peripheral (platelet and plasma) levels of BDNF and NGF in patients suffering from migraine, with or without aura, or cluster headache (CH), in the interictal phase, and in healthy volunteers. All primary headaches patients studied showed significantly decreased platelet levels of BDNF (migraine vs. controls P < 0.001; CH vs. controls P < 0.01), while a selective reduction of platelet NGF was observed in migraine sufferers and not in CH patients compared with control subjects (migraine vs. controls P < 0.001). These changes were not accompanied by significant modifications of neurotrophin plasma levels. Our findings show for the first time that changes in peripheral levels of neurotrophines (BDNF and NGF) occur in patients suffering from different types of primary headaches, suggesting a potential involvement of BDNF and NGF in the pathophysiology of these disorders, and raising the possibility that differences in peripheral neurotrophins may help to distinguish migraine biologically from CH.
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Affiliation(s)
- F Blandini
- Laboratory of Functional Neurochemistry, Neurological Institute C. Mondino, Pavia, Italy
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18
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Bersani G, Iannitelli A, Massoni E, Garavini A, Grilli A, Di Giannantonio M, Conti CMV, Pancheri P. Ultradian Variation of Nerve Growth Factor Plasma Levels in Healthy and Schizophrenic Subjects. Int J Immunopathol Pharmacol 2016; 17:367-72. [PMID: 15461870 DOI: 10.1177/039463200401700316] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Some studies in animal models showed that several neurotrophins may be implicated in the regulation of light-dependent suprachiasmatic pacemaker and in other functions implicated in long-term memory acquisition during sleep. However, no data are known about the role played by NGF in ultradian regulation in humans. The aim of this study was to investigate whether or not there is a natural diurnal fluctuation during daytime in healthy and schizophrenic subjects with a normal light/dark cycle. In a sample of 33 subjects (10 male schizophrenics and 23 healthy subjects) an ELISA assay was used to study the ultradian NGF cycle in blood samples at 9.00, 13.00 and 20.00 hours. The study showed an ultradian rhythm of NGF in healthy subjects with a “V” trend: higher at 9:00 and 20:00 and lower at 13:00. We also show significant differences between male and female controls. No NGF ultradian rhythm among schizophrenic patients compared to healthy subjects was found. The results of this study lead to a rhythmic NGF regulation that appears altered in schizophrenics, where higher levels in the morning and lower levels in the evening were observed, compared to the controls, and support the hypothesis of a role played by NGF in schizophrenia.
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Affiliation(s)
- G Bersani
- 3rd Psychiatric Clinic, Department of Psychiatry and Psychological Medicine, University of Rome "La Sapienza", Rome, Italy.
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19
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Han C, Huang J, Waxman SG. Sodium channel Nav1.8: Emerging links to human disease. Neurology 2016; 86:473-83. [PMID: 26747884 DOI: 10.1212/wnl.0000000000002333] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 10/07/2015] [Indexed: 12/19/2022] Open
Abstract
The NaV1.8 sodium channel, encoded by gene SCN10A, was initially termed sensory neuron-specific (SNS) due to prominent expression in primary sensory neurons including dorsal root ganglion (DRG) neurons. Early studies on rodent NaV1.8 demonstrated depolarized voltage dependence of channel inactivation, a slow rate of inactivation, and rapid recovery from inactivation. As a result of these biophysical properties, NaV1.8 supports repetitive firing in response to sustained depolarization. This article reviews recent studies that reveal multiple links of NaV1.8 to human disease: (1) It has recently been shown that functional attributes that distinguish NaV1.8 from other sodium channel subtypes are exaggerated in human NaV1.8; its influence on neuronal activity is thus greater than previously thought. (2) Gain-of-function mutations of NaV1.8 that produce DRG neuron hyperexcitability have been found in 3% of patients with painful neuropathy, establishing a role in pathogenesis. (3) NaV1.8 is ectopically expressed within Purkinje neurons in multiple sclerosis (MS), where it perturbs electrical activity. Recent evidence indicates that variants of SCN10A predict the degree of cerebellar dysfunction in MS. (4) Emerging evidence has linked SCN10A variants to disorders of cardiac rhythm, via mechanisms that may include an effect on cardiac innervation. Involvement of NaV1.8 in neurologic disease may have therapeutic implications. NaV1.8-specific blocking agents, under development, ameliorate pain and attenuate MS-like deficits in animal models. Recent studies suggest that pharmacogenomics may permit the matching of specific channel blocking agents to particular patients. The new links of NaV1.8 in human disease raise new questions, but also suggest new therapeutic strategies.
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Affiliation(s)
- Chongyang Han
- From the Department of Neurology, Yale University School of Medicine, New Haven; and the Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven
| | - Jianying Huang
- From the Department of Neurology, Yale University School of Medicine, New Haven; and the Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven
| | - Stephen G Waxman
- From the Department of Neurology, Yale University School of Medicine, New Haven; and the Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven.
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20
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Nunes AKS, Rapôso C, Rocha SWS, Barbosa KPDS, de Almeida Luna RL, da Cruz-Höfling MA, Peixoto CA. Involvement of AMPK, IKβα-NFκB and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model. Brain Res 2015; 1627:119-33. [DOI: 10.1016/j.brainres.2015.09.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 09/04/2015] [Accepted: 09/05/2015] [Indexed: 01/08/2023]
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21
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Binzer S, Stenager E, Binzer M, Kyvik KO, Hillert J, Imrell K. Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene. Mult Scler 2015; 22:733-40. [DOI: 10.1177/1352458515602338] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 07/21/2015] [Indexed: 11/15/2022]
Abstract
Background: In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted. Objective: The objective of this research paper is to search for rare genetic MS risk variants in the genetically homogenous population of the isolated Faroe Islands. Methods: Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome-chip. The individuals make up 1596 pair-combinations in which we searched for identical-by-descent shared segments using the PLINK-program. Results: A segment spanning 63 SNPs with excess case-case-pair sharing was identified (0.00173 < p > 0.00212). A haplotype consisting of 42 of the 63 identified SNPs which spanned the entire the Sortilin-related vacuolar protein sorting 10 domain containing receptor 3 ( SORCS3) gene had a carrier frequency of 0.34 in cases but was not present in any controls ( p = 0.0008). Conclusion: This study revealed an oversharing in case-case-pairs of a segment spanning 63 SNPs and the entire SORCS3. While not previously associated with MS, SORCS3 appears to be important in neuronal plasticity through its binding of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis.
