@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}
}
@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{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{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{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{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}
}
@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{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{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{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}
}