28 results on '"Fabian Szepanowski"'
Search Results
2. Enhancement of Heme-Oxygenase 1 in the Injured Peripheral Nerve Following Sulforaphane Administration Fosters Regeneration via Proliferation and Maintenance of Repair Schwann Cells
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Fabian Szepanowski, Jaqueline Zipfel, Rebecca D. Szepanowski, Bianca Eggert, Nail-Mert Güner, Leon-Phillip Szepanowski, Christoph Kleinschnitz, Anne K. Mausberg, and Mark Stettner
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HO-1 ,Nrf2 ,nerve injury ,nerve crush ,sulforaphane ,broccoli extract ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Nuclear erythroid 2-related factor 2 (Nrf2) and its downstream effector heme oxygenase 1 (HO-1) are commonly activated in response to cellular stresses. The elevated expression of HO-1 has been associated with markedly accelerated peripheral nerve regeneration. This study aimed to evaluate the impact of a naturally occurring dietary Nrf2/HO-1 activator—sulforaphane (SFN)—on regeneration in a murine sciatic nerve crush model. The beneficial safety profile of SFN has been thoroughly investigated and confirmed several times. Here, SFN was administered daily, starting immediately after C57BL/6 mice were subjected to sciatic nerve crush injury. Injured sciatic nerves were excised at various time points post injury for molecular, immunohistochemical and morphometric analyses. Moreover, functional assessment was performed by grip strength analysis and electrophysiology. Following SFN treatment, the early response to injury includes a modulation of autophagic pathways and marked upregulation of Nrf2/HO-1 expression. This enhancement of HO-1 expression was maintained throughout the regeneration phase and accompanied by a significant increase in repair Schwann cells. In these cells, elevated proliferation rates were observed. Significant improvements in grip strength test performance, nerve conduction velocity and remyelination were also noted following SFN treatment. Collectively, SFN modulates cytoprotective and autophagic pathways in the injured nerve, increasing the number of repair Schwann cells and contributing to effective nerve regeneration. Given the availability of SFN as a nutritional supplement, this compound might constitute a novel regenerative approach with broad patient accessibility and further studies on this topic are warranted.
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- 2024
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3. Cytokines (IL1β, IL6, TNFα) and serum cortisol levels may not constitute reliable biomarkers to identify individuals with post-acute sequelae of COVID-19
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Michael Fleischer, Fabian Szepanowski, Anne K Mausberg, Livia Asan, Ellen Uslar, Denise Zwanziger, Lothar Volbracht, Mark Stettner, and Christoph Kleinschnitz
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: Post-acute sequelae of COVID-19 (PASC) comprise a broad spectrum of symptoms such as fatigue, general weakness, compromised attention and sleep or anxiety disorders. PASC represents a medical and socio-economic challenge. Objectives: Our study evaluated cytokines (IL-1β, IL-6 and TNFα) and cortisol levels in a cohort of typical patients with PASC, suffering concentration problems, fatigue and difficulties finding words. Design: This was a prospective cohort study. Four groups were analysed and compared: those who had never contracted SARS-CoV-2 ( n = 13), infected but had no PASC ( n = 34), infected with former PASC that resolved ( n = 40) and patients with ongoing PASC after infection ( n = 91). Methods: Cytokine and cortisol serum levels were determined in patients’ blood samples. Results: Cytokine levels of IL-1β, IL-6, TNFα and cortisol levels did not differ between groups analysed. Conclusion: This may indicate a non-organic/psychosomatic genesis of PASC; further studies are needed to elucidate the underlying causes of PACS, and non-organic causes should not be overlooked.
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- 2024
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4. Time for a standardized diagnostic response test in patients with chronic inflammatory demyelinating polyradiculoneuropathy?
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Fabian Szepanowski, Benedikt Schoser, Anne K. Mausberg, Christoph Kleinschnitz, Hans‐Peter Hartung, and Mark Stettner
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CIDP ,dosing ,efficacy ,intravenous immunoglobulin ,therapy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2023
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5. Severe and long-lasting alteration of albumin redox state by plasmapheresis
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Kristina Boss, Mark Stettner, Fabian Szepanowski, Anne K. Mausberg, Margret Paar, Refik Pul, Christoph Kleinschnitz, Karl Oettl, and Andreas Kribben
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Medicine ,Science - Abstract
Abstract Plasmapheresis (PE) is an established form of therapeutic apheresis (TA). Purpose of this longitudinal prospective single center study was to investigate the effect of PE on albumin redox state (ARS), as infusion of commercial albumin during PE may alter albumin oxidation which has an impact on its functional properties and oxidative stress level. 43 subjects with autoimmune-mediated neurological disorders were included. 20 subjects in the experimental group received five treatments of PE. 13 subjects received five treatments of immunoadsorption and 10 subjects received no TA as controls. ARS was determined before and after TA and 12 days after the last TA by fractionating it into human mercaptalbumin (HMA), human non-mercaptalbumin 1 (HNA-1), and human non-mercaptalbumin 2 (HNA-2) by high-performance liquid chromatography. Irreversibly oxidised HNA-2 increased over the course of five PE treatments from 2.8% (IQR 1.3–3.7%) to 13.6% (IQR 10.9–15.9) (P
