Sven G Meuth

Publications of Sven G Meuth

• Blocking of bradykinin receptor B1 protects from focal closed head injury in mice by reducing axonal damage and astroglia activation.

  Authors: Christiane Albert-Weissenberger, Christian Stetter, Sven G Meuth, Kerstin Göbel, Michael Bader, Anna-Leena Sirén, Christoph Kleinschnitz

  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 05/2012;

  The two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kininsThe two bradykinin receptors B1R and B2R are central components of the kallikrein-kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration.Journal of Cerebral Blood Flow & Metabolism advance online publication, 9 May 2012; doi:10.1038/jcbfm.2012.62.

• Adenylyl Cyclases: Expression in the Developing Rat Thalamus and Their Role in Absence Epilepsy.

  Authors: Petra Ehling, Tatyana Kanyshkova, Arnd Baumann, Peter Landgraf, Sven G Meuth, Hans-Christian Pape, Thomas Budde

  Journal of molecular neuroscience : MN. 04/2012;

  Adenylyl cyclases (ACs) synthesize the second messenger cyclic AMP (cAMP) which influences the function of multiple ion channels. Former studies point to a malfunction of cAMP-dependent ion channelAdenylyl cyclases (ACs) synthesize the second messenger cyclic AMP (cAMP) which influences the function of multiple ion channels. Former studies point to a malfunction of cAMP-dependent ion channel regulation in thalamocortical relay neurons that contribute to the development of the absence epileptic phenotype of a rat genetic model (WAG/Rij). Here, we provide detailed information about the thalamic gene and protein expression of Ca(2+)/calmodulin-activated AC isoforms in rat thalamus. Data from WAG/Rij were compared to those from non-epileptic controls (August-Copenhagen Irish rats) to elucidate whether differential expression of ACs contributes to the dysregulation of thalamocortical activity. At one postnatal stage (P21), we found the gene expression of two specific Ca(2+)-activated AC isoforms (AC-1 and AC-3) to be significantly down-regulated in epileptic tissue, and we identified the isoform AC-1 to be the most prominent one in both strains. However, Western blot data and analysis of enzymatic AC activity revealed no differences between the two strains. While basal AC activity was low, cAMP production was boosted by application of a forskolin derivative up to sevenfold. Despite previous hints pointing to a major contribution of ACs, the presented data show that there is no apparent causality between AC activity and the occurrence of the epileptic phenotype.

• Neuron-directed autoimmunity in the central nervous system: entities, mechanisms, diagnostic clues, and therapeutic options.

  Authors: Nico Melzer, Sven G Meuth, Heinz Wiendl

  Current opinion in neurology. 04/2012;

  PURPOSE OF REVIEW: The human central nervous system (CNS) can mistakenly be the target of adaptive cellular and humoral immune responses causing both functional and structural impairment. We herePURPOSE OF REVIEW: The human central nervous system (CNS) can mistakenly be the target of adaptive cellular and humoral immune responses causing both functional and structural impairment. We here provide an overview of neuron-directed autoimmunity as a novel class of inflammatory CNS disorders, their differential diagnoses, clinical hallmarks, imaging features, characteristic laboratory, electrophysiological, cerebrospinal fluid and neuropathological findings, cellular and molecular disease mechanisms, as well as therapeutic options. RECENT FINDINGS: A growing number of immune-mediated CNS disorders of both autoimmune and paraneoplastic origin have emerged, in which neurons seem to be the target of the immune response. Antibodies binding to a variety of synaptic and extrasynaptic antigens located on the neuronal surface membrane can define distinct entities. Clinically, these disorders are characterized by subacute CNS-related [and sometimes peripheral nervous system (PNS)-related] symptoms involving a variety of cortical and subcortical gray matter areas, which often reflect the expression pattern and function of the respective target antigen. Antibodies seem to be pathogenic and cause (reversible) disturbance of synaptic transmission and neuronal excitability by selective functional inhibition or crosslinking and internalization of their antigen in the absence of overt cytotoxicity, at least at early disease stages. Whether at later disease stages antibody-mediated cytotoxicity, cytotoxic CD8 T cells, or other detrimental immune mechanisms contribute to neuronal impairment is unclear at present. SUMMARY: Adaptive humoral autoimmunity directed to neuronal cell-surface antigens offers first and unique insights and provokes further investigation into the systemic, cellular, and molecular consequences of immune-mediated disruption of distinct neuronal signaling pathways within the living human CNS.

