@article{WeilandBeezWestermaieretal.2021, author = {Weiland, Judith and Beez, Alexandra and Westermaier, Thomas and Kunze, Ekkehard and Sir{\´e}n, Anna-Leena and Lilla, Nadine}, title = {Neuroprotective strategies in aneurysmal subarachnoid hemorrhage (aSAH)}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {11}, issn = {1422-0067}, doi = {10.3390/ijms22115442}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260755}, year = {2021}, abstract = {Aneurysmal subarachnoid hemorrhage (aSAH) remains a disease with high mortality and morbidity. Since treating vasospasm has not inevitably led to an improvement in outcome, the actual emphasis is on finding neuroprotective therapies in the early phase following aSAH to prevent secondary brain injury in the later phase of disease. Within the early phase, neuroinflammation, thromboinflammation, disturbances in brain metabolism and early neuroprotective therapies directed against delayed cerebral ischemia (DCI) came into focus. Herein, the role of neuroinflammation, thromboinflammation and metabolism in aSAH is depicted. Potential neuroprotective strategies regarding neuroinflammation target microglia activation, metalloproteases, autophagy and the pathway via Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), NF-κB and finally the release of cytokines like TNFα or IL-1. Following the link to thromboinflammation, potential neuroprotective therapies try to target microthrombus formation, platelets and platelet receptors as well as clot clearance and immune cell infiltration. Potential neuroprotective strategies regarding metabolism try to re-balance the mismatch of energy need and supply following aSAH, for example, in restoring fuel to the TCA cycle or bypassing distinct energy pathways. Overall, this review addresses current neuroprotective strategies in aSAH, hopefully leading to future translational therapy options to prevent secondary brain injury.}, language = {en} } @article{VadokasKoehlerWeilandetal.2019, author = {Vadokas, Georg and Koehler, Stefan and Weiland, Judith and Lilla, Nadine and Stetter, Christian and Westermaier, Thomas}, title = {Early antiinflammatory therapy attenuates brain damage after SAH in rats}, series = {Translational Neuroscience}, volume = {10}, journal = {Translational Neuroscience}, number = {1}, doi = {10.1515/tnsci-2019-0018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201440}, pages = {104-111}, year = {2019}, abstract = {Background Early inflammatory processes may play an important role in the development of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Experimental studies suggest that anti-inflammatory and membrane-stabilizing drugs might have beneficial effects, although the underlying mechanisms are not fully understood. The aim of this study was to investigate the effect of early treatment with methylprednisolone and minocycline on cerebral perfusion and EBI after experimental SAH. Methods Male Sprague-Dawley rats were subjected to SAH using the endovascular filament model. 30 minutes after SAH, they were randomly assigned to receive an intravenous injection of methylprednisolone (16mg/kg body weight, n=10), minocycline (45mg/kg body weight, n=10) or saline (n=11). Mean arterial blood pressure (MABP), intracranial pressure (ICP) and local cerebral blood flow (LCBF) over both hemispheres were recorded continuously for three hours following SAH. Neurological assessment was performed after 24 hours. Hippocampal damage was analyzed by immunohistochemical staining (caspase 3). Results Treatment with methylprednisolone or minocycline did not result in a significant improvement of MABP, ICP or LCBF. Animals of both treatment groups showed a non-significant trend to better neurological recovery compared to animals of the control group. Mortality was reduced and hippocampal damage significantly attenuated in both methylprednisolone and minocycline treated animals. Conclusion The results of this study suggest that inflammatory processes may play an important role in the pathophysiology of EBI after SAH. Early treatment with the anti-inflammatory drugs methylprednisolone or minocycline in the acute phase of SAH has the potential to reduce brain damage and exert a neuroprotective effect.}, language = {en} } @article{SchuhmannStollBohretal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region attenuates neuronal loss and cytokine expression in the perifocal region of photothrombotic stroke in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms20092341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201355}, year = {2019}, abstract = {Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson's disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.