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- 2022
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6. LPA1 signaling drives Schwann cell dedifferentiation in experimental autoimmune neuritis
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Fabian Szepanowski, Maximilian Winkelhausen, Rebecca D. Steubing, Anne K. Mausberg, Christoph Kleinschnitz, and Mark Stettner
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Lysophosphatidic acid (LPA) ,Experimental autoimmune neuritis (EAN) ,Inflammatory neuropathy ,Guillain–Barré-syndrome ,Schwann cell ,Differentiation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Lysophosphatidic acid (LPA) is a pleiotropic lipid messenger that addresses at least six specific G-protein coupled receptors. Accumulating evidence indicates a significant involvement of LPA in immune cell regulation as well as Schwann cell physiology, with potential relevance for the pathophysiology of peripheral neuroinflammation. However, the role of LPA signaling in inflammatory neuropathies has remained completely undefined. Given the broad expression of LPA receptors on both Schwann cells and cells of the innate and adaptive immune system, we hypothesized that inhibition of LPA signaling may ameliorate the course of disease in experimental autoimmune neuritis (EAN). Methods We induced active EAN by inoculation of myelin protein 2 peptide (P255–78) in female Lewis rats. Animals received the orally available LPA receptor antagonist AM095, specifically targeting the LPA1 receptor subtype. AM095 was administered daily via oral gavage in a therapeutic regimen from 10 until 28 days post-immunization (dpi). Analyses were based on clinical testing, hemogram profiles, immunohistochemistry and morphometric assessment of myelination. Results Lewis rats treated with AM095 displayed a significant improvement in clinical scores, most notably during the remission phase. Cellular infiltration of sciatic nerve was only discretely affected by AM095. Hemogram profiles indicated no impact on circulating leukocytes. However, sciatic nerve immunohistochemistry revealed a reduction in the number of Schwann cells expressing the dedifferentiation marker Sox2 paralleled by a corresponding increase in differentiating Sox10-positive Schwann cells. In line with this, morphometric analysis of sciatic nerve semi-thin sections identified a significant increase in large-caliber myelinated axons at 28 dpi. Myelin thickness was unaffected by AM095. Conclusion Thus, LPA1 signaling may present a novel therapeutic target for the treatment of inflammatory neuropathies, potentially affecting regenerative responses in the peripheral nerve by modulating Schwann cell differentiation.
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- 2021
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7. Platelet depletion does not alter long-term functional outcome after cerebral ischaemia in mice
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Rebecca D. Steubing, Fabian Szepanowski, Christina David, Ayan Mohamud Yusuf, Stine Mencl, Anne-Kathrin Mausberg, Harald F. Langer, Manuela Sauter, Cornelius Deuschl, Michael Forsting, Anke C. Fender, Dirk M. Hermann, Ana I. Casas, Friederike Langhauser, and Christoph Kleinschnitz
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Behaviour ,Cerebral ischaemia ,Long-term ,Platelet depletion ,tMCAO ,Stroke ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Platelets are key mediators of thrombus formation and inflammation during the acute phase of ischaemic stroke. Particularly, the platelet glycoprotein (GP) receptors GPIbα and GPVI have been shown to mediate platelet adhesion and activation in the ischaemic brain. GPIbα and GPVI blockade could reduce infarct volumes and improve functional outcome in mouse models of acute ischaemic stroke, without concomitantly increasing intracerebral haemorrhage. However, the functional role of platelets during long-term stroke recovery has not been elucidated so far.Thus, we here examined the impact of platelet depletion on post-stroke recovery after transient middle cerebral artery occlusion (tMCAO) in adult male mice. Platelet depleting antibodies or isotype control were applied from day 3–28 after tMCAO in mice matched for infarct size. Long-term functional recovery was assessed over the course of 28 days by behavioural testing encompassing motor and sensorimotorical functions, as well as anxiety-like or spontaneous behaviour. Whole brain flow cytometry and light sheet fluorescent microscopy were used to identify resident and infiltrated immune cell types, and to determine the effects of platelet depletion on the cerebral vascular architecture, respectively.We found that delayed platelet depletion does not improve long-term functional outcome in the tMCAO stroke model. Immune cell abundance, the extent of thrombosis and the organisation of the cerebral vasculature were also comparable between platelet-depleted and control mice. Our study demonstrates that, despite their critical role in the acute stroke setting, platelets appear to contribute only marginally to tissue reorganisation and functional recovery at later stroke stages.