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Affiliation(s)
- S Binzer
- Institute of Regional Health Research, University of Southern Denmark, Denmark/Hospital of Southern Jutland, Denmark/Odense Patient data Explorative Network (OPEN), University of Southern Denmark, Denmark/ Torshavn National Hospital, Faroe Islands
| | - E Stenager
- Institute of Regional Health Research, University of Southern Denmark, Denmark/Hospital of Southern Jutland, Denmark/ MS Clinic of Southern Jutland (Sønderborg, Esbjerg, Vejle), Department of Neurology, Denmark
| | - M Binzer
- Institute of Regional Health Research, University of Southern Denmark, Denmark
| | - KO Kyvik
- Department of Clinical Research, University of Southern Denmark, Denmark/Odense Patient data Explorative Network (OPEN), University of Southern Denmark, Denmark
| | - J Hillert
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - K Imrell
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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22
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Soligo M, Protto V, Florenzano F, Bracci-Laudiero L, De Benedetti F, Chiaretti A, Manni L. The mature/pro nerve growth factor ratio is decreased in the brain of diabetic rats: Analysis by ELISA methods. Brain Res 2015; 1624:455-468. [PMID: 26282349 DOI: 10.1016/j.brainres.2015.08.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 07/21/2015] [Accepted: 08/08/2015] [Indexed: 01/08/2023]
Abstract
Nerve growth factor (NGF) is essential for the survival and functional maintenance of forebrain cholinergic neurons projecting mainly to the cortex and hippocampus. NGF is produced in these brain areas but while mature NGF (mNGF) has a survival/differentiative effect its precursor proNGF elicits apoptosis in cholinergic neurons. Impaired neurotransmission, loss of cholinergic phenotype and abnormal NGF content characterize the cholinergic circuitries in animal models of diabetic encephalopathy (DE). It is not known whether defective production or maturation of NGF could play a key role in cholinergic neurodegeneration in DE. Quantification of the mNGF/proNGF ratio is therefore needed to characterize the development and progression of NGF-related neuronal diseases. In our work, we aimed at developing ELISA methods to measure either mNGF or proNGF tissue concentration; and to define the mNGF/proNGF ratio in the rat cortex and hippocampus during the early stage of streptozotocin-induced type 1 diabetes. Using commercially available NGF ELISA kits and antibodies, we set up ELISAs for human and rat mNGF and proNGF. We then analyzed the mNGF/proNGF ratio in the cortex and hippocampus of DE rats and found that it decreased in both tissues starting from the fourth week after diabetes induction. In diabetic brain the increase in proNGF involves accumulation of the isoforms with molecular weights of 50 and 34 kDa. Our study for the first time specifically quantifies the absolute content of mature and proNGF and the mNGF/proNGF ratio in brain tissues, suggesting that early progression of experimental DE is characterized by defective maturation of NGF.
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Affiliation(s)
- Marzia Soligo
- Institute of Translational Pharmacology-CNR, via del Fosso del Cavaliere 100, 00133 Rome, Italy
| | - Virginia Protto
- Institute of Translational Pharmacology-CNR, via del Fosso del Cavaliere 100, 00133 Rome, Italy
| | - Fulvio Florenzano
- Confocal Microscopy Unit, European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65, 00143 Rome, Italy
| | - Luisa Bracci-Laudiero
- Institute of Translational Pharmacology-CNR, via del Fosso del Cavaliere 100, 00133 Rome, Italy; Bambino Gesu' Children's Hospital-IRCSS, Division of Rheumatology, Piazza S. Onofrio 4, 00165 Rome, Italy
| | - Fabrizio De Benedetti
- Bambino Gesu' Children's Hospital-IRCSS, Division of Rheumatology, Piazza S. Onofrio 4, 00165 Rome, Italy
| | - Antonio Chiaretti
- Department of Pediatrics, Catholic University of Rome, Largo A Gemelli 8, 00168 Rome, Italy
| | - Luigi Manni
- Institute of Translational Pharmacology-CNR, via del Fosso del Cavaliere 100, 00133 Rome, Italy.
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Liang P, Le W. Role of autophagy in the pathogenesis of multiple sclerosis. Neurosci Bull 2015; 31:435-44. [PMID: 26254059 DOI: 10.1007/s12264-015-1545-5] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 07/05/2015] [Indexed: 10/23/2022] Open
Abstract
Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively influences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Inflammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-inflammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinflammation associated with the pathogenesis of MS.