}, language = {en} } @phdthesis{Schlaberg2004, author = {Schlaberg, Robert}, title = {Neuroprotektiver Effekt von Ribavirin bei Borna Disease Virus infizierten Lewis-Ratten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-9772}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2004}, abstract = {Die Infektion mit dem Borna Disease Virus (BDV) ruft bei einem weiten Spektrum von Warmbl{\"u}tern ein teilweise progredientes, immunmediiertes neurologisches Syndrom hervor. BDV zeichnet sich durch ein einzelstr{\"a}ngiges RNA Genom negativer Polarit{\"a}t, einen ausgepr{\"a}gten Neurotropismus und einen nicht-lytischen Replikationszyklus aus, der in viraler Persistenz m{\"u}ndet. In vitro Experimente zeigten k{\"u}rzlich einen virostatischen Effekt des Guanosinanalogs Ribavirin gegen{\"u}ber BDV. Ziel der vorliegenden Studie war es, den therapeutischen Nutzen einer intrathekalen Ribavirinapplikation bei akuter Bornascher Erkrankung (BD) im Rattenmodell zu untersuchen. Toxikologische und pharmakokinetische Studien ergaben eine maximal vertr{\"a}gliche t{\"a}gliche Dosis von 2,5 mg/kg KG. Drei Wochen nach intranasaler Virusinokulation wurde Ribavirin in einer Dosis von 0, 1,25 und 2,5 mg/kg KG/Tag f{\"u}r 7 Tage intrathekal appliziert. Hierdurch gelang es, die klinische Symptomatik akuter BD dosisabh{\"a}ngig zu reduzieren. Die Bestimmung der Konzentration viraler RNA, Proteine, sowie infekti{\"o}ser Partikel in zentralnerv{\"o}sem Gewebe ergab jedoch keine signifikante Reduktion. Anschließende immunhistologische Untersuchungen konnten eine quantitative Reduktion von T-Lymphozyten und Mikrogliazellen in Hirnparenchym behandelter Tiere nachweisen. Sowohl CD4+, als auch CD8+ T-Lymphozyten sind wesentlich an der progressiven Neurodestruktion im Rahmen von BD beteiligt. Auch f{\"u}r Mikrogliazellen wird eine kausale Beteiligung an der Pathogenese von BD postuliert. Der klinisch protektive Effekt der zentralen Ribavirinapplikation scheint in dem vorliegenden Modell nicht auf eine Inhibition der Virusreplikation, sondern auf die Suppression der neuropathogenen Immunantwort des Wirtsorganismus zur{\"u}ckzuf{\"u}hren zu sein. Wie in anderen Studien wiederholt beschrieben, konnte virale RNA im Blut infizierter Lewis-Ratten detektiert werden. Die Vir{\"a}mie bei hochdosiert behandelten Tieren ist deutlich ausgepr{\"a}gter. Diese Beobachtung ist vermutlich durch eine systemische Infektion unter insuffizienter Immunkontrolle zu erkl{\"a}ren. Hieraus ergeben sich auch Implikationen f{\"u}r die diagnostische Nutzbarkeit des peripheren Nukleins{\"a}urenachweises zur Erkennung von BDV Infektionen. Die intrathekale Ribavirinapplikation ist der erste therapeutische Ansatz f{\"u}r BD, der zu einer Linderung des akuten Krankheitsbildes ohne gleichzeitige verst{\"a}rkte Virusreplikation f{\"u}hrt.}, language = {de} } @phdthesis{Schampel2017, author = {Schampel, Andrea}, title = {Beneficial therapeutic effects of the L-type calcium channel antagonist nimodipine in experimental autoimmune encephalomyelitis - an animal model for multiple sclerosis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148952}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Multiple sclerosis (MS) is the most prevalent neurological disease of the central nervous system (CNS) in young adults and is characterized by inflammation, demyelination and axonal pathology that result in multiple neurological and cognitive deficits. The focus of MS research remains on modulating the immune response, but common therapeutic strategies are only effective in slowing down disease progression and attenuating the symptoms; they cannot cure the disease. Developing an option to prevent neurodegeneration early on would be a valuable addition to the current standard of care for MS. Based on our results we suggest that application of nimodipine could be an effective way to target both neuroinflammation and neurodegeneration. We performed detailed analyses of neurodegeneration in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and in in vitro experiments regarding the effect of the clinically well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated the course of EAE and spinal cord histopathology. Furthermore, it promoted remyelination. The latter could be due to the protective effect on oligodendrocytes and oligodendrocyte precursor cells (OPCs) we observed in response to nimodipine treatment. To our surprise, we detected calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell type-specific and independent of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS expression and reactive oxygen species (ROS) activity in EAE. Overall, application of nimodipine seems to generate a favorable environment for regenerative processes and could therefore be a novel treatment option for MS, combining immunomodulatory effects while promoting neuroregeneration.