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- 2022
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8. Focus on LPA signaling: a promising therapeutic target to foster regeneration in immune-mediated neuropathies
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Fabian Szepanowski and Mark Stettner
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2023
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9. High-dose biotin neither fosters remyelination nor stimulates malonyl coenzyme A synthesis in the regenerating nerve
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Fabian Szepanowski, Rebecca D Steubing, Cansu Güngör, Jaqueline Zipfel, Anne K Mausberg, Christoph Kleinschnitz, and Mark Stettner
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2023
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10. Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection
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Michael Fleischer, Martin Köhrmann, Sebastian Dolff, Fabian Szepanowski, Karsten Schmidt, Frank Herbstreit, Cansu Güngör, Benjamin Stolte, Katharina Marie Steiner, Christine Stadtler, Joachim Riße, Melanie Fiedler, Gerd Meyer zu Hörste, Anne-K. Mausberg, Clemens Kill, Michael Forsting, Ulrich Sure, Ulf Dittmer, Oliver Witzke, Thorsten Brenner, Christoph Kleinschnitz, and Mark Stettner
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background: A growing number of reports suggest that infection with SARS-CoV-2 often leads to neurological involvement; however, data on the incidence and severity are limited to mainly case reports and retrospective studies. Methods: This prospective, cross-sectional study of 102 SARS-CoV-2 PCR positive patients investigated the frequency, type, severity and risk factors as well as underlying pathophysiological mechanisms of neurological involvement (NIV) in COVID-19 patients. Results: Across the cohort, 59.8% of patients had NIV. Unspecific NIV was suffered by 24.5%, mainly general weakness and cognitive decline or delirium. Mild NIV was found in 9.8%; most commonly, impaired taste or smell. Severe NIV was present in 23.5%; half of these suffered cerebral ischaemia. Incidence of NIV increased with respiratory symptoms of COVID-19. Mortality was higher with increasing NIV severity. Notably, 83.3% with severe NIV had a pre-existing neurological co-morbidity. All cerebrospinal fluid (CSF) samples were negative for SARS-CoV-2 RNA, and SARS-CoV-2 antibody quotient did not suggest intrathecal antibody synthesis. Of the patients with severe NIV, 50% had blood–brain barrier (BBB) disruption and showed a trend of elevated interleukin levels in CSF. Antibodies against neuronal and glial epitopes were detected in 35% of the patients tested. Conclusion: Cerebrovascular events were the most frequent severe NIV and severe NIV was associated with high mortality. Incidence of NIV increased with respiratory symptoms and NIV and pre-existing neurological morbidities were independent risk factors for fatality. Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather than direct viral invasion. These findings might help physicians define a further patient group requiring particular attention during the pandemic.
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- 2021
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11. Trapped in the epineurium: early entry into the endoneurium is restricted to neuritogenic T cells in experimental autoimmune neuritis
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Anne K. Mausberg, Fabian Szepanowski, Francesca Odoardi, Alexander Flügel, Christoph Kleinschnitz, Mark Stettner, and Bernd C. Kieseier
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Neuritogenic T cells ,Experimental autoimmune neuritis ,Guillain-Barré syndrome ,GBS ,Chronic inflammatory demyelinating neuropathy ,CIDP ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Autoimmune polyneuropathies are acquired inflammatory disorders of the peripheral nervous system (PNS) characterized by inflammation, demyelination, and axonal degeneration. Although the pathogenesis has not been fully elucidated, T cells recognizing self-antigens are believed to initiate inflammation in a subgroup of patients. However, the route and time of T cell entry into the PNS have not yet been described in detail. In this study, we analyzed both kinetics as well as localization of retrovirally transfected green fluorescent protein (GFP)-expressing neuritogenic T lymphocytes in experimental autoimmune neuritis (EAN). Methods T lymphocytes obtained from rats following EAN induction by immunization with peripheral nerve protein peptide P255–78 were retrovirally engineered to express GFP. Non-specific T cells were negatively selected by in vitro restimulation, whereas GFP-expressing neuritogenic T cells (reactive to P255–78) were adoptively transferred into healthy rats (AT-EAN). Antigen-specific T cell tracking and localization was performed by flow cytometry and immunohistochemistry during the course of disease. Results After induction of autoimmune neuritis, P2-reactive T cells were detectable in the liver, spleen, lymph nodes, lung, peripheral blood, and the sciatic nerves with distinct kinetics. A significant number of GFP+ T cells appeared early in the lung with a peak at day four. In the peripheral nerves within the first days, GFP-negative T cells rapidly accumulated and exceeded the number of GFP-expressing cells, but did not enter the endoneurium. Very early after adoptive transfer, T cells are found in proximity to peripheral nerves and in the epineurium. However, only GFP-expressing neuritogenic T cells are able to enter the endoneurium from day five after transfer. Conclusions Our findings suggest that neuritogenic T cells invade the PNS early in the course of disease. However, neuritogenic T cells cross the blood-nerve barrier with a certain delay without preference to dorsal roots. Further understanding of the pathophysiological role of autoagressive T cells may help to improve therapeutic strategies in immune-mediated neuropathies.
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- 2018
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12. Glyphosate-based herbicide: a risk factor for demyelinating conditions of the peripheral nervous system?