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Affiliation(s)
- Peizhou Liang
- Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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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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NGF in Early Embryogenesis, Differentiation, and Pathology in the Nervous and Immune Systems. Curr Top Behav Neurosci 2015; 29:125-152. [PMID: 26695167 DOI: 10.1007/7854_2015_420] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The physiology of NGF is extremely complex, and although the study of this neurotrophin began more than 60 years ago, it is far from being concluded. NGF, its precursor molecule pro-NGF, and their different receptor systems (i.e., TrkA, p75NTR, and sortilin) have key roles in the development and adult physiology of both the nervous and immune systems. Although the NGF receptor system and the pathways activated are similar for all types of cells sensitive to NGF, the effects exerted during embryonic differentiation and in committed mature cells are strikingly different and sometimes opposite. Bearing in mind the pleiotropic effects of NGF, alterations in its expression and synthesis, as well as variations in the types of receptor available and in their respective levels of expression, may have profound effects and play multiple roles in the development and progression of several diseases. In recent years, the use of NGF or of inhibitors of its receptors has been prospected as a therapeutic tool in a variety of neurological diseases and injuries. In this review, we outline the different roles played by the NGF system in various moments of nervous and immune system differentiation and physiology, from embryonic development to aging. The data collected over the past decades indicate that NGF activities are highly integrated among systems and are necessary for the maintenance of homeostasis. Further, more integrated and multidisciplinary studies should take into consideration these multiple and interactive aspects of NGF physiology in order to design new therapeutic strategies based on the manipulation of NGF and its intracellular pathways.
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Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol Commun 2014; 2:84. [PMID: 25047180 PMCID: PMC4149233 DOI: 10.1186/s40478-014-0084-z] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Accepted: 07/09/2014] [Indexed: 02/07/2023] Open
Abstract
Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood–brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.
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Dedoni S, Olianas MC, Ingianni A, Onali P. Type I interferons up-regulate the expression and signalling of p75 NTR/TrkA receptor complex in differentiated human SH-SY5Y neuroblastoma cells. Neuropharmacology 2014; 79:321-34. [PMID: 24333329 DOI: 10.1016/j.neuropharm.2013.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 10/25/2013] [Accepted: 12/02/2013] [Indexed: 01/10/2023]
Abstract
Both type I interferons (IFNs) and neurotrophins regulate neuroadaptive responses, but relatively little is known on the interaction between these two classes of regulatory proteins. Here we investigated the effect of IFN-β on the expression and functional activity of the common neurotrophin receptor p75NTR and the nerve growth factor (NGF) receptor TrkA. In differentiated human SH-SY5Y neuroblastoma cells prolonged exposure to IFN-β up-regulated p75NTR and TrkA levels, failed to affect the content of sortilin, a p75NTR co-receptor, and, consistent with our previous finding, down-regulated the brain-derived neurotrophic factor receptor TrkB. Quantitative real time RT-PCR indicated that IFN-β increased p75NTR and TrkA mRNA levels. In control and IFN-β treated cells proNGF failed to induce c-Jun N-terminal kinase and nuclear factor/kB activation, two p75NTR/sortilin signalling pathways mediating neuronal death. On the other hand, IFN-β treatment enhanced TrkA autophosphorylation and signalling induced by NGF and proNGF. Knockdown of p75NTR by siRNA reduced TrkA activation by proNGF and a subnanomolar concentration of NGF, whereas co-immunoprecipitation indicated close association of p75NTR and TrkA. Co-treatment with either NGF or proNGF reduced IFN-β pro-apoptotic and anti-neurotrophic effects. Similarly, in primary mouse hippocampal neurons IFN-β increased p75NTR and TrkA expression, down-regulated TrkB and enhanced NGF-induced phosphorylation of the pro-survival protein kinase Akt. The data demonstrate that in neuronal cells IFN-β differentially affects the expression and signalling of neurotrophin receptors and suggest that the up-regulation of the p75NTR/TrkA signalling complex may constitute a novel mechanism by which this cytokine selectively attenuates its pro-apoptotic effect in NGF-responsive cells.
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Affiliation(s)
- Simona Dedoni
- Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, and Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Maria C Olianas
- Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, and Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Angela Ingianni
- Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, and Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Pierluigi Onali
- Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences and Clinical Pharmacology, and Section of Applied Microbiology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
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Chavarría A, Cárdenas G. Neuronal influence behind the central nervous system regulation of the immune cells. Front Integr Neurosci 2013; 7:64. [PMID: 24032006 PMCID: PMC3759003 DOI: 10.3389/fnint.2013.00064] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 08/07/2013] [Indexed: 12/29/2022] Open
Abstract
Central nervous system (CNS) has a highly specialized microenvironment, and despite being initially considered an immune privileged site, this immune status is far from absolute because it varies with age and brain topography. The brain monitors immune responses by several means that act in parallel; one pathway involves afferent nerves (vagal nerve) and the other resident cells (neurons and glia). These cell populations exert a strong role in the regulation of the immune system, favoring an immune-modulatory environment in the CNS. Neurons control glial cell and infiltrated T-cells by contact-dependent and -independent mechanisms. Contact-dependent mechanisms are provided by several membrane immune modulating molecules such as Sema-7A, CD95L, CD22, CD200, CD47, NCAM, ICAM-5, and cadherins; which can inhibit the expression of microglial inflammatory cytokines, induce apoptosis or inactivate infiltrated T-cells. On the other hand, soluble neuronal factors like Sema-3A, cytokines, neurotrophins, neuropeptides, and neurotransmitters attenuate microglial and/or T-cell activation. In this review, we focused on all known mechanism driven only by neurons in order to control the local immune cells.