• Platelets Contribute to the Pathogenesis of Experimental Autoimmune Encephalomyelitis.

  Authors: Harald F Langer, Eun Young Choi, Hong Zhou, Rebecca Schleicher, Kyoung-Jin Chung, Zhongshu Tang, Kerstin Göbel, Khalil Bdeir, Antonios Chatzigeorgiou, Connie Wong [......] Elin Lehrmann, Kevin G Becker, Yunmei Wang, Daniel I Simon, Bernhard Nieswandt, John D Lambris, Xuri Li, Sven G Meuth, Paul Kubes, Triantafyllos Chavakis

  Circulation research. 03/2012;

  Rationale:Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets inRationale:Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE), are inflammatory disorders of the central nervous system (CNS). The function of platelets in inflammatory and autoimmune pathologies is thus far poorly defined.Objective:We addressed the role of platelets in mediating CNS inflammation in EAE.Methods and Results:We found that platelets were present in human MS lesions as well as in the CNS of mice subjected to EAE but not in the CNS from control nondiseased mice. Platelet depletion at the effector-inflammatory phase of EAE in mice resulted in significantly ameliorated disease development and progression. EAE suppression on platelet depletion was associated with reduced recruitment of leukocytes to the inflamed CNS, as assessed by intravital microscopy, and with a blunted inflammatory response. The platelet-specific receptor glycoprotein Ibα (GPIbα) promotes both platelet adhesion and inflammatory actions of platelets and targeting of GPIbα attenuated EAE in mice. Moreover, targeting another platelet adhesion receptor, glycoprotein IIb/IIIa (GPIIb/IIIa), also reduced EAE severity in mice.Conclusions:Platelets contribute to the pathogenesis of EAE by promoting CNS inflammation. Targeting platelets may therefore represent an important new therapeutic approach for MS treatment.

• CD4+ CD25+ FoxP3+ regulatory T cells suppress cytotoxicity of CD8+ effector T cells: implications for their capacity to limit inflammatory central nervous system damage at the parenchymal level.

  Authors: Kerstin Göbel, Stefan Bittner, Nico Melzer, Susann Pankratz, Angela Dreykluft, Michael K Schuhmann, Sven G Meuth, Heinz Wiendl

  Journal of neuroinflammation. 02/2012; 9:41.

  ABSTRACT: CD4+ CD25+ forkhead box P3 (FoxP3)+ regulatory T cells (T reg cells) are known to suppress adaptive immune responses, key control tolerance and autoimmunity. We challenged the role of CD4+ABSTRACT: CD4+ CD25+ forkhead box P3 (FoxP3)+ regulatory T cells (T reg cells) are known to suppress adaptive immune responses, key control tolerance and autoimmunity. We challenged the role of CD4+ T reg cells in suppressing established CD8+ T effector cell responses by using the OT-I/II system in vitro and an OT-I-mediated, oligodendrocyte directed ex vivo model (ODC-OVA model). CD4+ T reg cells dampened cytotoxicity of an ongoing CD8+ T effector cell attack in vitro and within intact central nervous system tissue ex vivo. However, their suppressive effect was limited by the strength of the antigen signal delivered to the CD8+ T effector cells and the ratio of regulatory to effector T cells. CD8+ T effector cell suppression required T cell receptor-mediated activation together with costimulation of CD4+ T reg cells, but following activation, suppression did not require restimulation and was antigen non-specific. Our results suggest that CD4+ T reg cells are capable of suppressing CD8+ T effector cell responses at the parenchymal site, that is, limiting parenchymal damage in autoimmune central nervous system inflammation.

• Report on the 3'rd scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 4'th - Nov. 6'th, 2011.

  Authors: Christoph Kleinschnitz, Sven G Meuth, Tim Magnus, Thomas Korn, Ralf A Linker

  Experimental & translational stroke medicine. 02/2012; 4(1):2.