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Fabian Szepanowski, Christoph Kleinschnitz, and Mark Stettner
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2019
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13. Targeting lysophospholipid signaling as a therapeutic approach towards improved peripheral nerve regeneration
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Fabian Szepanowski and Bernd C Kieseier
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2016
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14. Secondary Immunodeficiency and Risk of Infection Following Immune Therapies in Neurology
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Christoph Kleinschnitz, Gerd Meyer zu Hörste, Anne K. Mausberg, Mark Stettner, Fabian Szepanowski, Clemens Warnke, and Hans-Peter Hartung
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medicine.medical_specialty ,Dimethyl Fumarate ,Medizin ,Chronic inflammatory demyelinating polyneuropathy ,Review Article ,Infections ,Pharmacotherapy ,Natalizumab ,Risk Factors ,medicine ,Animals ,Humans ,Immunologic Factors ,Pharmacology (medical) ,Risk factor ,Intensive care medicine ,Alemtuzumab ,business.industry ,Coinfection ,Fingolimod Hydrochloride ,Multiple sclerosis ,Age Factors ,medicine.disease ,Fingolimod ,Psychiatry and Mental health ,Neurology ,Immunoglobulin G ,Rituximab ,Neurology (clinical) ,Immunotherapy ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Secondary immunodeficiencies (SIDs) are acquired conditions that may occur as sequelae of immune therapy. In recent years a number of disease-modifying therapies (DMTs) has been approved for multiple sclerosis and related disorders such as neuromyelitis optica spectrum disorders, some of which are frequently also used in- or off-label to treat conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, myositis, and encephalitis. In this review, we focus on currently available immune therapeutics in neurology to explore their specific modes of action that might contribute to SID, with particular emphasis on their potential to induce secondary antibody deficiency. Considering evidence from clinical trials as well as long-term observational studies related to the patients’ immune status and risks of severe infections, we delineate long-term anti-CD20 therapy, with the greatest data availability for rituximab, as a major risk factor for the development of SID, particularly through secondary antibody deficiency. Alemtuzumab and cladribine have relevant effects on circulating B-cell counts; however, evidence for SID mediated by antibody deficiency appears limited and urgently warrants further systematic evaluation. To date, there has been no evidence suggesting that treatment with fingolimod, dimethyl fumarate, or natalizumab leads to antibody deficiency. Risk factors predisposing to development of SID include duration of therapy, increasing age, and pre-existing low immunoglobulin (Ig) levels. Prevention strategies of SID comprise awareness of risk factors, individualized treatment protocols, and vaccination concepts. Immune supplementation employing Ig replacement therapy might reduce morbidity and mortality associated with SIDs in neurological conditions. In light of the broad range of existing and emerging therapies, the potential for SID warrants urgent consideration among neurologists and other healthcare professionals.
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- 2021
15. Neurological Manifestations of COVID-19 Feature T Cell Exhaustion and Dedifferentiated Monocytes in Cerebrospinal Fluid
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Michael Fleischer, Saskia Räuber, Thorsten Brenner, Nir Yosef, Anne K. Mausberg, Fabian Szepanowski, Xiaolin Li, Michael Heming, Gerd Meyer zu Hörste, Arpita Singhal, Heinz Wiendl, I-Na Lu, Ulf Dittmer, Anna-Lena Börsch, Oliver Witzke, Christoph Kleinschnitz, Maike Hartlehnert, and Mark Stettner
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0301 basic medicine ,T-Lymphocytes ,T cell ,Cellular differentiation ,Cell ,Immunology ,Receptors, Antigen, T-Cell ,Medizin ,neurological manifestation ,Biology ,Lymphocyte Activation ,Article ,single-cell RNA sequencing ,cerebrospinal fluid ,Monocytes ,transcriptomics ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cerebrospinal fluid ,interferon-stimulated genes ,Neuro-COVID ,Interferon ,Leukocytes ,medicine ,Humans ,Immunology and Allergy ,Encephalitis, Viral ,T cell exhaustion ,SARS-CoV-2 ,Gene Expression Profiling ,Viral encephalitis ,COVID-19 ,Cell Differentiation ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Infectious Diseases ,030220 oncology & carcinogenesis ,Etiology ,Interferons ,Nervous System Diseases ,Single-Cell Analysis ,medicine.drug - Abstract
Patients suffering from Coronavirus disease 2019 (COVID-19) can develop neurological sequelae, such as headache and neuroinflammatory or cerebrovascular disease. These conditions—termed here as Neuro-COVID—are more frequent in patients with severe COVID-19. To understand the etiology of these neurological sequelae, we utilized single-cell sequencing and examined the immune cell profiles from the cerebrospinal fluid (CSF) of Neuro-COVID patients compared with patients with non-inflammatory and autoimmune neurological diseases or with viral encephalitis. The CSF of Neuro-COVID patients exhibited an expansion of dedifferentiated monocytes and of exhausted CD4+ T cells. Neuro-COVID CSF leukocytes featured an enriched interferon signature; however, this was less pronounced than in viral encephalitis. Repertoire analysis revealed broad clonal T cell expansion and curtailed interferon response in severe compared with mild Neuro-COVID patients. Collectively, our findings document the CSF immune compartment in Neuro-COVID patients and suggest compromised antiviral responses in this setting., Graphical Abstract, Highlights • Single-cell atlas of cerebrospinal fluid in Neuro-COVID and controls • Expansion of dedifferentiated monocytes and exhausted CD4+ T cells in Neuro-COVID • Less pronounced interferon signature in Neuro-COVID than in viral encephalitis • Curtailed interferon-response in severe Neuro-COVID, Neurological manifestations associated with COVID-19 (Neuro-COVID) are recognized but under-studied. Using single-cell transcriptomics, Heming et al. identify expansion of dedifferentiated monocytes and exhausted CD4+ T cells in the cerebral spinal fluid of Neuro-COVID patients. This work provides a basis for improved understanding of the neurological sequelae associated with COVID-19.