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Affiliation(s)
- Anahí Chavarría
- Laboratorio de Neuroinmunología, Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México México City, México
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Oligodendroglia and neurotrophic factors in neurodegeneration. Neurosci Bull 2013; 29:216-28. [PMID: 23558590 DOI: 10.1007/s12264-013-1321-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 01/26/2013] [Indexed: 12/12/2022] Open
Abstract
Myelination by oligodendroglial cells (OLs) enables the propagation of action potentials along neuronal axons, which is essential for rapid information flow in the central nervous system. Besides saltatory conduction, the myelin sheath also protects axons against inflammatory and oxidative insults. Loss of myelin results in axonal damage and ultimately neuronal loss in demyelinating disorders. However, accumulating evidence indicates that OLs also provide support to neurons via mechanisms beyond the insulating function of myelin. More importantly, an increasing volume of reports indicates defects of OLs in numerous neurodegenerative diseases, sometimes even preceding neuronal loss in pre-symptomatic episodes, suggesting that OL pathology may be an important mechanism contributing to the initiation and/or progression of neurodegeneration. This review focuses on the emerging picture of neuronal support by OLs in the pathogenesis of neurodegenerative disorders through diverse molecular and cellular mechanisms, including direct neuron-myelin interaction, metabolic support by OLs, and neurotrophic factors produced by and/or acting on OLs.
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Costanza M, Colombo MP, Pedotti R. Mast cells in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. Int J Mol Sci 2012. [PMID: 23203114 PMCID: PMC3509630 DOI: 10.3390/ijms131115107] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Mast cells (MCs) are best known as key immune players in immunoglobulin E (IgE)-dependent allergic reactions. In recent years, several lines of evidence have suggested that MCs might play an important role in several pathological conditions, including autoimmune disorders such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Since their first description in MS plaques in the late 1800s, much effort has been put into elucidating the contribution of MCs to the development of central nervous system (CNS) autoimmunity. Mouse models of MC-deficiency have provided a valuable experimental tool for dissecting MC involvement in MS and EAE. However, to date there is still major controversy concerning the function of MCs in these diseases. Indeed, although MCs have been classically proposed as having a detrimental and pro-inflammatory role, recent literature has questioned and resized the contribution of MCs to the pathology of MS and EAE. In this review, we will present the main evidence obtained in MS and EAE on this topic, and discuss the critical and controversial aspects of such evidence.
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Affiliation(s)
- Massimo Costanza
- Neuroimmunology and Neuromuscular Disorder Unit, Neurological Institute Foundation IRCCS C. Besta, via Amadeo 42, Milan 20133, Italy; E-Mail:
| | - Mario P. Colombo
- Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, Milan 20133, Italy; E-Mail:
| | - Rosetta Pedotti
- Neuroimmunology and Neuromuscular Disorder Unit, Neurological Institute Foundation IRCCS C. Besta, via Amadeo 42, Milan 20133, Italy; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +39-02-23944654; Fax: +39-02-23944708
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Chen X, Ma L, Jiang Y, Chen S, Zhu C, Liu M, Ma X, Zhu D, Liu Y, Peng F, Wang Q, Pi R. Minocycline up-regulates the expression of brain-derived neurotrophic factor and nerve growth factor in experimental autoimmune encephalomyelitis. Eur J Pharmacol 2012; 686:124-9. [DOI: 10.1016/j.ejphar.2012.04.043] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2011] [Revised: 04/18/2012] [Accepted: 04/21/2012] [Indexed: 12/30/2022]
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Mc Guire C, Beyaert R, van Loo G. Death receptor signalling in central nervous system inflammation and demyelination. Trends Neurosci 2011; 34:619-28. [PMID: 21999927 DOI: 10.1016/j.tins.2011.09.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 09/13/2011] [Accepted: 09/18/2011] [Indexed: 12/31/2022]
Abstract
Death receptors (DRs) are members of the tumor necrosis factor receptor (TNF-R) superfamily that are characterised by the presence of a conserved intracellular death domain and are able to trigger a signalling pathway leading to apoptosis. Strong evidence suggests that DRs contribute to the pathology of tissue destructive diseases, including multiple sclerosis (MS), the most common inflammatory demyelinating disease of the central nervous system (CNS). Here, we review the evidence supporting a role for DRs in MS pathology and its implications for the development of therapeutic strategies for MS and other demyelinating pathologies of the CNS.
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Affiliation(s)
- Conor Mc Guire
- Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, B-9052 Ghent, Belgium
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Hahn WH, Suh JS, Cho BS. Linkage and association study of neurotrophins and their receptors as novel susceptibility genes for childhood IgA nephropathy. Pediatr Res 2011; 69:299-305. [PMID: 21178826 DOI: 10.1203/pdr.0b013e31820b9365] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Neurotrophins (NTs) and their receptors (NTRs) are known to be important for pathogenesis of various inflammatory diseases that occur in not only neuronal but also nonneuronal tissues, including kidney. Here, we investigated association between childhood IgA nephropathy (IgAN) and single nucleotide polymorphisms (SNPs) of genes encoding NTs [nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)] and NTRs [nerve growth factor receptor (NGFR) and neurotrophic tyrosine kinase receptor 1-3 (NTRK1-3)]. The genotyping data of 197 patients and 289 control subjects revealed significant association between NGF SNP rs11102930 and presence of IgAN. Patient subgroup analysis revealed that that the presence of nephrotic range proteinuria (>40 mg/m/h) was associated with rs6334 of NTRK1 and rs11030104, rs7103411, rs7103873, and rs6484320 of BDNF. Significant genotype differences were observed in podocyte foot process effacement for rs1187321 and rs1187323 of NTRK2. Furthermore, some SNPs showed significantly different genotype distribution between patients with or without pathologically advanced disease markers, specifically in rs6334 of NTRK1. Our results suggest that SNPs of NTs and NTRs are associated with susceptibility, pathological advancement, podocyte foot process effacement, and development of proteinuria in childhood IgAN.