  ABSTRACT: From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientificABSTRACT: From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientific exchange and the presentation of innovative projects for young colleagues in the fields of neurovascular research, neuroinflammation and neurodegeneration. As kick-off to the scientific sessions, Reinhard Hohlfeld, Head of the Institute for Clinical Neuroimmunology in Munich, gave an illustrious overview on the many fascinations of neuroimmunologic research. A particular highlight on the second day of the meeting was the award of the 1'st NEUROWIND e.V. prize for young academics in the field of experimental neurology. This award is posted for young colleagues under the age of 35 with a significant achievement in the field of neurovascular research, neuroinflammation or neurodegeneration and comprises an amount of 20.000 Euro, founded by Merck Serono GmbH, Darmstadt. Germany. The first prize was awarded to Ivana Nikic from Martin Kerschensteiner's group in Munich for her brilliant work on a reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis, published in Nature Medicine in 2011. This first prize award ceremony was a great incentive for the next call for proposals now upcoming in 2012.

• CD4+ T Cells Predominate in Cerebrospinal Fluid and Leptomeningeal and Parenchymal Infiltrates in Cerebral Amyloid β-Related Angiitis.

  Authors: Nico Melzer, Anja Harder, Catharina C Gross, Johannes Wölfer, Walter Stummer, Thomas Niederstadt, Sven G Meuth, Martin Marziniak, Oliver Martin Grauer, Heinz Wiendl

  Archives of neurology. 02/2012;

  BACKGROUND: In amyloid β (Aβ)-related angiitis (ABRA) of the central nervous system (CNS), cerebral amyloid angiopathy occurs in association with primary vasculitis of small- and medium-sizedBACKGROUND: In amyloid β (Aβ)-related angiitis (ABRA) of the central nervous system (CNS), cerebral amyloid angiopathy occurs in association with primary vasculitis of small- and medium-sized leptomeningeal and cortical arteries. It has been suggested that ABRA is triggered by vascular deposition of Aβ followed by an Aβ-directed (auto)immune response. OBJECTIVE: To provide a detailed description of the cellular composition of the inflammatory infiltrates in the cerebrospinal fluid (CSF) and CNS and their response to immunotherapy in a typical case of ABRA. DESIGN: Report of a single case. SETTING: Neurologic referral center. Patient 67-year-old white woman. MAIN OUTCOME MEASURES: Neurologic examination, magnetic resonance imaging, lumbar puncture, flow cytometry, leptomeningeal biopsy, and histopathologic analysis. RESULTS: In a typical case of ABRA, we demonstrate for the first time the presence of a vast majority of partially activated CD4(+) T cells in CSF and leptomeningeal and parenchymal (peri)vascular infiltrates, which were frequently found in close proximity to major histocompatibility complex (MHC) class II-expressing microglia, epithelioid macrophages, and multinucleated giant cells containing intracellular deposits of Aβ. CONCLUSION: Our findings support the notion of adaptive Aß-directed autoimmunity as the underlying pathogenic mechanism in ABRA.

• Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS.

  Authors: Angela Dann, Hendrik Poeck, Andrew L Croxford, Stefanie Gaupp, Katrin Kierdorf, Markus Knust, Dietmar Pfeifer, Cornelius Maihoefer, Stefan Endres, Ulrich Kalinke, Sven G Meuth, Heinz Wiendl, Klaus-Peter Knobeloch, Shizuo Akira, Ari Waisman, Gunther Hartmann, Marco Prinz

  Nature neuroscience. 12/2011; 15(1):98-106.

  The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1The action of cytosolic RIG-I-like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5'-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed T(H)1 and T(H)17 cells, whereas T-cell differentiation was not altered. Notably, T(H)1 and T(H)17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of T(H)1 and T(H)17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis.

• Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis.

  Authors: Anke S Lonsdorf, Björn F Krämer, Manuela Fahrleitner, Tanja Schönberger, Stephan Gnerlich, Sabine Ring, Sarah Gehring, Stefan W Schneider, Michael J Kruhlak, Sven G Meuth, Bernhard Nieswandt, Meinrad Gawaz, Alexander H Enk, Harald F Langer

  The Journal of biological chemistry. 11/2011; 287(3):2168-78.