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- 2021
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16. Observational cohort study of neurological involvement among patients with SARS-CoV-2 infection
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Michael, Fleischer, Martin, Köhrmann, Sebastian, Dolff, Fabian, Szepanowski, Karsten, Schmidt, Frank, Herbstreit, Cansu, Güngör, Benjamin, Stolte, Katharina Marie, Steiner, Christine, Stadtler, Joachim, Riße, Melanie, Fiedler, Gerd, Meyer Zu Hörste, Anne-K, Mausberg, Clemens, Kill, Michael, Forsting, Ulrich, Sure, Ulf, Dittmer, Oliver, Witzke, Thorsten, Brenner, Christoph, Kleinschnitz, and Mark, Stettner
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Cerebrovascular events ,Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Neurologie ,Medizin ,COVID-19 ,Medizinische Fakultät » Universitätsklinikum Essen » Institut für Virologie ,lcsh:RC346-429 ,Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Infektiologie ,Medizinische Fakultät » Universitätsklinikum Essen » Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie ,Neuro-COVID ,Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Neurochirurgie Wirbelsäulenchirurgie ,ddc:610 ,Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Anästhesiologie und Intensivmedizin ,lcsh:Neurology. Diseases of the nervous system ,Original Research - Abstract
Background: A growing number of reports suggest that infection with SARS-CoV-2 often leads to neurological involvement; however, data on the incidence and severity are limited to mainly case reports and retrospective studies. Methods: This prospective, cross-sectional study of 102 SARS-CoV-2 PCR positive patients investigated the frequency, type, severity and risk factors as well as underlying pathophysiological mechanisms of neurological involvement (NIV) in COVID-19 patients. Results: Across the cohort, 59.8% of patients had NIV. Unspecific NIV was suffered by 24.5%, mainly general weakness and cognitive decline or delirium. Mild NIV was found in 9.8%; most commonly, impaired taste or smell. Severe NIV was present in 23.5%; half of these suffered cerebral ischaemia. Incidence of NIV increased with respiratory symptoms of COVID-19. Mortality was higher with increasing NIV severity. Notably, 83.3% with severe NIV had a pre-existing neurological co-morbidity. All cerebrospinal fluid (CSF) samples were negative for SARS-CoV-2 RNA, and SARS-CoV-2 antibody quotient did not suggest intrathecal antibody synthesis. Of the patients with severe NIV, 50% had blood–brain barrier (BBB) disruption and showed a trend of elevated interleukin levels in CSF. Antibodies against neuronal and glial epitopes were detected in 35% of the patients tested. Conclusion: Cerebrovascular events were the most frequent severe NIV and severe NIV was associated with high mortality. Incidence of NIV increased with respiratory symptoms and NIV and pre-existing neurological morbidities were independent risk factors for fatality. Inflammatory involvement due to BBB disruption and cytokine release drives NIV, rather than direct viral invasion. These findings might help physicians define a further patient group requiring particular attention during the pandemic. OA Förderung 2021
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- 2021
17. Lysophosphatidic acid propagates post-injury Schwann cell dedifferentiation through LPA1 signaling
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Mark Stettner, Leon-Phillip Szepanowski, Anne K. Mausberg, Christoph Kleinschnitz, Bernd C. Kieseier, and Fabian Szepanowski
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0301 basic medicine ,Wallerian degeneration ,Medizin ,Schwann cell ,03 medical and health sciences ,Myelin ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Lysophosphatidic acid ,medicine ,biology ,General Neuroscience ,Nerve injury ,medicine.disease ,Myelin basic protein ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,chemistry ,Immunology ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Schwann cell differentiation ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Lysophosphatidic acid (LPA) is a pleiotropic signaling lipid that acts as ligand for at least six specific G-protein coupled receptors. Schwann cells (SC) are known to mainly express the LPA1 receptor subtype. An emerging body of evidence has linked LPA with injury-induced peripheral nerve demyelination as well as neuropathic pain. However, the molecular mechanisms underlying its demyelinating effect have not been conclusively elucidated. We aimed to decipher the demyelinating effect in vitro as well as in vivo by studying markers of SC differentiation and dedifferentiation: Myelinated dorsal root ganglia (DRG) cultures were treated either with LPA, LPA plus AM095 (LPA1 antagonist) or vehicle. Myelin content was subsequently investigated by Sudan Black staining and immunocytochemistry. In vivo, we performed sciatic nerve crush in C57BL/6 mice treated with AM095 at 10mg/kg. In DRG cultures, LPA caused a significant reduction of myelin as demonstrated by both Sudan Black staining and immunocytochemical analysis of myelin basic protein. Demyelination was paralleled by an upregulation of TNF-alpha as well as downregulation of Sox10, a marker for SC differentiation. LPA mediated effects were largely blocked by the addition of the LPA1 receptor antagonist AM095. In the in vivo model, AM095 treatment prior to crush injury increased Sox10 expression in SCs in the distal nerve stump while reducing the number of cells expressing the SC dedifferentiation marker Sox2. Additionally, TNF-alpha immunofluorescence was reduced in CD11b-positive cells. These data indicate that LPA may be a critical factor that shifts SCs towards a post-injury phenotype and contributes to the onset of Wallerian degeneration.