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Affiliation(s)
- Won-Ho Hahn
- Department of Pediatrics, School of Medicine, Kyung Hee University, Seoul 130-702, Republic of Korea
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Vergo S, Craner MJ, Etzensperger R, Attfield K, Friese MA, Newcombe J, Esiri M, Fugger L. Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain 2011; 134:571-84. [DOI: 10.1093/brain/awq337] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Mc Guire C, Volckaert T, Wolke U, Sze M, de Rycke R, Waisman A, Prinz M, Beyaert R, Pasparakis M, van Loo G. Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination. THE JOURNAL OF IMMUNOLOGY 2010; 185:7646-53. [PMID: 21068410 DOI: 10.4049/jimmunol.1000930] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Apoptosis of oligodendrocytes (ODCs), the myelin-producing glial cells in the CNS, plays a central role in demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To investigate the mechanism behind ODC apoptosis in EAE, we made use of conditional knockout mice lacking the adaptor protein FADD specifically in ODCs (FADD(ODC-KO)). FADD mediates apoptosis by coupling death receptors with downstream caspase activation. In line with this, ODCs from FADD(ODC-KO) mice were completely resistant to death receptor-induced apoptosis in vitro. In the EAE model, FADD(ODC-KO) mice followed an ameliorated clinical disease course in comparison with control littermates. Lymphocyte and macrophage infiltration into the spinal cord parenchyma was significantly reduced, as was the extent of demyelination and proinflammatory gene expression. Collectively, our data show that FADD is critical for ODC apoptosis and the development of autoimmune demyelinating disease.
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Affiliation(s)
- Conor Mc Guire
- Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, Flanders Institute for Biotechnology (VIB), Ghent, Belgium
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Jana A, Pahan K. Sphingolipids in multiple sclerosis. Neuromolecular Med 2010; 12:351-61. [PMID: 20607622 DOI: 10.1007/s12017-010-8128-4] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2010] [Accepted: 06/26/2010] [Indexed: 02/02/2023]
Abstract
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the CNS. Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), are target cells in MS. Although the etiology of MS is poorly known, new insights suggest oligodendrocyte apoptosis as one of the critical events followed by glial activation and infiltration of lymphocytes and macrophages. A major breakthrough in delineation of the mechanism of cell death, perivascular cuffing, and glial activation came from elucidation of the sphingolipid signal transduction pathway. The sphingolipid signal transduction pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and downstream targets. Sphingomyelin, a major component of myelin membrane formed by mature oligodendrocytes, is abundant in the CNS and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Similarly, under certain conditions, sphingosine produced from ceramide by ceramidase is phosphorylated by sphingosine kinases to sphingosine-1 phosphate, another potent second messenger molecule. Both ceramide and sphingosine-1 phosphate regulate life and death of many cell types including brain cells and participate in pathogenic processes of MS. In this review, we have made an honest attempt to compile recent findings made by others and us relating to the role of sphingolipids in the disease process of MS.
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Affiliation(s)
- Arundhati Jana
- Department of Neurological Sciences, Rush University Medical Center, Cohn Research Building, Suite 320, 1735 West Harrison St., Chicago, IL 60612, USA
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Scalabrino G, Galimberti D, Mutti E, Scalabrini D, Veber D, De Riz M, Bamonti F, Capello E, Mancardi GL, Scarpini E. Loss of epidermal growth factor regulation by cobalamin in multiple sclerosis. Brain Res 2010; 1333:64-71. [PMID: 20347721 DOI: 10.1016/j.brainres.2010.03.073] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Revised: 03/18/2010] [Accepted: 03/21/2010] [Indexed: 11/24/2022]
Abstract
We investigated whether the physiological regulation of cerebrospinal fluid (CSF) levels of tumor necrosis factor (TNF)-alpha, epidermal growth factor (EGF), and nerve growth factor (NGF) by cobalamin (Cbl) that is observed in rat and human central nervous system (CNS) is retained in the CSF of patients with multiple sclerosis (MS). The study involved 158 MS patients grouped on the basis of the different clinical courses (relapsing-remitting (RR), secondary-progressive (SP), and primary-progressive (PP)), and 76 gender- and age-matched control patients with other non-inflammatory and non-neoplastic neurological diseases. The MS patients were therapy-free at the time of lumbar puncture. CSF Cbl and EGF were blindly measured by means of radioimmunoassays, and CSF TNF-alpha, and NGF by means of highly sensitive enzyme-linked immunosorbent assays. Serum EGF was also measured in 38 of the MS patients and 20 healthy controls. CSF Cbl levels were significantly higher (RR patients 27.9+/-9.7 pg/ml, p<0.0001 vs. C; SP patients 25.4+/-8 pg/ml, p<0.02 vs. C), and CSF TNF-alpha and EGF levels significantly lower in the patients with the RR (TNF-alpha 28.3+/-23.4 x 10(-3) pg/ml, p<0.0001 vs. C; EGF 129.9+/-44.8 pg/ml, p<0.02 vs. C) or SP (TNF-alpha 20.5+/-20.5 x 10(-3) pg/ml, p<0.001 vs. C; EGF 116.5+/-24.8 pg/ml, p<0.05 vs. C) clinical course than in controls (Cbl 21+/-4.6 pg/ml; TNF-alpha 75.6+/-34.7 x 10(-3) pg/ml; EGF 170.2+/-54.8 pg/ml). There were no differences in CSF NGF or serum EGF levels between any of the MS clinical courses and controls. Our results indicate that: (a) the positive Cbl-mediated regulation of myelino- and oligodendrocyte-trophic EGF is lost in the CSF of RR- or SP-MS patients; (b) the decrease in EGF levels in the CSF may be one factor impeding CNS remyelination in MS; and (c) the PP clinical course may have different pathogenetic mechanism(s) also on the basis of the molecules investigated in this study.
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Affiliation(s)
- Giuseppe Scalabrino
- Institute of General Pathology, University of Milan, Via Mangiagalli 31, 20133 Milan, Italy.