  A mutual relationship exists between metastasizing tumor cells and components of the coagulation cascade. The exact mechanisms as to how platelets influence blood-borne metastasis, however, remainA mutual relationship exists between metastasizing tumor cells and components of the coagulation cascade. The exact mechanisms as to how platelets influence blood-borne metastasis, however, remain poorly understood. Here, we used murine B16 melanoma cells to observe functional aspects of how platelets contribute to the process of hematogenous metastasis. We found that platelets interfere with a distinct step of the metastasis cascade, as they promote adhesion of melanoma cells to the endothelium in vitro under shear conditions. Constitutively active platelet receptor GPIIb/IIIa (integrin αIIbβ3) expressed on Chinese hamster ovary cells promoted melanoma cell adhesion in the presence of fibrinogen, whereas blocking antibodies to aνβ3 integrin on melanoma cells or to GPIIb/IIIa significantly reduced melanoma cell adhesion to platelets. Furthermore, using intravital microscopy, we observed functional platelet-melanoma cell interactions, as platelet depletion resulted in significantly reduced melanoma cell adhesion to the injured vascular wall in vivo. Using a mouse model of hematogenous metastasis to the lung, we observed decreased metastasis of B16 melanoma cells to the lung by treatment with a mAb blocking the aν subunit of aνβ3 integrin. This effect was significantly reduced when platelets were depleted in vivo. Thus, the engagement of GPIIb/IIIa with aνβ3 integrin interaction mediates tumor cell-platelet interactions and highlights how this interaction is involved in hematogenous tumor metastasis.

• Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons.

  Authors: Pawan Bista, Sven G Meuth, Tatyana Kanyshkova, Manuela Cerina, Matthias Pawlowski, Petra Ehling, Peter Landgraf, Marc Borsotto, Catherine Heurteaux, Hans-Christian Pape, Thomas Baukrowitz, Thomas Budde

  Pflügers Archiv : European journal of physiology. 11/2011; 463(1):89-102.

  Modulation of the standing outward current (I (SO)) by muscarinic acetylcholine (ACh) receptor (MAChR) stimulation is fundamental for the state-dependent change in activity mode of thalamocorticalModulation of the standing outward current (I (SO)) by muscarinic acetylcholine (ACh) receptor (MAChR) stimulation is fundamental for the state-dependent change in activity mode of thalamocortical relay (TC) neurons. Here, we probe the contribution of MAChR subtypes, G proteins, phospholipase C (PLC), and two pore domain K(+) (K(2P)) channels to this signaling cascade. By the use of spadin and A293 as specific blockers, we identify TWIK-related K(+) (TREK)-1 channel as new targets and confirm TWIK-related acid-sensitve K(+) (TASK)-1 channels as known effectors of muscarinic signaling in TC neurons. These findings were confirmed using a high affinity blocker of TASK-3 and TREK-1, namely, tetrahexylammonium chloride. It was found that the effect of muscarinic stimulation was inhibited by M(1)AChR-(pirenzepine, MT-7) and M(3)AChR-specific (4-DAMP) antagonists, phosphoinositide-specific PLCβ (PI-PLC) inhibitors (U73122, ET-18-OCH(3)), but not the phosphatidylcholine-specific PLC (PC-PLC) blocker D609. By comparison, depleting guanosine-5'-triphosphate (GTP) in the intracellular milieu nearly completely abolished the effect of MAChR stimulation. The block of TASK and TREK channels was accompanied by a reduction of the muscarinic effect on I (SO). Current-clamp recordings revealed a membrane depolarization following MAChR stimulation, which was sufficient to switch TC neurons from burst to tonic firing under control conditions but not during block of M(1)AChR/M(3)AChR and in the absence of intracellular GTP. These findings point to a critical role of G proteins and PLC as well as TASK and TREK channels in the muscarinic modulation of thalamic activity modes.

• Immunological and clinical consequences of treating a patient with natalizumab.