}, subject = {Nimodipin}, language = {en} } @article{RoesingSalvadorGuentzeletal.2020, author = {R{\"o}sing, Nils and Salvador, Ellaine and G{\"u}ntzel, Paul and Kempe, Christoph and Burek, Malgorzata and Holzgrabe, Ulrike and Soukhoroukov, Vladimir and Wunder, Christian and F{\"o}rster, Carola}, title = {Neuroprotective Effects of Isosteviol Sodium in Murine Brain Capillary Cerebellar Endothelial Cells (cerebEND) After Hypoxia}, series = {Frontiers in Cellular Neuroscience}, volume = {14}, journal = {Frontiers in Cellular Neuroscience}, issn = {1662-5102}, doi = {10.3389/fncel.2020.573950}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215013}, year = {2020}, abstract = {Ischemic stroke is one of the leading causes of death worldwide. It damages neurons and other supporting cellular elements in the brain. However, the impairment is not only confined to the region of assault but the surrounding area as well. Besides, it also brings about damage to the blood-brain barrier (BBB) which in turn leads to microvascular failure and edema. Hence, this necessitates an on-going, continuous search for intervention strategies and effective treatment. Of late, the natural sweetener stevioside proved to exhibit neuroprotective effects and therapeutic benefits against cerebral ischemia-induced injury. Its injectable formulation, isosteviol sodium (STVNA) also demonstrated favorable results. Nonetheless, its effects on the BBB have not yet been investigated to date. As such, this present study was designed to assess the effects of STVNA in our in vitro stroke model of the BBB.The integrity and permeability of the BBB are governed and maintained by tight junction proteins (TJPs) such as claudin-5 and occludin. Our data show increased claudin-5 and occludin expression in oxygen and glucose (OGD)-deprived murine brain capillary cerebellar endothelial cells (cerebEND) after STVNa treatment. Likewise, the upregulation of the transmembrane protein integrin-αv was also observed. Finally, cell volume was reduced with the simultaneous administration of STVNA and OGD in cerebEND cells. In neuropathologies such as stroke, the failure of cell volume control is a major feature leading to loss of cells in the penumbra as well as adverse outcomes. Our initial findings, therefore, point to the neuroprotective effects of STVNA at the BBB in vitro, which warrant further investigation for a possible future clinical intervention.}, language = {en} } @article{RottlaenderKuerten2015, author = {Rottlaender, Andrea and Kuerten, Stefanie}, title = {Stepchild or prodigy? Neuroprotection in multiple sclerosis (MS) research}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160714850}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148416}, pages = {14850-14865}, year = {2015}, abstract = {Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) and characterized by the infiltration of immune cells, demyelination and axonal loss. Loss of axons and nerve fiber pathology are widely accepted as correlates of neurological disability. Hence, it is surprising that the development of neuroprotective therapies has been neglected for a long time. A reason for this could be the diversity of the underlying mechanisms, complex changes in nerve fiber pathology and the absence of biomarkers and tools to quantify neuroregenerative processes. Present therapeutic strategies are aimed at modulating or suppressing the immune response, but do not primarily attenuate axonal pathology. Yet, target-oriented neuroprotective strategies are essential for the treatment of MS, especially as severe damage of nerve fibers mostly occurs in the course of disease progression and cannot be impeded by immune modulatory drugs. This review shall depict the need for neuroprotective strategies and elucidate difficulties and opportunities.