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- 2018
18. Glyphosate-based herbicide: a risk factor for demyelinating conditions of the peripheral nervous system?
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Christoph Kleinschnitz, Mark Stettner, and Fabian Szepanowski
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Medizin ,Risk factor (computing) ,Biology ,Bioinformatics ,lcsh:RC346-429 ,chemistry.chemical_compound ,medicine.anatomical_structure ,Developmental Neuroscience ,chemistry ,Peripheral nervous system ,Glyphosate ,Perspective ,medicine ,lcsh:Neurology. Diseases of the nervous system - Abstract
CA - Szepanowski
- Published
- 2019
19. Neuronal ADAM10 Promotes Outgrowth of Small-Caliber Myelinated Axons in the Peripheral Nervous System
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Melissa Thanos, Angelika Derksen, Fabian Szepanowski, Gerd Meyer zu Hörste, Ruth M. Stassart, Helmar C. Lehmann, Hans-Peter Hartung, Christina Boettcher, Bernd C. Kieseier, and Mark Stettner
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Nervous system ,Cell signaling ,ADAM10 ,Neural Conduction ,Action Potentials ,Mice, Transgenic ,In Vitro Techniques ,Nerve Fibers, Myelinated ,Pathology and Forensic Medicine ,ADAM10 Protein ,Mice ,Cellular and Molecular Neuroscience ,Organ Culture Techniques ,Ganglia, Spinal ,Peripheral Nervous System ,medicine ,Disintegrin ,Animals ,Remyelination ,Motor Neurons ,Hand Strength ,biology ,Membrane Proteins ,General Medicine ,Sciatic Nerve ,ADAM Proteins ,Axons ,Nerve Regeneration ,Disease Models, Animal ,Microscopy, Electron ,medicine.anatomical_structure ,nervous system ,Neurology ,Peripheral nervous system ,biology.protein ,Neurology (clinical) ,Amyloid Precursor Protein Secretases ,Sciatic Neuropathy ,Signal transduction ,Neuroscience - Abstract
The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases.
- Published
- 2015
20. Dimethyl fumarate accelerates peripheral nerve regeneration via activation of the anti-inflammatory and cytoprotective Nrf2/HO-1 signaling pathway
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Mark Stettner, Anne K. Mausberg, Christoph Kleinschnitz, Hans-Peter Hartung, Bernd C. Kieseier, Daniel M Donaldson, and Fabian Szepanowski
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0301 basic medicine ,NF-E2-Related Factor 2 ,medicine.drug_class ,Dimethyl Fumarate ,Medizin ,Anti-Inflammatory Agents ,Anti-inflammatory ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Peripheral nerve ,Malondialdehyde ,medicine ,Animals ,Muscle Strength ,Dimethyl fumarate ,Regeneration (biology) ,Membrane Proteins ,Recovery of Function ,Sciatic Nerve ,Nerve Regeneration ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,Neuroprotective Agents ,030104 developmental biology ,Membrane protein ,chemistry ,Biochemistry ,Nrf2 ho 1 ,Neurology (clinical) ,Sciatic nerve ,Signal transduction ,Heme Oxygenase-1 ,030217 neurology & neurosurgery ,Signal Transduction - Published
- 2017
21. NK cell markers predict the efficacy of IV immunoglobulins in CIDP
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Mark Stettner, Michael Fleischer, Bernd C. Kieseier, Steffen Cordes, Hans-Peter Hartung, Maximilian K. Heininger, Fabian Szepanowski, Anne K. Mausberg, Christoph Kleinschnitz, and Gerd Meyer zu Hörste
- Subjects
Adult ,Male ,Cell ,Population ,Medizin ,Chronic inflammatory demyelinating polyneuropathy ,Stem cell marker ,Article ,Flow cytometry ,hemic and lymphatic diseases ,Outcome Assessment, Health Care ,medicine ,Humans ,Immunologic Factors ,Cytotoxic T cell ,Longitudinal Studies ,Mode of action ,education ,Aged ,education.field_of_study ,Predictive marker ,medicine.diagnostic_test ,business.industry ,Immunoglobulins, Intravenous ,Middle Aged ,medicine.disease ,CD56 Antigen ,Killer Cells, Natural ,medicine.anatomical_structure ,Polyradiculoneuropathy, Chronic Inflammatory Demyelinating ,Neurology ,Immunology ,Female ,Neurology (clinical) ,business ,Biomarkers - Abstract
ObjectiveTo assess whether IV immunoglobulins (IVIgs) as a first-line treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) have a regulative effect on natural killer (NK) cells that is related to clinical responsiveness to IVIg.MethodsIn a prospective longitudinal study, we collected blood samples of 29 patients with CIDP before and after initiation of IVIg treatment for up to 6 months. We used semiquantitative PCR and flow cytometry in the peripheral blood to analyze the effects of IVIg on the NK cells. The results were correlated with clinical aspects encompassing responsiveness.ResultsWe found a reduction in the expression of several typical NK cell genes 1 day after IVIg administration. Flow cytometry furthermore revealed a reduced cytotoxic CD56dim NK cell population, whereas regulatory CD56bright NK cells remained mostly unaffected or were even increased after IVIg treatment. Surprisingly, the observed effects on NK cells almost exclusively occurred in IVIg-responsive patients with CIDP.ConclusionsThe correlation between the altered NK cell population and treatment efficiency suggests a crucial role for NK cells in the still speculative mode of action of IVIg treatment. Analyzing NK cell subsets after 24 hours of treatment initiation appeared as a predictive marker for IVIg responsiveness. Further studies are warranted investigating the potential of NK cell status as a routine parameter in patients with CIDP before IVIg therapy.Classification of evidenceThis study provides Class I evidence that NK cell markers predict clinical response to IVIg in patients with CIDP.
