Tim Magnus

Publications of Tim Magnus

• Immune mechanisms of stroke.

  Authors: Tim Magnus, Heinz Wiendl, Christoph Kleinschnitz

  Current opinion in neurology. 06/2012; 25(3):334-40.

  Only recently has it been realized that immune mechanisms contribute to the pathophysiology of ischemic stroke, which for many years was regarded mainly as a vascular disease. These immunologicOnly recently has it been realized that immune mechanisms contribute to the pathophysiology of ischemic stroke, which for many years was regarded mainly as a vascular disease. These immunologic processes are present during all stages of stroke and involve both the innate and adaptive immune systems. This review highlights the latest findings related to the 'immunology of stroke'. During the early phase of an ischemic insult, 'danger signals' such as ATP are released from dying tissue to subsequently attract inflammatory cells. Unexpectedly, T cells have been identified as prominent mediators of stroke-induced tissue damage. Whereas during the acute stage of infarction T cells act independently from antigen-specific stimuli but rather interact with thrombotic pathways, antigen-dependent T-cell activation might be relevant at later stages. Moreover, certain T-cell subsets like γδ T cells or regulatory T cells are able to influence stroke outcome either in a detrimental or beneficial way. Finally, proof-of-principle studies using FTY720 or VLA-4 blockers have demonstrated that the concept of 'immunomodulation in stroke' is feasible. The insight that ischemic stroke at least in part is an immune-mediated disease may open new avenues for the treatment of this devastating neurologic condition.

• Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease.

  Authors: Frank Leypoldt, Ralph Buchert, Ingo Kleiter, Jörg Marienhagen, Mathias Gelderblom, Tim Magnus, Josep Dalmau, Christian Gerloff, Jan Lewerenz

  Journal of neurology, neurosurgery, and psychiatry. 05/2012;

  BackgroundPatients with encephalitis associated with antibodies against N-methyl-D-aspartate-receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures andBackgroundPatients with encephalitis associated with antibodies against N-methyl-D-aspartate-receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose(FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported.MethodsThe authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease.ResultsGroupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery.ConclusionsA characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.

• Intravenous immunoglobulin (IVIg) protects neurons against amyloid beta-peptide toxicity and ischemic stroke by attenuating multiple cell death pathways.

  Authors: Alexander Widiapradja, Viktor Vegh, Ker Zhing Lok, Silvia Manzanero, John Thundyil, Mathias Gelderblom, Yi-Lin Cheng, Dale Pavlovski, Sung-Chun Tang, Dong-Gyu Jo, Tim Magnus, Sic L Chan, Christopher G Sobey, David Reutens, Milan Basta, Mark P Mattson, Thiruma V Arumugam

  Journal of neurochemistry. 04/2012;

  Intravenous immunoglobulin (IVIg) preparations obtained by fractionating blood plasma, are increasingly being used increasingly as an effective therapeutic agent in treatment of several inflammatoryIntravenous immunoglobulin (IVIg) preparations obtained by fractionating blood plasma, are increasingly being used increasingly as an effective therapeutic agent in treatment of several inflammatory diseases. Its use as a potential therapeutic agent for treatment of stroke and Alzheimer's disease (AD) has been proposed, but little is known about the neuroprotective mechanisms of IVIg. In this study we investigated the effect of IVIg on downstream signaling pathways that are involved in neuronal cell death in experimental models of stroke and AD. Treatment of cultured neurons with IVIg reduced simulated ischemia- and amyloid βpeptide (Aβ)-induced caspase-3 cleavage, and phosphorylation of the cell death-associated kinases p38MAPK, JNK and p65, in vitro. Additionally, Aβ-induced accumulation of the lipid peroxidation product 4-HNE was attenuated in neurons treated with IVIg. IVIg treatment also upregulated the anti-apoptotic protein, Bcl2 in cortical neurons under ischemia-like conditions and exposure to Aβ. Treatment of mice with IVIg reduced neuronal cell loss, apoptosis and infarct size, and improved functional outcome in a model of focal ischemic stroke. Together, these results indicate that IVIg acts directly on neurons to protect them against ischemic stroke and Aβ-induced neuronal apoptosis by inhibiting cell death pathways and by elevating levels of the anti-apoptotic protein Bcl2. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

• C5a Receptor (CD88) Inhibition Improves Hypothermia-Induced Neuroprotection in an In Vitro Ischemic Model.