}, language = {en} } @article{RiedererterMeulen2020, author = {Riederer, Peter and ter Meulen, Volker}, title = {Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses}, series = {Journal of Neural Transmission}, volume = {127}, journal = {Journal of Neural Transmission}, number = {9}, issn = {0300-9564}, doi = {10.1007/s00702-020-02230-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314637}, pages = {1217-1228}, year = {2020}, abstract = {While there is abounding literature on virus-induced pathology in general and coronavirus in particular, recent evidence accumulates showing distinct and deleterious brain affection. As the respiratory tract connects to the brain without protection of the blood-brain barrier, SARS-CoV-2 might in the early invasive phase attack the cardiorespiratory centres located in the medulla/pons areas, giving rise to disturbances of respiration and cardiac problems. Furthermore, brainstem regions are at risk to lose their functional integrity. Therefore, long-term neurological as well as psychiatric symptomatology and eventual respective disorders cannot be excluded as evidenced from influenza-A triggered post-encephalitic Parkinsonism and HIV-1 triggered AIDS-dementia complex. From the available evidences for coronavirus-induced brain pathology, this review concludes a number of unmet needs for further research strategies like human postmortem brain analyses. SARS-CoV-2 mirroring experimental animal brain studies, characterization of time-dependent and region-dependent spreading behaviours of coronaviruses, enlightening of pathological mechanisms after coronavirus infection using long-term animal models and clinical observations of patients having had COVID-19 infection are calling to develop both protective strategies and drug discoveries to avoid early and late coronavirus-induced functional brain disturbances, symptoms and eventually disorders. To fight SARS-CoV-2, it is an urgent need to enforce clinical, molecular biological, neurochemical and genetic research including brain-related studies on a worldwide harmonized basis.}, language = {en} } @article{MuellerMuellerRiederer2021, author = {M{\"u}ller, Thomas and Mueller, Bernhard Klaus and Riederer, Peter}, title = {Perspective: Treatment for disease modification in chronic neurodegeneration}, series = {Cells}, volume = {10}, journal = {Cells}, number = {4}, issn = {2073-4409}, doi = {10.3390/cells10040873}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236644}, year = {2021}, abstract = {Symptomatic treatments are available for Parkinson's disease and Alzheimer's disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.}, language = {en} } @article{MinnerupSutherlandBuchanetal.2012, author = {Minnerup, Jens and Sutherland, Brad A. and Buchan, Alastair M. and Kleinschnitz, Christoph}, title = {Neuroprotection for Stroke: Current Status and Future Perspectives}, series = {International Journal of Molecular Science}, volume = {13}, journal = {International Journal of Molecular Science}, number = {9}, doi = {10.3390/ijms130911753}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134730}, pages = {11753-11772}, year = {2012}, abstract = {Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade.}, language = {en} } @article{KunzeLillaStetteretal.2018, author = {Kunze, Ekkehard and Lilla, Nadine and Stetter, Christian and Ernestus, Ralf-Ingo and Westermaier, Thomas}, title = {Magnesium protects in episodes of critical perfusion after aneurysmal SAH}, series = {Translational Neuroscience}, volume = {9}, journal = {Translational Neuroscience}, number = {1}, doi = {10.1515/tnsci-2018-0016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177078}, pages = {99-105}, year = {2018}, abstract = {Background: To analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH). Methods: 107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 - 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT. Results: In the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05). Conclusion: DIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion.}, language = {en} } @phdthesis{Korte2007, author = {Korte, Gabriele}, title = {Flavonoid-induzierte Cytotoxizit{\"a}t, Neuroprotektion und Immunmodulation im Zellmodell}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-26627}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2007}, abstract = {Flavonoide sind weitverbreitete sekund{\"a}re Pflanzeninhaltsstoffe. Ihr Beitrag zur Pr{\"a}vention von chronischen Erkrankungen wird zu großen Teilen auf immunmodulatorische und neuroprotektive Effekte zur{\"u}ckgef{\"u}hrt. Eine Voraussetzung f{\"u}r die Nutzung dieser Eigenschaften der Flavonoide stellt die Erfassung cytotoxischer Effekte dar. Mit Ausnahme von Xanthohumol und Quercetin ist f{\"u}r alle im Rahmen der vorliegenden Arbeit untersuchten Flavonoide, Hispidulin, Baicalein, Scutellarein, Hesperetin, Chrysin, Apigenin, Naringenin, Catechin, Pelargonidinchlorid