  Authors: Nicholas Schwab, Karin G Höhn, Tilman Schneider-Hohendorf, Imke Metz, Max-Philipp Stenner, Samantha Jilek, Renaud A Du Pasquier, Ralf Gold, Sven G Meuth, Richard M Ransohoff, Wolfgang Brück, Heinz Wiendl

  Multiple sclerosis (Houndmills, Basingstoke, England). 09/2011; 18(3):335-44.

  Background: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). Objectives: We present a patient study through therapy, the diagnosis of PMLBackground: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). Objectives: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS). Methods: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis. Results: CD49d decreased after 12 months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes. Conclusion: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.

• Volume regulation of murine T lymphocytes relies on voltage-dependent and two-pore domain potassium channels.

  Authors: Nicole Bobak, Stefan Bittner, Joseph Andronic, Susanne Hartmann, Friederike Mühlpfordt, Tilman Schneider-Hohendorf, Karen Wolf, Carsten Schmelter, Kerstin Göbel, Patrick Meuth, Heiko Zimmermann, Frank Döring, Erhard Wischmeyer, Thomas Budde, Heinz Wiendl, Sven G Meuth, Vladimir L Sukhorukov

  Biochimica et biophysica acta. 08/2011; 1808(8):2036-44.

  A variety of ion channels are supposed to orchestrate the homoeostatic volume regulation in T lymphocytes. However, the relative contribution of different potassium channels to the osmotic volumeA variety of ion channels are supposed to orchestrate the homoeostatic volume regulation in T lymphocytes. However, the relative contribution of different potassium channels to the osmotic volume regulation and in particular to the regulatory volume decrease (RVD) in T cells is far from clear. This study explores a putative role of the newly identified K(2P) channels (TASK1, TASK2, TASK3 and TRESK) along with the voltage-gated potassium channel K(V)1.3 and the calcium-activated potassium channel K(Ca)3.1 in the RVD of murine T lymphocytes, using genetic and pharmacological approaches. K(2P) channel knockouts exerted profound effects on the osmotic properties of murine T lymphocytes, as revealed by reduced water and RVD-related solute permeabilities. Moreover, both genetic and pharmacological data proved a key role of K(V)1.3 and TASK2 channels in the RVD of murine T cells exposed to hypotonic saline. Our experiments demonstrate a leading role of potassium channels in the osmoregulation of T lymphocytes under different conditions. In summary, the present study sheds new light on the complex and partially redundant network of potassium channels involved in the basic physiological process of the cellular volume homeostasis and extends the repertoire of potassium channels by the family of K(2P) channels.

• Immune mechanisms of new therapeutic strategies in multiple sclerosis-A focus on alemtuzumab.

  Authors: Luisa Klotz, Sven G Meuth, Heinz Wiendl

  Clinical immunology (Orlando, Fla.). 04/2011; 142(1):25-30.

  Alemtuzumab is a humanized monoclonal antibody targeting CD52, a broadly expressed cell surface molecule on immune cells. Application results in a rapid and long-lasting removal of lymphocyteAlemtuzumab is a humanized monoclonal antibody targeting CD52, a broadly expressed cell surface molecule on immune cells. Application results in a rapid and long-lasting removal of lymphocyte populations from the circulation. Alemtuzumab-treatment of MS patients with relapsing-remitting forms of the disease significantly reduced the risk of relapse and accumulation of disability compared to interferon β-1a treatment in a phase II trial. Interestingly, further analysis together with parallel experimental studies suggested that alemtuzumab not only reduces disease activity due to its immune cell-depleting effect, but also confers neuroprotective effects, presumably by inducing production of neurotrophic factors in autoreactive T cells. However, alemtuzumab-treated MS patients experienced increased rates of novel autoimmunity and a slight increase in infections, demonstrating that alemtuzumab-mediated skewing of the immune cell compartment has a broad influence on immune functions. This review discusses the current concepts about the underlying mechanisms causing these altered immune responses in alemtuzumab-treated MS patients.

• Ion channels in autoimmune neurodegeneration.

  Authors: Petra Ehling, Stefan Bittner, Thomas Budde, Heinz Wiendl, Sven G Meuth

  FEBS letters. 04/2011; 585(23):3836-42.

  Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by widespread inflammation, focal demyelination and a variable degree of axonal and neuronalMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by widespread inflammation, focal demyelination and a variable degree of axonal and neuronal loss. Ionic conductances regulate T cell activation as well as neuronal function and thus have been found to play a crucial role in MS pathogenesis. Since present therapeutical approaches are only partially effective so far, ion channel modulation as a future strategy was brought into focus. Here, we review the status quo concerning recent findings from ion channel research in MS and its animal model, experimental autoimmune encephalomyelitis.

• Report on the 2nd scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 29'th - Oct. 31'st, 2010.

  Authors: Tim Magnus, Ralf A Linker, Sven G Meuth, Christoph Kleinschnitz, Thomas Korn

  Experimental & translational stroke medicine. 04/2011; 3(1):3.

  ABSTRACT: Summary of the scientific contributions to the NEUROWIND meeting 2010: Contributions in the fields of neuroimmunology and neurodegeneration.

• A-type K+ currents in intralaminar thalamocortical relay neurons.

  Authors: Tatyana Kanyshkova, Tilman Broicher, Sven G Meuth, Hans-Christian Pape, Thomas Budde

  Pflügers Archiv : European journal of physiology. 03/2011; 461(5):545-56.

  Transient A-type K+ currents (I(A)) are known to influence the firing pattern of a number of thalamic cell types, but have not been investigated in intralaminar thalamocortical (TC) relay neuronsTransient A-type K+ currents (I(A)) are known to influence the firing pattern of a number of thalamic cell types, but have not been investigated in intralaminar thalamocortical (TC) relay neurons yet. We therefore combined whole-cell patch-clamp techniques, PCR analysis, and immunohistochemistry to investigate the voltage-dependent and pharmacological properties of I(A) and to determine its molecular basis in TC neurons from the centrolateral, paracentral, and centromedial thalamic nuclei. I(A) revealed half-maximal (V (h)) activation and inactivation at about -17 and -67 mV, respectively. At a concentration of 5-10 mM 4-aminopyridine (4-AP) completely blocked I(A). Furthermore, I(A) was nearly unaffected by two sea anemone toxins (blood depressing substances 1 and 2, BDS1 and BDS2; 6-8% block at a concentration of 1 μM) but strongly sensitive to the K(V)4 channel blocker Heteropoda venatoria toxin 2 (HpTx2; about 45% block at a concentration of 5 μM). PCR screening revealed the expression of K(V)4.1-4.3, with strongest expression for K(V)4.2 and weak expression for K(V)4.1. Accordingly K(V)4.1 was not detected in immunohistochemical staining. Furthermore, K(V)4.2 and K(V)4.3 revealed mainly dendritic and somatic staining, respectively. Together with current clamp recordings, these findings point to a scenario where the fast transient I(A) in intralaminar TC neurons has a depolarized threshold at potentials negative to -50 mV, is substantially generated by K(V)4.2 and K(V)4.3 channels, allows prominent burst firing at hyperpolarized potentials, prevents the generation of high-threshold potentials, generates a delayed onset of firing at more depolarized potentials, and allows fast tonic firing.

• Natalizumab restores evoked potential abnormalities in patients with relapsing-remitting multiple sclerosis.

  Authors: Sven G Meuth, Stefan Bittner, Carola Seiler, Kerstin Göbel, Heinz Wiendl

  Multiple sclerosis (Houndmills, Basingstoke, England). 02/2011; 17(2):198-203.

  The objective of this study was to examine the effects of natalizumab on functional parameters assessed by evoked potentials (visual [VEP], somatosensory [SEP] and motor evoked potentials [MEP]) in aThe objective of this study was to examine the effects of natalizumab on functional parameters assessed by evoked potentials (visual [VEP], somatosensory [SEP] and motor evoked potentials [MEP]) in a cohort study in relapsing-remitting multiple sclerosis patients. EP data of 44 patients examined 12 months prior to natalizumab treatment, at the timepoint of treatment initiation and 1 year later were compared. Sum scores (VEP, MEP, SEP) were evaluated and correlated with the Expanded Disability Status Scale. Improvement of the VEP sum score was found in 33% of natalizumab-treated patients but only in 9% of the same patients prior to treatment (p = 0.041). A comparable situation was found for SEP (improvement: 32% versus 5%; worsening: 11% versus 37%; p = 0.027). For MEP no significant differences were seen (improvement: 10% versus 18%; worsening: 5% versus 29%; p = 0.60). EP recordings (VEP = SEP > MEP) have the capacity to demonstrate treatment effects of natalizumab on a functional level. Natalizumab therapy increases the percentage of patients showing stable or even ameliorated electrophysiological parameters in the investigated functional systems.