  Authors: John Thundyil, Dale Pavlovski, Yu-Hsuan Hsieh, Mathias Gelderblom, Tim Magnus, David P Fairlie, Thiruma V Arumugam

  Neuromolecular medicine. 03/2012; 14(1):30-9.

  The concept of 'salvageble penumbra' has prompted both scientists and physicians to explore various neuroprotective approaches that could be beneficial during stroke therapy. Unfortunately, most ofThe concept of 'salvageble penumbra' has prompted both scientists and physicians to explore various neuroprotective approaches that could be beneficial during stroke therapy. Unfortunately, most of them have proved ineffective in targeting multiple cellular death cascades incited within the ischemic penumbra. Hypothermia has been shown to be capable of addressing this problem to some extent. Although many studies have shown that hypothermia targets several cellular processes, its effects on innate immune receptor-mediated apoptotic death still remain unclear. Moreover, whether inhibiting the signaling of innate immune receptors like complement anaphylatoxin C5a receptor (CD88) plays a role in this hypothermic neuroprotection still need to be deciphered. Using various types of ischemic insults in different neuronal cells, we confirm that hypothermia does indeed attenuate apoptotic neuronal cell death in vitro and this effect can be further enhanced by pharmacologically blocking or knocking out CD88. Thus, our study raises a promising therapeutic possibility of adding CD88 antagonists along with hypothermia to improve stroke outcomes.

• 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.

• The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice.

  Authors: Mathias Gelderblom, Frank Leypoldt, Jan Lewerenz, Gabriel Birkenmayer, Denise Orozco, Peter Ludewig, John Thundyil, Thiruma V Arumugam, Christian Gerloff, Eva Tolosa, Pamela Maher, Tim Magnus

  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 01/2012;

  The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, aThe development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor α (TNFα) production. Fisetin also inhibited LPS-induced TNFα production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor κB activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia.Journal of Cerebral Blood Flow & Metabolism advance online publication, 11 January 2012; doi:10.1038/jcbfm.2011.189.

• Calorie restriction and stroke.

  Authors: Silvia Manzanero, Mathias Gelderblom, Tim Magnus, Thiruma V Arumugam

  Experimental & translational stroke medicine. 09/2011; 3:8.

  ABSTRACT: Stroke, a major cause of disability and mortality in the elderly, occurs when a cerebral blood vessel is occluded or ruptured, resulting in ischemic damage and death of brain cells. TheABSTRACT: Stroke, a major cause of disability and mortality in the elderly, occurs when a cerebral blood vessel is occluded or ruptured, resulting in ischemic damage and death of brain cells. The injury mechanism involves metabolic and oxidative stress, excitotoxicity, apoptosis and inflammatory processes, including activation of glial cells and infiltration of leukocytes. In animal models, dietary energy restriction, by daily calorie reduction (CR) or intermittent fasting (IF), extends lifespan and decreases the development of age-related diseases. Dietary energy restriction may also benefit neurons, as suggested by experimental evidence showing that CR and IF protect neurons against degeneration in animal models. Recent findings by our group and others suggest the possibility that dietary energy restriction may protect against stroke induced brain injury, in part by inducing the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF); protein chaperones, including heat shock protein 70 (Hsp70) and glucose regulated protein 78 (GRP78); antioxidant enzymes, such as superoxide dismutases (SOD) and heme oxygenase-1 (HO-1), silent information regulator T1 (SIRT1), uncoupling proteins and anti-inflammatory cytokines. This article discusses the protective mechanisms activated by dietary energy restriction in ischemic stroke.