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Rezaee F, Rellick SL, Piedimonte G, Akers SM, O'Leary HA, Martin K, Craig MD, Gibson LF. Neurotrophins regulate bone marrow stromal cell IL-6 expression through the MAPK pathway. PLoS One 2010; 5:e9690. [PMID: 20300619 PMCID: PMC2837737 DOI: 10.1371/journal.pone.0009690] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2009] [Accepted: 02/06/2010] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The host's response to infection is characterized by altered levels of neurotrophins and an influx of inflammatory cells to sites of injured tissue. Progenitor cells that give rise to the differentiated cellular mediators of inflammation are derived from bone marrow progenitor cells where their development is regulated, in part, by cues from bone marrow stromal cells (BMSC). As such, alteration of BMSC function in response to elevated systemic mediators has the potential to alter their function in biologically relevant ways, including downstream alteration of cytokine production that influences hematopoietic development. METHODOLOGY/PRINCIPAL FINDINGS In the current study we investigated BMSC neurotrophin receptor expression by flow cytometric analysis to determine differences in expression as well as potential to respond to NGF or BDNF. Intracellular signaling subsequent to neurotrophin stimulation of BMSC was analyzed by western blot, microarray analysis, confocal microscopy and real-time PCR. Analysis of BMSC Interleukin-6 (IL-6) expression was completed using ELISA and real-time PCR. CONCLUSION BMSC established from different individuals had distinct expression profiles of the neurotrophin receptors, TrkA, TrkB, TrkC, and p75(NTR). These receptors were functional, demonstrated by an increase in Akt-phosphorylation following BMSC exposure to recombinant NGF or BDNF. Neurotrophin stimulation of BMSC resulted in increased IL-6 gene and protein expression which required activation of ERK and p38 MAPK signaling, but was not mediated by the NFkappaB pathway. BMSC response to neurotrophins, including the up-regulation of IL-6, may alter their support of hematopoiesis and regulate the availability of inflammatory cells for migration to sites of injury or infection. As such, these studies are relevant to the growing appreciation of the interplay between neurotropic mediators and the regulation of hematopoiesis.
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Affiliation(s)
- Fariba Rezaee
- Department of Pediatrics, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
| | - Stephanie L. Rellick
- Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
| | - Giovanni Piedimonte
- Department of Pediatrics, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
| | - Stephen M. Akers
- Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
| | - Heather A. O'Leary
- Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
| | - Karen Martin
- Department of Neurobiology and Anatomy, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
- Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
| | - Michael D. Craig
- Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
| | - Laura F. Gibson
- Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
- Department of Microbiology and Immunology, West Virginia University School of Medicine, Morgantown, West Virginia, United States of America
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Abstract
The characteristic presenting complaint of patients with fibromyalgia syndrome (FMS) is chronic widespread allodynia. Research findings support the view that FMS is an understandable and treatable neuropathophysiologic disorder. The pain of FMS is often accompanied by one or more other manifestations, such as affective moods, cognitive insecurity, autonomic dysfunction, or irritable bowel or bladder. Growing evidence suggests that this is a familial disorder with many underlying genetic associations. New findings from brain imaging and polysomnography imply that FMS may be a disorder of premature neurologic aging. A conceptual model at the molecular level is proposed to explain many of the observed features of FMS. The model can also explain anticipated responses to FDA approved pharmacologic therapies.
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Marinova TT, Velikova KK, Petrov DB, Kutev NS, Stankulov IS, Chaldakov GN, Triaca V, Manni L, Aloe L. Structural and Ultrastructural Localization of NGF and NGF Receptors in the Thymus of Subjects Affected by Myasthenia Gravis. Autoimmunity 2009; 37:587-92. [PMID: 15763921 DOI: 10.1080/08916930400016717] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
We have previously reported that the thymus of patients affected by myasthenia gravis (MG) is characterized by an elevated level of nerve growth factor (NGF), an endogenous polypeptide which plays a marked role in the cell biology of nervous and immune system. A consistent number of studies has shown altered expression of NGF in diseases associated with inflammatory and/or autoimmune responses. To evaluate the biochemical and molecular mechanisms implicated in NGF action in human myasthenic thymus, it is important to identify the cellular and structural organization of NGF receptors. To address this question, we investigated, both at light and electron microscopic levels, the cellular distribution of immunoreactivity for NGF and its low-affinity receptors, (p75) and its high-affinity receptor (TrkA) in the thymus of patients with MG. The present investigation shows that NGF and NGF receptors are overexpressed in the thymic cells of patients with MG compared to control subjects.
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Fumagalli F, Molteni R, Calabrese F, Maj PF, Racagni G, Riva MA. Neurotrophic factors in neurodegenerative disorders : potential for therapy. CNS Drugs 2009; 22:1005-19. [PMID: 18998739 DOI: 10.2165/0023210-200822120-00004] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Finding an effective therapy to treat chronic neurodegenerative disorders still represents an unmet and elusive goal, mainly because so many pathogenic variables come into play in these diseases. Recent emphasis has been placed on the role of neurotrophic factors in the aetiology of such disorders because of their role in the survival of different cell phenotypes under various adverse conditions, including neurodegeneration.This review summarizes the current status and the efforts to treat neurodegenerative disorders by the exogenous administration of neurotrophic factors in an attempt to replenish trophic supply, the paucity of which may contribute to the development of the illness. Although promising results have been seen in animal models, this approach still meets disparate and often insurmountable problems in clinical settings, presumably related to the unique nature of the human being.
