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Öğe ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury(Nature Research, 2022) Rohlfing, Anne-Katrin; Kolb, Kyra; Sigle, Manuel; Ziegler, Melanie; Bild, Alexander; Münzer, Patrick; Sudmann, Jessica; Dicenta, Valerie; Harm, Tobias; Manke, Mailin-Christin; Geue, Sascha; Kremser, Marcel; Chatterjee, Madhumita; Liang, Chunguang; Eysmondt, Hendrik von; Dandekar, Thomas; Heinzmann, David; Günter, Manina; Ungern-Sternberg, Saskia von; Büttcher, Manuela; Castor, Tatsiana; Mencl, Stine; Langhauser, Friederike; Sies, Katharina; Ashour, Diyaa; Beker, Mustafa Çağlar; Lämmerhofer, Michael; Autenrieth, Stella E.; Schäffer, Tilman E.; Laufer, Stefan; Szklanna, Paulina; Maguire, Patricia; Heikenwalder, Matthias; Müller, Karin Anne Lydia; Hermann, Dirk M.; Kılıç, Ertuğrul; Stumm, Ralf; Ramos, Gustavo; Kleinschnitz, Christoph; Borst, Oliver; Langer, Harald F.; Rath, Dominik; Gawaz, MeinradPlatelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.Öğe Adipose-derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR-25(Taylor & Francis Ltd, 2020) Kuang, Yaoyun; Zheng, Xuan; Zhang, Lin; Ai, Xiaoyu; Venkataramani, Vivek; Kılıç, Ertuğrul; Hermann, Dirk M.; Majid, Arshad; Baehr, Mathias; Doeppner, Thorsten R.Grafted mesenchymal stem cells (MSCs) yield neuroprotection in preclinical stroke models by secreting extracellular vesicles (EVs). The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such cargo and its underlying mechanism, primary neurons were exposed to oxygen-glucose-deprivation (OGD) and cocultured with adipose-derived MSCs (ADMSCs) or ADMSC-secreted EVs. Under such conditions, both ADMSCs and ADMSC-secreted EVs significantly reduced neuronal death. Screening for signalling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53-BNIP3 activity in neurons receiving either treatment paradigm. However, the aforementioned effects were reversed when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869 or when Hrs was knocked down. In light of miR-25-3p being the most highly expressed miRNA in ADMSC-EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Indeed, a miR-25-3p oligonucleotide mimic reduced cell death, whereas the anti-oligonucleotide increased autophagic flux and cell death by modulating p53-BNIP3 signalling in primary neurons exposed to OGD. Likewise, native ADMSC-EVs but not EVs obtained from ADMSCs pretreated with the anti-miR-25-3p oligonucleotide (ADMSC-EVs(anti-miR-25-3p)) confirmed the aforementioned in vitro observations in C57BL/6 mice exposed to cerebral ischemia. The infarct size was reduced, and neurological recovery was increased in mice treated with native ADMSC-EVs when compared to ADMSC-EVs(anti-miR-25-3p). ADMSCs induce neuroprotection by improved autophagic flux through secreted EVs containing miR-25-3p. Hence, our work uncovers a novel key factor in naturally secreted ADMSC-EVs for the regulation of autophagy and induction of neuroprotection in a preclinical stroke model.Öğe Age-associated resilience against ischemic injury in mice exposed to transient middle cerebral artery occlusion(Springer, 2023) Beker, Mustafa Çağlar; Aydınlı, Fatmagül İlayda; Çağlayan, Ahmet Burak; Beker, Merve; Baygül, Oğuzhan; Çağlayan, Aysun; Popa-Wagner, Aurel; Doeppner, Thorsten R.; Hermann, Dirk M.; Kılıç, ErtuğrulIschemic stroke is the leading cause of death and disability. Although stroke mainly affects aged individuals, animal research is mostly one on young rodents. Here, we examined the development of ischemic injury in young (9-12-week-old) and adult (72-week-old) C57BL/6 and BALB/c mice exposed to 30 min of intraluminal middle cerebral artery occlusion (MCAo). Post-ischemic reperfusion did not differ between young and adult mice. Ischemic injury assessed by infarct area and blood-brain barrier (BBB) integrity assessed by IgG extravasation analysis was smaller in adult compared with young mice. Microvascular viability and neuronal survival assessed by CD31 and NeuN immunohistochemistry were higher in adult than young mice. Tissue protection was associated with stronger activation of cell survival pathways in adult than young mice. Microglial/macrophage accumulation and activation assessed by F4/80 immunohistochemistry were more restricted in adult than young mice, and pro- and anti-inflammatory cytokine and chemokine responses were reduced by aging. By means of liquid chromatography-mass spectrometry, we identified a hitherto unknown proteome profile comprising the upregulation of glycogen degradation-related pathways and the downregulation of mitochondrial dysfunction-related pathways, which distinguished post-ischemic responses of the aged compared with the young brain. Our study suggests that aging increases the brain's resilience against ischemic injury.