• Seventy years of episodic stiffness: an unusual case of neuromyotonia.

  Authors: Christos Ganos, Alexander Münchau, Tobias Bäumer, Christian Gerloff, Tim Magnus

  Movement disorders : official journal of the Movement Disorder Society. 06/2011; 26(7):1360-1.

• 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.

• Evidence that gamma-secretase-mediated Notch signaling induces neuronal cell death via the nuclear factor-kappaB-Bcl-2-interacting mediator of cell death pathway in ischemic stroke.

  Authors: Thiruma V Arumugam, Yi-Lin Cheng, Yuri Choi, Yun-Hyung Choi, Sunghee Yang, Young-Kwang Yun, Jong-Sung Park, Dong Kwon Yang, John Thundyil, Mathias Gelderblom, Vardan T Karamyan, Sung-Chun Tang, Sic L Chan, Tim Magnus, Christopher G Sobey, Dong-Gyu Jo

  Molecular pharmacology. 03/2011; 80(1):23-31.

  Notch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of itsNotch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of its ligands results in the proteolytic cleavage of Notch by the γ-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription. Here we show that activation of Notch modulates ischemic neuronal cell death in vitro and in vivo. Specifically, our findings from the use of Notch-1 siRNA or the overexpression of NICD indicate that Notch activation contributes to cell death. Using modified NICD, we demonstrate an apoptosis-inducing function of NICD in both the nucleus and the cytosol. NICD transfection-induced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, γ-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-κB (NF-κB), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a γ-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, γ-secretase inhibition reduced NICD, p-p65, and Bim levels in vivo. These findings suggest that Notch signaling endangers neurons after ischemic stroke by modulating the NF-κB, pro-death protein Bim, and caspase pathways.

• Correction: CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.

  Authors: Chi-Un Choe, Kerstin Lardong, Mathias Gelderblom, Peter Ludewig, Frank Leypoldt, Friedrich Koch-Nolte, Christian Gerloff, Tim Magnus

  PloS one. 01/2011; 6(7).

  [This corrects the article on p. e19046 in vol. 6.].

• Nitroxyl in the central nervous system.

  Authors: Chi-Un Choe, Jan Lewerenz, Christian Gerloff, Tim Magnus, Sonia Donzelli

  Antioxidants & redox signaling. 01/2011; 14(9):1699-711.

  Nitroxyl (HNO) is the one-electron-reduced and protonated congener of nitric oxide (NO). Compared to NO, it is far more reactive with thiol groups either in proteins or in small antioxidant moleculesNitroxyl (HNO) is the one-electron-reduced and protonated congener of nitric oxide (NO). Compared to NO, it is far more reactive with thiol groups either in proteins or in small antioxidant molecules either converting those into sulfinamides or inducing disulfide bond formation. HNO might mediate cytoprotective changes of protein function through thiol modifications. However, HNO is a strong oxidant that in vitro reacts with glutathione to form glutathione disulfide and glutathione sulfinamide. The resulting oxidative stress might aggravate tissue damage in inflammatory diseases. In this review, we will summarize the current knowledge of how exogenous HNO affects the central nervous system, especially nerve cells and glia in health and disease. Unlike most other organs, the brain is separated from the circulation by the blood-brain barrier, which limits access of many pharmacological compounds. Given that, we will review what is known about the ability of currently used HNO donors to cross the blood-brain barrier. Moreover, considering that the physiology and composition of the brain has unique properties, for example, expression of brain-specific enzymes like neuronal NO synthase, its high iron content, and increased energy metabolism, we will discuss possible sources of endogenous HNO in the brain.

• CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.

  Authors: Chi-un Choe, Kerstin Lardong, Mathias Gelderblom, Peter Ludewig, Frank Leypoldt, Friedrich Koch-Nolte, Christian Gerloff, Tim Magnus

  PloS one. 01/2011; 6(5):e19046.