und EMD 21388, sowohl in T-Zellen (Jurkat) als auch in neuronalen (SK-N-SH)-Zellen nach 24-st{\"u}ndiger Inkubation eine geringgradige Cytotoxizit{\"a}t festzuhalten. F{\"u}r Xanthohumol bzw. Quercetin wird ein halbmaximaler Verlust der Zellvitalit{\"a}t je nach Modell in Konzentrationen von 33-45 µM bzw. 118-208 µM erreicht. Der weiterf{\"u}hrenden Charakterisierung (zVAD, DNA-Laddering) ist zu entnehmen, dass die zellul{\"a}ren Ver{\"a}nderungen substanzabh{\"a}ngig differieren und sowohl nekrotische Mechanismen (Xanthohumol) als auch apoptotische Vorg{\"a}nge (Quercetin) einschließen. Eine erh{\"o}hte Lipidperoxidation im oberen Dosisbereich l{\"a}sst dar{\"u}ber hinaus auf eine Beteiligung von oxidativem Stress an den von Xanthohumol-induzierten nekrotischen Prozessen schließen. Eine positive Einflussnahme auf die Zellvitalit{\"a}t durch Antioxidantien wie GSH und NAC l{\"a}sst des Weiteren vermuten, dass die erfassten Flavonoid-induzierten Prozesse jeweils sensitiv zum Redoxzustand der Zelle sind. W{\"a}hrend die Effekte von Xanthohumol auch in anderen Zellmodellen (HL-60) nachweisbar bleiben, verh{\"a}lt sich Quercetin nicht durchgehend vitalit{\"a}tsmindernd. Unterschiede zwischen den Testsubstanzen bestehen auch hinsichtlich antioxidativer Effekte. Das Eliminieren freier Radikale z{\"a}hlt zu den wichtigsten Mechanismen, die bei Flavonoid-vermittelter Neuroprotektion eine Rolle spielen. Insgesamt sind alle diesbez{\"u}glich untersuchten Substanzen als starke Superoxidanionen-Radikalf{\"a}nger einzustufen. Im Co-Inkubationsversuch zeigt Scutellarein den st{\"a}rksten Effekt, gefolgt von Quercetin, Hispidulin und Xanthohumol. Im Pr{\"a}-Inkubations-Versuchsmodell liegen in der Reihenfolge ihrer Effektst{\"a}rken Xanthohumol vor Quercetin, Hispidulin und schließlich Scutellarein. Die modellabh{\"a}ngigen Konstanten k{\"o}nnen, unter Beteiligung einer passiven Diffusion der hydrophoben Flavonoidaglykone, auf eine substanzgebundene Membranpermeabilit{\"a}t zur{\"u}ckzuf{\"u}hren sein. Das antioxidative Potential der Flavonoide resultiert u.a. aus einer komplexen Einflußnahme auf die Genexpression in der Zelle. In der vorliegenden Arbeit sind anhand von cDNA-Arrays f{\"u}r mehrere Vertreter {\"u}bereinstimmend Wechselwirkungen mit Genen der zellul{\"a}ren Abwehr dargestellt. Demnach f{\"u}hren Scutellarein, Hispidulin, Quercetin und Xanthohumol zu einer deutlich reduzierten Expressionsst{\"a}rke von STK4, CHD4, ARHGDIB, IL16, ISG20, PFN1 und SOD2. Unter den Flavonoid-induzierten Ver{\"a}nderungen ragen die Effekte auf ADAR1 heraus, dessen Genexpression von Scutellarein bis auf ein 0,1-faches der Referenzwerte reduziert wird. Gleichsinnige Auswirkungen von Scutellarein auf die Expression von ADAR1-Protein in Western Blots unterstreichen diese Interaktion und legen nahe, dass ADAR-vermittelte enzymatische Deaminierungen durch Flavonoide moduliert werden k{\"o}nnen. Diese Beobachtung wird erg{\"a}nzt durch den nachgewiesenen Effekt von Flavonoiden auf die Expression einer Reihe weiterer Gene (ADAR2, APOBEC3B, APOBEC3C, APOBEC3F und APOBEC3G), die analoge posttranskriptionale Mechanismen steuern und gleichermaßen in Immunabwehr und Neuroprotektion eingebunden sind. Zu den wichtigsten Substraten von ADAR z{\"a}hlen Glutamatrezeptoren. Erwartungsgem{\"a}ß ist nach der Einwirkung von Scutellarein auf humane Zellen, die Glutamatrezeptoren exprimieren, ein R{\"u}ckgang der Deaminierung im Bereich der Glutamatrezeptoruntereinheit GluR 2 zu verzeichnen (Q/R-Position). Dem entspricht in elektrophysiologischen Modellen eine gesteigerte Ca2+-Permeabilit{\"a}t der jeweiligen Ionenkan{\"a}le und eine ver{\"a}nderte neuronale Exzitabilit{\"a}t. Hieraus ergibt sich ein breites Spektrum zus{\"a}tzlicher Optionen f{\"u}r die Induktion von gesundheitsrelevanten Flavonoidfunktionen in der Zelle. So spielt die Modulation von Deaminierungen zugleich eine entscheidende Rolle im Vermehrungszyklus viraler Erreger. Die Annahme einer m{\"o}glichen antiviralen Qualit{\"a}t von Scutellarein wird durch ein HBV-Infektionsmodell anhand drei Parameter der Virusreplikation (Virus-DNA-Konzentration, HBs- bzw. HBe-Antigenproduktion) best{\"a}tigt. Offen bleibt auch nach ausf{\"u}hrlicher Pr{\"u}fung, ob der deutliche antivirale Effekt als das Produkt von Flavonoid-induzierten Ver{\"a}nderungen der Deaminierungsraten oder als Folge eines Effekts auf die virale Polymerase zu interpretieren ist. Die hier dargestellten Wirkmechanismen leisten einen Beitrag zum Verst{\"a}ndnis der Bedeutung von Flavonoiden f{\"u}r neue Anwendungen in Neuroprotektion und Immunabwehr.