- Published
- 2020
22. The Role of Peripheral Myelin Protein 2 in Remyelination
- Author
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Christoph Kleinschnitz, Hans Hartung, Fabian Szepanowski, Anne K. Mausberg, Bernd C. Kieseier, Fabian Klingler, Roman Chrast, Mark Stettner, and Jennifer Zenker
- Subjects
0301 basic medicine ,Neural Conduction ,Medizin ,Biology ,Myelin P2 Protein ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Myelin ,0302 clinical medicine ,In vivo ,medicine ,Animals ,Remyelination ,Mice, Knockout ,Cell Biology ,General Medicine ,PMP2 ,Coculture Techniques ,Peripheral ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Peripheral nervous system ,Schwann Cells ,Sciatic Neuropathy ,NODAL ,Neuroscience ,030217 neurology & neurosurgery ,Ex vivo - Abstract
The protein component of the myelin layer is essential for all aspects of peripheral nerves, and its deficiency can lead to structural and functional impairment. The presence of peripheral myelin protein 2 (P2, PMP2, FABP8, M-FABP) in Schwann cells has been known for decades and shown recently to be involved in the lipid homeostasis in the peripheral neural system. However, its precise role during de- and remyelination has yet to be elucidated. To this end, we assessed remyelination after sciatic nerve crush injury in vivo, and in an experimental de/remyelination ex vivo myelinating culture model in P2-deficient (P2 -/- ) and wild-type (WT) animals. In vivo, the nerve crush paradigm revealed temporal structural and functional changes in P2 -/- mice as compared to WT animals. Concomitantly, P2 -/- DRG cultures demonstrated the presence of shorter internodes and enlarged nodes after ex vivo de/remyelination. Together, these data indicate that P2 may play a role in remyelination of the injured peripheral nervous system, presumably by affecting the nodal and internodal configuration.
- Published
- 2018
23. Differential impact of pure glyphosate and glyphosate-based herbicide in a model of peripheral nervous system myelination
- Author
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Anne K. Mausberg, Christoph Kleinschnitz, Mark Stettner, Fabian Szepanowski, Bernd C. Kieseier, Leon-Phillip Szepanowski, and Philipp Albrecht
- Subjects
0301 basic medicine ,Organ Culture Technique ,Drug ,In Vitro Techniques ,media_common.quotation_subject ,Glycine ,Intermediate Filaments ,Medizin ,010501 environmental sciences ,Biology ,Pharmacology ,Nitric Oxide ,01 natural sciences ,Pathology and Forensic Medicine ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Organ Culture Techniques ,Ganglia, Spinal ,Neurites ,medicine ,Animals ,Myelin Sheath ,0105 earth and related environmental sciences ,Differential impact ,media_common ,Dose-Response Relationship, Drug ,Propylamines ,Herbicides ,Tumor Necrosis Factor-alpha ,S100 Proteins ,Peripheral Nervous System Diseases ,Myelin Basic Protein ,Embryo ,Embryo, Mammalian ,Nitric oxide metabolism ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Glyphosate ,Peripheral nervous system ,Lipid Peroxidation ,Schwann Cells ,Neurology (clinical) - Published
- 2018
24. Lysophosphatidic acid propagates post-injury Schwann cell dedifferentiation through LPA
- Author
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Fabian, Szepanowski, Leon-Phillip, Szepanowski, Anne K, Mausberg, Christoph, Kleinschnitz, Bernd C, Kieseier, and Mark, Stettner
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Male ,Mice, Inbred C57BL ,Ganglia, Spinal ,Animals ,Cell Differentiation ,Schwann Cells ,Lysophospholipids ,Receptors, Lysophosphatidic Acid ,Wallerian Degeneration ,Sciatic Nerve ,Cells, Cultured ,Myelin Sheath ,Signal Transduction - Abstract
Lysophosphatidic acid (LPA) is a pleiotropic signaling lipid that acts as ligand for at least six specific G-protein coupled receptors. Schwann cells (SC) are known to mainly express the LPA
- Published
- 2017
25. Targeting lysophospholipid signaling as a therapeutic approach towards improved peripheral nerve regeneration
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Bernd C. Kieseier and Fabian Szepanowski
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0301 basic medicine ,business.industry ,Regeneration (biology) ,lcsh:RC346-429 ,03 medical and health sciences ,Therapeutic approach ,030104 developmental biology ,0302 clinical medicine ,Text mining ,Developmental Neuroscience ,Peripheral nerve ,Perspective ,Medicine ,business ,Neuroscience ,lcsh:Neurology. Diseases of the nervous system ,030217 neurology & neurosurgery - Published
- 2017
26. EP 12. Fingolimod promotes nerve regeneration by modulating Lysophospholipid signaling
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Angelika Derksen, Fabian Szepanowski, B. C. Kieseier, G. Meyer zu Hörste, H.-P. Hartung, Thomas Daldrup, and I. Steiner
- Subjects
Cell signaling ,Sphingosine-1-phosphate receptor ,Fingolimod ,Sensory Systems ,Cell biology ,Myelin ,chemistry.chemical_compound ,medicine.anatomical_structure ,Neurology ,chemistry ,Physiology (medical) ,Peripheral nervous system ,Immunology ,Lysophosphatidic acid ,medicine ,lipids (amino acids, peptides, and proteins) ,Neurology (clinical) ,Sciatic nerve ,Autotaxin ,medicine.drug - Abstract