  Converging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes,Converging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes, recent data has emphasized the orchestrating function of innate immunity, i.e., macrophages and microglia. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose), which have been shown to be necessary for activation and migration of myeloid immune cells. Therefore, we investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion. We show that the local expression of the chemokine MCP-1 was attenuated in CD38-deficient mice compared with wildtype mice after focal cerebral ischemia and reperfusion. In contrast, no significant induction of MCP-1 expression was observed in peripheral blood after 6 hours. Flow cytometry analysis revealed less infiltrating macrophages and lymphocytes in the ischemic hemisphere of CD38-deficient mice, whereas the amount of resident microglia was unaltered. An up-regulation of CD38 expression was observed in macrophages and CD8(+) cells after focal cerebral ischemia in wildtype mice, whereas CD38 expression was unchanged in microglia. Finally, we demonstrate that CD38-deficiency decreases the cerebral ischemic injury and the persistent neurological deficit after three days of reperfusion in this murine temporary middle cerebral artery occlusion (tMCAO) model. CD38 is differentially regulated following stroke and its deficiency attenuates the postischemic chemokine production, the immune cell infiltration and the cerebral injury after temporary ischemia and reperfusion. Therefore CD38 might prove a therapeutic target in ischemic stroke.

• Report on the 1st scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Mittenwalde/Motzen, Germany, Oct. 30th - Nov. 1st, 2009.

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

  Experimental & translational stroke medicine. 03/2010; 2:7.

  Report on the 1st scientific meeting of the "Verein zur Forderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Mittenwalde/Motzen, Germany, Oct. 30th - Nov. 1st,Report on the 1st scientific meeting of the "Verein zur Forderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Mittenwalde/Motzen, Germany, Oct. 30th - Nov. 1st, 2009. A scientific meeting report.

• HNO exacerbates ischemic cerebral injury and oxidative neurotoxicity.

  Authors: Chi-Un Choe, Jan Lewerenz, Gerry Fischer, Tracy F Uliasz, Michael Graham Espey, Friedhelm C Hummel, S Bruce King, Edzard Schwedhelm, Rainer H Böger, Christian Gerloff, Sandra J Hewett, Tim Magnus, Sonia Donzelli

  Journal of neurochemistry. 08/2009;

  Abstract Nitroxyl (HNO) donor compounds function as potent vasorelaxants, improve myocardial contractility and reduce ischemia-reperfusion injury in the cardiovascular system. With respect to theAbstract Nitroxyl (HNO) donor compounds function as potent vasorelaxants, improve myocardial contractility and reduce ischemia-reperfusion injury in the cardiovascular system. With respect to the nervous system, HNO donors have been shown to attenuate N-methyl-D-aspartic acid (NMDA) receptor activity and neuronal injury, suggesting that its production may be protective against cerebral ischemic damage. Hence, we studied the effect of the classical HNO-donor, Angeli's salt (AS), on a cerebral ischemia/reperfusion injury in a mouse model of experimental stroke and on related in vitro paradigms of neurotoxicity. Intraperitoneal injection of AS (40mumol/kg) in mice prior to middle cerebral artery occlusion (MCAO) exacerbated cortical infarct size and worsened the persistent neurological deficit. AS not only decreased systolic blood pressure, but also induced systemic oxidative stress in vivo indicated by increased isoprostane levels in urine and serum. In vitro, neuronal damage induced by oxygen-glucose deprivation (OGD) of mature neuronal cultures was exacerbated by AS, although there was no direct effect on glutamate excitotoxicity. Finally, AS exacerbated oxidative glutamate toxicity - that is, cell death propagated via oxidative stress in immature neurons devoid of ionotropic glutamate receptors. Taken together, our data indicate that HNO might worsen cerebral ischemia-reperfusion injury by increasing oxidative stress and decreasing brain perfusion at concentrations shown to be cardioprotective in vivo.

• Temporal and Spatial Dynamics of Cerebral Immune Cell Accumulation in Stroke.