}, subject = {Flavonoide}, language = {de} } @article{GerlachMaetzlerBroichetal.2012, author = {Gerlach, Manfred and Maetzler, Walter and Broich, Karl and Hampel, Harald and Rems, Lucas and Reum, Torsten and Riederer, Peter and St{\"a}ffler, Albrecht and Streffer, Johannes and Berg, Daniela}, title = {Biomarker candidates of neurodegeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics}, series = {Journal of Neural Transmission}, volume = {119}, journal = {Journal of Neural Transmission}, number = {1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125375}, pages = {39-52}, year = {2012}, abstract = {Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson's disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies.}, language = {en} } @phdthesis{Dreiseitel2011, author = {Dreiseitel, Andrea}, title = {In vitro bioactivities of dietary anthocyanins and proanthocyanidins: implications for bioavailability, neuroprotection and safety}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-57550}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Over the past decades, awareness has increased of multiple health-promoting effects of diets rich in anthocyanins and proanthocyanidins and, specifically, of these compounds' potential for conferring neuroprotection. The present study compiles evidence obtained in vitro that expands our understanding of anthocyanin and proanthocyanidin functionalities at multiple levels. Firstly, anthocyanin and anthocyanidin bioavailability was addressed using a combination of ATPase assays, dye extrusion assays and vesicular transport assays. This approach highlights the contribution made by efflux transporters MDR1 and BCRP to the absorption of berry polyphenols and to their distribution to target tissues including the central nervous system. All test compounds interacted with the BCRP transporter in vitro, seven emerged as potential BCRP substrates and 12 as potential inhibitors of BCRP. Two anthocyanidins, malvidin and petunidin, exhibited bimodal activities, serving as BCRP substrates at low micromolar concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak, as only aglycones exerted mild inhibitory activity in the high micromolar range. Distinct affinities of several anthocyanins and the respective aglycones for BCRP suggest that they may be actively transported out of endothelia. Agents that interfere with BCRP activity are therefore likely to facilitate crossing of the intestinal and blood-brain barriers and to augment anthocyanin bioavailability. Secondly, novel modes of action were sought to rationalize berry polyphenols' direct modulation of neuronal transmission as opposed to their non-specific antioxidant activities. The candidate effectors include cellular monoamine oxidases (MAO) A and B, hypoxia inducible factor (HIF), the proteasome, and phospholipase A2 (PLA2). Elevated MAO activity has long been implicated in the etiology of depression, anxiety and neurodegenerative illness. MAO inhibiting compounds may thus hold promise in the prevention of behavioral symptoms and cognitive decline. For both MAO isoforms, inhibitory effects of anthocyanins and anthocyanidins are illustrated by IC50 values in the low micromolar range whereas proanthocyanidins and phenolic metabolites were less effective inhibitors. Kinetic analyses, performed with cyanidin and cyanidin-3-glucoside, indicated a competitive interaction of cyanidin in terms of MAO A, plus a mixed competitive and non-competitive mode of interaction of cyanidin in terms of MAO B as well as of cyanidin-3-glucoside with respect to both enzyme isoforms. Thus MAO inhibition by anthocyanins and their aglycones in vitro lends support to central nervous functionalities of diets rich in berry polyphenols and opens new opportunities in the prevention of neuronal pathologies. Effects on HIF expression were examined to assess candidate compounds' role in enhancing cellular resistance to oxidative stress. By inducing a dose-dependent increase in HIF expression, delphinidin may initiate a variety of cellular survival processes that are inhibited by free iron. This finding argues in favor of iron-chelating properties as a further means of mediating neuroprotection. Other inducers of HIF expression in neuroblastoma cells included gallic acid, cyanidin and bilberry extract, all of which may modulate HIF-dependent transcription of downstream genes.}, subject = {Anthocyane}, language = {en} } @article{CoxLimpensVlesvandenHoveetal.2014, author = {Cox-Limpens, Kimberly E. M. and Vles, Johan S. H. and van den Hove, Daniel L. A. and Zimmermann, Luc Ji and Gavilanes, Antonio W. D.