The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P 1 receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatment of multiple sclerosis. An emerging body of experimental evidence points to additional direct effects on cells of the central and peripheral nervous system. Furthermore, fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Here we investigated whether modulation of particular signaling aspects of S1P as well as LPA by fingolimod might propagate peripheral nerve regeneration in vivo and independent of its anti-inflammatory potency. To distinguish potential direct nerve specific effects from the established immunosuppressive action of fingolimod, we performed sciatic nerve crush in wildtype C57BL/6 as well as in immunodeficient Rag 1 - / - and Foxn 1 - / - mice. Analyses were based on walking track analysis and electrophysiology, histology, cAMP formation as well as oxidative stress assessment by dinitrophenyl-labeling of free protein carbonyls. Quantification of different LPA species was performed by liquid chromatography coupled to tandem mass spectrometry. Furthermore, functional consequences of LPA level reduction by the autotaxin inhibitor PF-8380 were investigated. Clinical, electrophysiological and histological measures indicated an improvement of nerve regeneration under fingolimod treatment that is partly independent of its anti-inflammatory properties. Fingolimod induced an elevation of axonal cAMP, a crucial factor for axonal outgrowth. Consistently, immunohistochemistry indicated S1P 1 receptor internalization in cells of the sciatic nerve. Additionally, fingolimod attenuated oxidative tissue damage and significantly reduced LPA levels in the injured nerve. PF-8380 induced reduction of LPA levels correlated with improved myelin thickness. Collectively, our work demonstrates that modulation of lysophospholipid signaling in the peripheral nervous system by fingolimod may enhance nerve regeneration by acting on multiple molecular and cellular levels and partly independent of its anti-inflammatory effects. In addition to the established role of fingolimod as a modulator of S1P receptor mediated signaling, the inhibition of LPA synthesis may represent a yet unrecognized mechanism that contributes to the presumptive remyelinating effect of fingolimod.
- Published
- 2016
27. The sphingosine-1-phosphate receptor agonist FTY720 promotes peripheral nerve regeneration
- Author
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Gerd Meyer zu Hörste, Hans-Peter Hartung, Fabian Szepanowski, Angelika Derksen, and Bernd C. Kieseier
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Agonist ,Neurology ,medicine.drug_class ,Peripheral nerve ,Chemistry ,Sphingosine-1-phosphate receptor ,Regeneration (biology) ,Immunology ,medicine ,Immunology and Allergy ,Neurology (clinical) ,Cell biology - Published
- 2014
28. Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling
- Author
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Thomas Daldrup, Angelika Derksen, Bernd C. Kieseier, Fabian Szepanowski, Hans-Peter Hartung, Irina Steiner, and Gerd Meyer zu Hörste
- Subjects
Male ,0301 basic medicine ,Neural Conduction ,Peripheral nerve regeneration ,Pharmacology ,Piperazines ,Mice ,chemistry.chemical_compound ,Myelin ,0302 clinical medicine ,Neurofilament Proteins ,Lysophosphatidic acid ,Cyclic AMP ,Benzoxazoles ,General Neuroscience ,Forkhead Transcription Factors ,Fingolimod ,medicine.anatomical_structure ,Neurology ,Peripheral nervous system ,Cytokines ,lipids (amino acids, peptides, and proteins) ,Sciatic nerve ,Autotaxin ,Immunosuppressive Agents ,Signal Transduction ,medicine.drug ,Sphingosine-1-phosphate ,Immunology ,Mice, Transgenic ,Biology ,PF-8380 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Fingolimod Hydrochloride ,medicine ,Animals ,Homeodomain Proteins ,Research ,Nerve Regeneration ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,Lysophospholipids ,Sciatic Neuropathy ,Neuroscience ,030217 neurology & neurosurgery - Abstract
The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P1 receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatment of multiple sclerosis. An emerging body of experimental evidence points to additional direct effects on cells of the central and peripheral nervous system. Furthermore, fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Here we investigated whether modulation of particular signaling aspects of S1P as well as LPA by fingolimod might propagate peripheral nerve regeneration in vivo and independent of its anti-inflammatory potency. Sciatic nerve crush was performed in wildtype C57BL/6, in immunodeficient Rag1 −/− and Foxn1 −/− mice. Analyses were based on walking track analysis and electrophysiology, histology, and cAMP formation. Quantification of different LPA species was performed by liquid chromatography coupled to tandem mass spectrometry. Furthermore, functional consequences of autotaxin inhibition by the specific inhibitor PF-8380 and the impact of fingolimod on early cytokine release in the injured sciatic nerve were investigated. Clinical and electrophysiological measures indicated an improvement of nerve regeneration under fingolimod treatment that is partly independent of its anti-inflammatory properties. Fingolimod treatment correlated with a significant elevation of axonal cAMP, a crucial factor for axonal outgrowth. Additionally, fingolimod significantly reduced LPA levels in the injured nerve. PF-8380 treatment correlated with improved myelin thickness. Sciatic nerve cytokine levels were not found to be significantly altered by fingolimod treatment. Our findings provide in vivo evidence for direct effects of fingolimod on cells of the peripheral nervous system that may propagate nerve regeneration via a dual mode of action, differentially affecting axonal outgrowth and myelination by modulating relevant aspects of S1P and LPA signaling.
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