  Authors: Mathias Gelderblom, Frank Leypoldt, Karin Steinbach, Doerthe Behrens, Chi-Un Choe, Dominic A Siler, Thiruma V Arumugam, Ellen Orthey, Christian Gerloff, Eva Tolosa, Tim Magnus

  Stroke; a journal of cerebral circulation. 04/2009;

  BACKGROUND AND PURPOSE: Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment anBACKGROUND AND PURPOSE: Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage. The understanding of postischemic inflammation is very limited. The objectives of this study were to define the temporal and spatial infiltration of immune cell populations and their activation patterns in a murine cerebral ischemia-reperfusion injury model. METHODS: Transient middle cerebral artery occlusion was induced for 1 hour followed by 12-hour to 7-day reperfusion in C57/BL6 mice. Immunohistochemistry and flow cytometry were used to quantify the infiltrating immune cell subsets. RESULTS: Accumulation of microglia and infiltration of the ischemic hemisphere by macrophages, lymphocytes, and dendritic cells (DCs) preceded the neutrophilic influx. DCs were found to increase 20-fold and constituted a substantial proportion of infiltrating cells. DCs exhibited a significant upregulation of major histocompatibility complex II and major histocompatibility complex II high-expressing DCs were found 100 times more abundant than in sham conditions. Upregulation of the costimulatory molecule CD80 was observed in DCs and microglial cells but did not further increase in major histocompatibility complex II high-expressing DCs. No lymphocyte activation was observed. Additionally, regulatory immune cells (natural killer T-cells, CD4(-)/CD8(-)T lymphocytes) cumulated in the ischemic hemisphere. CONCLUSIONS: This study provides a detailed analysis of the temporal dynamics of immune cell accumulation in a rodent stroke model. The peculiar activation pattern and massive increase of antigen-presenting cells in temporal conjunction with regulatory cells might provide additional insight into poststroke immune regulation.

• Dimethylarginine dimethylaminohydrolase-1 transgenic mice are not protected from ischemic stroke.

  Authors: Frank Leypoldt, Chi-Un Choe, Mathias Gelderblom, Eike-Christin von Leitner, Dorothee Atzler, Edzard Schwedhelm, Christian Gerloff, Karsten Sydow, Rainer H Böger, Tim Magnus

  PloS one. 01/2009; 4(10):e7337.

  BACKGROUND: Methylated arginines are endogenous analogues of L-arginine, the substrate for nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) interferes with NO formation, causingBACKGROUND: Methylated arginines are endogenous analogues of L-arginine, the substrate for nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) interferes with NO formation, causing endothelial dysfunction. ADMA is a predictor of cardiovascular events and mortality in humans. It is eliminated primarily by enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH). METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether human DDAH-1 (hDDAH-1) transgenicity protects from ischemic tissue damage in temporary middle cerebral artery occlusion (tMCAO) in mice. Infarct sizes did not significantly differ between hDDAH-1 transgenic (TG) mice and wild-type littermates (WT). As expected, ADMA plasma concentrations were significantly decreased, cerebral hDDAH expression and protein significantly increased in transgenic animals. Interestingly, neither brain tissue DDAH activity nor ADMA concentrations were different between TG and WT mice. In contrast, muscular DDAH activity was generally lower than in brain but significantly increased in TG mice. CONCLUSION/SIGNIFICANCE: Our study demonstrates that hDDAH-1 transgenic mice are not protected from ischemic cerebral tissue damage in tMCAO. This lack of protection is due to high basal cerebral DDAH activity, which is not further increasable by transgenic overexpression of DDAH.

• Toll-Like Receptor 3 Is a Negative Regulator of Embryonic Neural Progenitor Cell Proliferation.

  Authors: Justin D Lathia, Eitan Okun, Sung-Chun Tang, Kathleen Griffioen, Aiwu Cheng, Mohamed R Mughal, Gloria Laryea, Pradeep K Selvaraj, Charles Ffrench-Constant, Tim Magnus, Thiruma V Arumugam, Mark P Mattson

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 01/2009; 28(51):13978-13984.