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Affiliation(s)
- Fabio Fumagalli
- Department of Pharmacological Sciences, Center of Neuropharmacology, University of Milan, Milan, Italy
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42
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Lipps BV. PART 3: ELEVATED LEVELS OF THE SALIVARY PROTEIN IMMUNOGLOBULIN E, NERVE GROWTH FACTOR, MYOGLOBIN, AND INSULIN IN PATIENTS WITH TYPE 2 DIABETES OR WITH AUTOIMMUNITY CAN BE PREVENTED BY LT-10-TREATMENT. TOXIN REV 2008. [DOI: 10.1080/15569540802125530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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43
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Rasi G, Serafino A, Bellis L, Lonardo MT, Andreola F, Zonfrillo M, Vennarecci G, Pierimarchi P, Sinibaldi Vallebona P, Ettorre GM, Santoro E, Puoti C. Nerve growth factor involvement in liver cirrhosis and hepatocellular carcinoma. World J Gastroenterol 2007; 13:4986-95. [PMID: 17854142 PMCID: PMC4434623 DOI: 10.3748/wjg.v13.i37.4986] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To define NGF (nerve growth factor) and its high-affinity receptor trkANGF presence and distribution in fibrotic liver and in HCC, and to verify if NGF might have a role in fibrosis and HCC.
METHODS: Intracellular distribution of NGF and trkANGF were assessed by immunohistochemistry and immuno-electron microscopy in liver specimens from HCC, cirrhosis or both. ELISA was used to measure circulating NGF levels.
RESULTS: NGF and trkANGF were highly expressed in HCC tissue, mainly localized in hepatocytes, endothelial and some Kupffer cells. In the cirrhotic part of the liver they were also markedly expressed in bile ducts epithelial and spindle-shaped cells. Surprisingly, in cirrhotic tissue from patients without HCC, both NGF and trkANGF were negative. NGF serum levels in cirrhotic and/or HCC patient were up to 25-fold higher than in controls.
CONCLUSION: NGF was only detected in liver tissue with HCC present. Intracellular distribution suggests paracrine and autocrine mechanisms of action. Better definition of mechanisms may allow for therapeutic and diagnostic/prognostic use of NGF.
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Affiliation(s)
- Guido Rasi
- National Research Council, Istituto di Neurobiologia e Medicina Molecolare, Via Fosso del Cavaliere 100, 00133 Rome, Italy
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45
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de Romo ACR. Chance, creativity, and the discovery of the nerve growth factor. JOURNAL OF THE HISTORY OF THE NEUROSCIENCES 2007; 16:268-87. [PMID: 17620191 DOI: 10.1080/09647040500536558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
This essay analyzes the history of the Nerve Growth Factor (NGF) discovery, relating some of the principles of the theory of scientific creativity to the cognitive and personal qualities of the scientists that participated in the discovery, particularly Rita Levi-Montalcini and Viktor Hamburger. The discovery of NGF is especially attractive for the history of science as it involves chance, luck, creativity, and some extraordinary scientists.
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Affiliation(s)
- Ana Cecilia Rodríguez de Romo
- Department of the History and Philosophy of Medicine, Faculty of Medicine, UNAM, Laboratory of the History of Medicine, National Institute of Neurology and Neurosurgery, Del Tlalpan, CP, Mexico.
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46
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Hamamcioglu K, Reder AT. Interferon-β regulates cytokines and BDNF: greater effect in relapsing than in progressive multiple sclerosis. Mult Scler 2007; 13:459-70. [PMID: 17463069 DOI: 10.1177/1352458506069672] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The mechanism of action of interferon (IFN)-β therapy in multiple sclerosis (MS) is only partially known, and its efficacy changes with disease stage. In different forms of MS, we determined how IFN-β regulates mononuclear cell production of the important anti-inflammatory Th2 cytokine - IL-10, the Th1 cytokine - IFN-γ, and the brain-derived neurotrophic protein - BDNF. Activated T cells and monocytes from therapy-naïve patients secreted more IL-10 than healthy controls. During IFN-β therapy, however, T cells produced less IL-10. In vitro, IFN-β stimulated IL-10 production by activated T cells, but inhibited IL-10 secretion by activated monocytes, a richer source of IL-10 than T cells. The form of MS also affected cytokine production. IL-10 and BDNF levels in MNC were high during relapsing/remitting (RR) MS, but low in progressive MS. Surprisingly, IFN-β therapy increased BDNF levels in antidepressant-naïve patients, but BDNF was lower during concurrent antidepressant drug therapy, suggesting an interaction between MS, depression, and neurodegeneration. IFN-β in vitro strongly induced IL-10 and IFN-γ in activated T cells in RRMS, but not in progressive MS, suggesting IFN resistance. IFN-β effects are specific for disease state and immune subsets, possibly explaining why IFN-β therapy is most effective in early T cell-regulated RRMS, but less beneficial in progressive MS, where chronic plaques contain few T cells and high numbers of monocytes. Multiple Sclerosis 2007; 13: 459-470. http://msj.sagepub.com
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Affiliation(s)
- K Hamamcioglu
- Department of Neurology, Gülhane Military Medical Academy, Etlik, Ankara 06018, Turkey
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47
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Waxman SG. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 2007; 7:932-41. [PMID: 17115075 DOI: 10.1038/nrn2023] [Citation(s) in RCA: 286] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Multiple sclerosis (MS) is the most common cause of neurological disability in young adults. Recent studies have implicated specific sodium channel isoforms as having an important role in several aspects of the pathophysiology of MS, including the restoration of impulse conduction after demyelination, axonal degeneration and the mistuning of Purkinje neurons that leads to cerebellar dysfunction. By manipulating the activity of these channels or their expression, it might be possible to develop new therapeutic approaches that will prevent or limit disability in MS.
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Affiliation(s)
- Stephen G Waxman
- Department of Neurology and Center for Neuroscience and Regeneration Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.