• Expression of K2P5.1 potassium channels on CD4+ T lymphocytes correlates with disease activity in rheumatoid arthritis patients.

  Authors: Stefan Bittner, Nicole Bobak, Martin Feuchtenberger, Alexander M Herrmann, Kerstin Göbel, Raimund W Kinne, Anker J Hansen, Thomas Budde, Christoph Kleinschnitz, Oliver Frey, Hans-Peter Tony, Heinz Wiendl, Sven G Meuth

  Arthritis research & therapy. 02/2011; 13(1):R21.

  CD4+ T cells express K(2P)5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cellCD4+ T cells express K(2P)5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K(2P)5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K(2P)5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. Expression levels of K(2P)5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K(2P)5.1. K(2P)5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K(2P)5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K(2P)5.1 expression to disease activity parameters during a longitudinal follow-up for six months. Disease activity in RA patients correlates strongly with K(2P)5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K(2P)5.1 as a potential biomarker for disease activity and differential diagnosis.

• No association between genetic polymorphism at codon 129 of the prion protein gene and primary progressive multiple sclerosis.

  Authors: Olaf Stüve, Joanne Wang, Andrew Chan, Bernhard Hemmer, Sabine Cepok, Stefan Nessler, Frauke Zipp, Myla D Goldman, Sven G Meuth, Carsten Korth, Doris Lambracht-Washington

  Archives of neurology. 02/2011; 68(2):264-5.

• Glucocorticoid insensitivity at the hypoxic blood-brain barrier can be reversed by inhibition of the proteasome.

  Authors: Christoph Kleinschnitz, Kinga Blecharz, Timo Kahles, Tobias Schwarz, Peter Kraft, Kerstin Göbel, Sven G Meuth, Malgorzata Burek, Thomas Thum, Guido Stoll, Carola Förster

  Stroke; a journal of cerebral circulation. 02/2011; 42(4):1081-9.

  Glucocorticoids potently stabilize the blood-brain barrier and ameliorate tissue edema in certain neoplastic and inflammatory disorders of the central nervous system, but they are largely ineffectiveGlucocorticoids potently stabilize the blood-brain barrier and ameliorate tissue edema in certain neoplastic and inflammatory disorders of the central nervous system, but they are largely ineffective in patients with acute ischemic stroke. The reasons for this discrepancy are unresolved. To address the molecular basis for the paradox unresponsiveness of the blood-brain barrier during hypoxia, we used murine brain microvascular endothelial cells exposed to O(2)/glucose deprivation as an in vitro model. In an in vivo approach, mice were subjected to transient middle cerebral artery occlusion to induce brain infarctions. Blood-brain barrier damage and edema formation were chosen as surrogate markers of glucocorticoid sensitivity in the presence or absence of proteasome inhibitors. O(2)/glucose deprivation reduced the expression of tight junction proteins and transendothelial resistance in murine brain microvascular endothelial cells in vitro. Dexamethasone treatment failed to reverse these effects during hypoxia. Proteasome-dependent degradation of the glucocorticoid receptor impaired glucocorticoid receptor transactivation thereby preventing physiological glucocorticoid activity. Inhibition of the proteasome, however, fully restored the blood-brain barrier stabilizing properties of glucocorticoid during O(2)/glucose deprivation. Importantly, mice treated with the proteasome inhibitor Bortezomib in combination with steroids several hours after stroke developed significantly less brain edema and functional deficits, whereas respective monotherapies were ineffective. We for the first time show that inhibition of the proteasome can overcome glucocorticoid resistance at the hypoxic blood-brain barrier. Hence, combined treatment strategies may help to combat stroke-induced brain edema formation in the future and prevent secondary clinical deterioration.