}, title = {Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia}, series = {BMC Neuroscience}, volume = {15}, journal = {BMC Neuroscience}, doi = {10.1186/1471-2202-15-67}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116185}, pages = {67}, year = {2014}, abstract = {Background: Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates. Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and whole-genome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance. Results: We observed minimal, 25\% or less, overlap of differentially regulated transcripts across different experimental groups which leads us to conclude that the transcriptional phenotype of these groups is largely unique. In both the PA and FAPA group we observe an upregulation of transcripts involved in cellular stress. Contrastingly, transcripts with a function in the cell nucleus were mostly downregulated in PA animals, while we see considerable upregulation in the FAPA group. Furthermore, we observed that histone deacetylases (HDACs) are exclusively regulated in FAPA animals. Conclusions: This study is the first to investigate whole-genome transcription in the neonatal brain after PA alone, and after perinatal asphyxia preceded by preconditioning (FAPA). We describe several genes/pathways, such as ubiquitination and proteolysis, which were not previously linked to preconditioning-induced neuroprotection. Furthermore, we observed that the majority of upregulated genes in preconditioned animals have a function in the cell nucleus, including several epigenetic players such as HDACs, which suggests that epigenetic mechanisms are likely to play a role in preconditioning-induced neuroprotection.}, language = {en} } @article{BoltzeKleinschnitzReymannetal.2012, author = {Boltze, Johannes and Kleinschnitz, Christoph and Reymann, Klaus G. and Reiser, Georg and Wagner, Daniel-Christoph and Kranz, Alexander and Michalski, Dominik}, title = {Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain - current trends in basic, translational and clinical research}, series = {Experimental \& Translational Stroke Medicine}, volume = {4}, journal = {Experimental \& Translational Stroke Medicine}, number = {14}, doi = {doi:10.1186/2040-7378-4-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126679}, year = {2012}, abstract = {The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood-brain barrier, recent findings regarding the pathomechanism of Alzheimer's disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting.}, language = {en} } @article{BauneKonradGrotegerdetal.2012, author = {Baune, Bernhard T. and Konrad, Carsten and Grotegerd, Dominik and Suslow, Thomas and Birosova, Eva and Ohrmann, Patricia and Bauer, Jochen and Arolt, Volker and Heindel, Walter and Domschke, Katharina and Sch{\"o}ning, Sonja and Rauch, Astrid V. and Uhlmann, Christina and Kugel, Harald and Dannlowski, Udo}, title = {Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain}, series = {Journal of Neuroinflammation}, volume = {9}, journal = {Journal of Neuroinflammation}, number = {125}, doi = {10.1186/1742-2094-9-125}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130804}, year = {2012}, abstract = {Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e. g., Stampa algorigthm), yielding a capture 97.08\% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results In a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.}, language = {en} } @article{BadrMcFlederWuetal.2022, author = {Badr, Mohammad and McFleder, Rhonda L. and Wu, Jingjing and Knorr, Susanne and Koprich, James B. and H{\"u}nig, Thomas and Brotchie, Jonathan M. and Volkmann, Jens and Lutz, Manfred B. and Ip, Chi Wang}, title = {Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson's disease mice}, series = {Journal of Neuroinflammation}, volume = {19}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-022-02685-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300580}, year = {2022}, abstract = {Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson's disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson's disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson's disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson's disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson's disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson's disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson's disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson's disease patients.}, language = {en} }