Öğe CCL11 differentially affects post-stroke brain injury and neuroregeneration in mice depending on age(MDPI, 2020) Lieschke, Simone; Zechmeister, Bozena; Haupt, Matteo; Zheng, Xuan; Jin, Fengyan; Hein, Katharina; Weber, Martin S.; Hermann, Dirk M.; Bähr, Mathias; Kılıç, Ertuğrul; Doeppner, Thorsten R.CCL11 has recently been shown to differentially affect cell survival under various pathological conditions including stroke. Indeed, CCL11 promotes neuroregeneration in neonatal stroke mice. The impact of CCL11 on the adult ischemic brain, however, remains elusive. We therefore studied the effect of ectopic CCL11 on both adolescent (six-week) and adult (six-month) C57BL6 mice exposed to stroke. Intraperitoneal application of CCL11 significantly aggravated acute brain injury in adult mice but not in adolescent mice. Likewise, post-stroke neurological recovery after four weeks was significantly impaired in adult mice whilst CCL11 was present. On the contrary, CCL11 stimulated gliogenesis and neurogenesis in adolescent mice. Flow cytometry analysis of blood and brain samples revealed a modification of inflammation by CCL11 at subacute stages of the disease. In adolescent mice, CCL11 enhances microglial cell, B and T lymphocyte migration towards the brain, whereas only the number of B lymphocytes is increased in the adult brain. Finally, the CCL11 inhibitor SB297006 significantly reversed the aforementioned effects. Our study, for the first time, demonstrates CCL11 to be a key player in mediating secondary cell injury under stroke conditions. Interfering with this pathway, as shown for SB297006, might thus be an interesting approach for future stroke treatment paradigms.Öğe Conditioned medium derived from neural progenitor cells induces long-term post-ischemic neuroprotection, sustained neurological recovery, neurogenesis, and angiogenesis(Springer, 2017) Doeppner, Thorsten R.; Traut, Viktorija; Heidenreich, Alexander; Kaltwasser, Britta; Bosche, Bert; Bahr, Mathias; Hermann, Dirk M.Adult neural progenitor cells (NPCs) induce post-ischemic long-term neuroprotection and brain remodeling by releasing of survival- and plasticity-promoting mediators. To evaluate whether secreted factors may mimic neuroprotective and restorative effects of NPCs, we exposed male C57BL6 mice to focal cerebral ischemia and intravenously applied conditioned medium (CM) derived from subventricular zone NPCs. CM dose-dependently reduced infarct volume and brain leukocyte infiltration after 48 h when delivered up to 12 h after focal cerebral ischemia. Neuroprotection persisted in the post-acute stroke phase yielding enhanced neurological recovery that lasted throughout the 28-day observation period. Increased Bcl-2, phosphorylated Akt and phosphorylated STAT-3 abundance, and reduced caspase-3 activity and Bax abundance were noted in ischemic brains of CM-treated mice at 48 h post-stroke, indicative of enhanced cell survival signaling. Long-term neuroprotection was associated with increased brain glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) concentrations at 28 days resulting in increased neurogenesis and angiogenesis. The observation that NPC-derived CM induces sustained neuroprotection and neurological recovery suggests that cell transplantation may be dispensable when secreted factors are instead administered.