  Toll-like receptors (TLRs) play important roles in innate immunity. Several TLR family members have recently been shown to be expressed by neurons and glial cells in the adult brain, and may mediateToll-like receptors (TLRs) play important roles in innate immunity. Several TLR family members have recently been shown to be expressed by neurons and glial cells in the adult brain, and may mediate responses of these cells to injury and infection. To address the possibility that TLRs play a functional role in development of the nervous system, we analyzed the expression of TLRs during different stages of mouse brain development and assessed the role of TLRs in cell proliferation. TLR3 protein is present in brain cells in early embryonic stages of development, and in cultured neural stem/progenitor cells (NPC). NPC from TLR3-deficient embryos formed greater numbers of neurospheres compared with neurospheres from wild-type embryos. Numbers of proliferating cells, as assessed by phospho histone H3 and proliferating cell nuclear antigen labeling, were also increased in the developing cortex of TLR3-deficient mice compared with wild-type mice in vivo. Treatment of cultured embryonic cortical neurospheres with a TLR3 ligand (polyIC) significantly reduced proliferating (BrdU-labeled) cells and neurosphere formation in wild type but not TLR3(-/-)-derived NPCs. Our findings reveal a novel role for TLR3 in the negative regulation of NPC proliferation in the developing brain.

• Adult glial precursor proliferation in mutant SOD1G93A mice.

  Authors: Tim Magnus, Jessica Carmen, Jessica Deleon, Haipeng Xue, Andrea C Pardo, Angelo C Lepore, Mark P Mattson, Mahendra S Rao, Nicholas J Maragakis

  Glia. 02/2008; 56(2):200-8.

  The focus of most neurodegenerative disease studies has been on neuronal death in particular subpopulations of the central nervous system. The associated response of glial populations has beenThe focus of most neurodegenerative disease studies has been on neuronal death in particular subpopulations of the central nervous system. The associated response of glial populations has been ascribed the term "reactive astrocytosis." This has been defined as the proliferation of astrocytes accompanied by cellular hypertrophy and changes in gene expression following injury to the central nervous system. Yet the significance of that response to disease course is debated. In both human ALS and in the SOD1G93A mouse model of ALS, reactive astrocytosis is a hallmark of the disease--particularly at endstage. The brain also harbors immature progenitors which have the capacity for differentiation into both glial and neuronal lineages. We examined whether glial progenitors in the adult spinal cord of SOD1G93A mice become activated and contribute the astroglial response observed in this model. We found that the glial progenitor proteoglycan NG2 is increased in parallel with GFAP during the symptomatic phase of the disease and that there is a differential in vitro response of SOD1G93A glial progenitors to inflammatory cytokines when compared to wildtype mouse glial progenitors. This response was accompanied by the proliferation of glial progenitors but not mature GFAP+ astrocytes, through the translocation of the transcription factor Olig2 from the nucleus to the cytoplasm-resulting in astrocyte differentiation. These data suggest that adult glial progenitors from SOD1G93A mice differentially respond to inflammatory cytokines and contribute to the observed reactive astrocytosis observed in SOD1G93A mouse lumbar spinal cord.

• Stem cell myths.

  Authors: Tim Magnus, Ying Liu, Graham C Parker, Mahendra S Rao

  Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 02/2008; 363(1489):9-22.

  Stem cells, although difficult to define, hold great promise as tools for understanding development and as therapeutic agents. However, as with any new field, uncritical enthusiasm can outstripStem cells, although difficult to define, hold great promise as tools for understanding development and as therapeutic agents. However, as with any new field, uncritical enthusiasm can outstrip reality. In this review, we have listed nine common myths that we believe affect our approach to evaluating stem cells for therapy. We suggest that careful consideration needs to be given to each of these issues when evaluating a particular cell for its use in therapy. Data need to be collected and reported for failed as well as successful experiments and a rigorous scientific approach taken to evaluate the undeniable promise of stem cell biology.