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Lambiase A, Pagani L, Di Fausto V, Sposato V, Coassin M, Bonini S, Aloe L. Nerve growth factor eye drop administrated on the ocular surface of rodents affects the nucleus basalis and septum: biochemical and structural evidence. Brain Res 2006; 1127:45-51. [PMID: 17113055 DOI: 10.1016/j.brainres.2006.09.102] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2006] [Revised: 09/27/2006] [Accepted: 09/29/2006] [Indexed: 11/15/2022]
Abstract
It has been shown that conjunctivally applied NGF in rats can reach the retina and optic nerve. Whether topical eye NGF application reaches the central nervous system is not known. In the present study, we have addressed this question. It was found that topical eye NGF application affects brain cells. Time-course studies revealed that repeated NGF application leads to high concentration of this neurotrophins after 6 h and normal levels after 24 h. Our results also showed that topical eye application of NGF causes an enhanced expression of NGF receptors and ChAT immunoreactivity in forebrain cholinergic neurons, suggesting that ocular NGF application could have a functional role on damaged brain cells. The present findings suggest that eye NGF application can represent an alternative route to prevent degeneration of NGF-receptive neurons involved in disorders such as Alzheimer and Parkinson.
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Affiliation(s)
- Alessandro Lambiase
- Department of Ophthalmology, University Campus Bio-Medico, G. B. Bietti Eye Foundation, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
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Zhang HT, Li LY, Zou XL, Song XB, Hu YL, Feng ZT, Wang TTH. Immunohistochemical distribution of NGF, BDNF, NT-3, and NT-4 in adult rhesus monkey brains. J Histochem Cytochem 2006; 55:1-19. [PMID: 16899765 DOI: 10.1369/jhc.6a6952.2006] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Immunohistochemical distribution and cellular localization of neurotrophins was investigated in adult monkey brains using antisera against nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Western blot analysis showed that each antibody specifically recognized appropriate bands of approximately 14.7 kDa, 14.2 kDa, 13.6 kDa, and 14.5 kDa, for NGF, BDNF, NT-3, and NT-4, respectively. These positions coincided with the molecular masses of the neurotrophins studied. Furthermore, sections exposed to primary antiserum preadsorbed with full-length NGF, BDNF, NT-3, and NT-4 exhibited no detectable immunoreactivity, demonstrating specificities of the antibodies against the tissues prepared from rhesus monkeys. The study provided a systematic report on the distribution of NGF, BDNF, NT-3, and NT-4 in the monkey brain. Varying intensity of immunostaining was observed in the somata and processes of a wide variety of neurons and glial cells in the cerebrum, cerebellum, hippocampus, and other regions of the brain. Neurons in some regions such as the cerebral cortex and the hippocampus, which stained for neurotrophins, also expressed neurotrophic factor mRNA. In some other brain regions, there was discrepancy of protein distribution and mRNA expression reported previously, indicating a retrograde or anterograde action mode of neurotrophins. Results of this study provide a morphological basis for the elucidation of the roles of NGF, BDNF, NT-3, and NT-4 in adult primate brains.
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Affiliation(s)
- Hong-Tian Zhang
- Institute for Research on Neuroscience, Kunming Medical College, Kunming, China
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Küst B, Mantingh-Otter I, Boddeke E, Copray S. Deficient p75 low-affinity neurotrophin receptor expression does alter the composition of cellular infiltrate in experimental autoimmune encephalomyelitis in C57BL/6 mice. J Neuroimmunol 2006; 174:92-100. [PMID: 16519950 DOI: 10.1016/j.jneuroim.2006.01.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2005] [Revised: 01/17/2006] [Accepted: 01/30/2006] [Indexed: 11/28/2022]
Abstract
We have shown earlier that induction of experimental autoimmune encephalomyelitis (EAE)-a model for the human disease multiple sclerosis-in C57BL/6 wild-type mice resulted in the expression of the p75 low-affinity neurotrophin receptor (p75NTR) in endothelial cells in the CNS. In comparison to the clinical manifestation of EAE observed in wild-type C57BL/6 mice, C57BL/6 mice deficient for p75NTR (p75NTR knockout mice) developed a more severe or even lethal disease and concomitant increased levels of inflammation in the CNS. In order to elucidate the role of endothelial p75NTR in cellular infiltration under these pathological circumstances, we have performed a more detailed, quantitative examination of the composition of the cellular infiltrate invading the CNS in EAE wild-type and EAE p75NTR knockout mice. We compared spinal cords of EAE wild-type with those of EAE p75NTR knockout mice of the same clinical score (3.5) using immunohistochemical markers for the cell types present in the infiltratory cuffs in EAE: T-cells, B-cells, monocytes, microglia, resident and infiltrating macrophages and polymorphonuclear cells. Interestingly, we detected that the proportion of B-cells, cells of the monocyte-macrophage lineage and polymorphonuclear cells in the infiltratory cuff of EAE-p75NTR knockout mice was decreased at the account of the proportion of T-cells which appeared to be almost doubled in comparison to the EAE wild-type mice. The altered composition of the infiltrate in p75NTR deficient mice argues for an involvement of endothelial p75NTR in the interaction between the inflamed endothelium and the activated cells of the immune system, in particular the T-cells, in EAE.
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MESH Headings
- Analysis of Variance
- Animals
- Calcium-Binding Proteins/metabolism
- Cell Count/methods
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Fibronectins/metabolism
- Immunohistochemistry/methods
- Lymphocyte Activation
- Macrophages/metabolism
- Macrophages/pathology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Microfilament Proteins
- Microglia/metabolism
- Microglia/pathology
- Receptor, Nerve Growth Factor/deficiency
- Receptor, Nerve Growth Factor/metabolism
- T-Lymphocytes/metabolism
- T-Lymphocytes/pathology
- Time Factors
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Affiliation(s)
- Britta Küst
- Department of Medical Physiology, University Medical Centre Groningen, University of Groningen, A.Deusinglaan 1, 9713 AV Groningen KZ, Netherlands
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