Öğe Developing a novel tool to assess the ability to self-administer medication - A systematic evaluation of patients' video recordings in the ABLYMED study(Frontiers Media S.A., 2023) Luegering, Anneke; Langner, Robert; Wilm, Stefan; Doeppner, Thorsten R.; Hermann, Dirk M.; Frohnhofen, Helmut; Gronewold, JanineBackground: Older people often experience medication management problems due to multimorbidity, polypharmacy and medication complexity. There is often a large gap between patients' self-reported and actual abilities to handle the self -administration of their medication. Here we report on the development and evaluation of a new tool to assess the ability of non-demented hospitalized patients to self-administer medication in different dosage forms. To this end, we video-recorded the patients' medication management performance and implemented a novel assessment scheme, which was applied by several independent raters.Methods: Sixty-seven in-patients > 70 years of age and regularly taking > 5 different drugs autonomously of the ABLYMED study agreed to the video recording of their medication management performance with five different dosage forms. All raters underwent a training and applied a standardized assessment form and written guide with rating rules for evaluation. In a pilot phase, video recordings of three patients were rated by 19 raters (15 medical students, two expert raters to determine a reference standard, and two main raters who later rated the total sample). In the rating phase, based on the ratings obtained from the two main raters, we determined interrater (assessed every section of 20 patients as agreement between the raters at one point of time) and intrarater (assessed as consistency within each rater across three points of time) agreement by intraclass correlation analysis.Results: In the pilot phase we obtained an overall sufficient agreement pattern, with an adjustment of the rating rules for patches. In the rating phase we achieved satisfactory agreement between the two raters (interrater reliability) and across different points of time (intrarater reliability). For two dosage forms (eye-drops and pen), rater training needed to be repeated to reach satisfactory levels.Discussion: Our novel rating procedure was found to be objective, valid and reproducible, given appropriate training of the raters. Our findings are an important part of a larger research project to implement a novel assessment for the ability to self-administer medication in different dosage forms. Further, they can support the development of patient trainings to improve medication management and secure independent living.Öğe Emerging roles of extracellular vesicle-associated non-coding RNAs in hypoxia: Insights from cancer, myocardial infarction and ischemic stroke(Ivyspring International Publisher, 2022) Hermann, Dirk M.; Xin, Wenqiang; Baehr, Mathias; Giebel, Bernd; Doeppner, Thorsten R.Hypoxia is a central pathophysiological component in cancer, myocardial infarction and ischemic stroke, which represent the most common medical conditions resulting in long-term disability and death. Recent evidence suggests common signaling pathways in these diverse settings mediated by non-coding RNAs (ncRNAs), which are packaged in extracellular vesicles (EVs) protecting ncRNAs from degradation. EVs are a heterogeneous group of lipid bilayer-covered vesicles released from virtually all cells, which have important roles in intercellular communication. Recent studies pointed out that ncRNAs including long non-coding RNAs (IncRNAs) and microRNAs (miRNAs) are selectively sorted into EVs, modulating specific aspects of cancer development, namely cell proliferation, migration, invasion, angiogenesis, immune tolerance or drug resistance, under conditions of hypoxia in recipient cells. In myocardial infarction and stroke, ncRNAs shuttled via EVs have been shown to control tissue survival and remodeling post-hypoxia by regulating cell injury, inflammatory responses, angiogenesis, neurogenesis or neuronal plasticity. This review discusses recent evidence on EV-associated ncRNAs in hypoxic cancer, myocardial infarction and stroke, discussing their cellular origin, biological function and disease significance. The emerging concept of IncRNA-circular RNA/ miRNA/ mRNA networks is outlined, upon which ncRNAs synergistically respond to hypoxia in order to modify disease responses. Particular notion is given to ncRNAs participating in at least two of the three conditions, which revealed a large degree of overlaps across pathophysiological conditions. Possible roles of EV-ncRNAs as therapeutic products or theranostic markers are defined.Öğe Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-beta/Smad2/3 pathway(Springer Nature, 2021) Zhang, Lin; Wei, Wei; Ai, Xiaoyu; Kılıç, Ertuğrul; Hermann, Dirk M.; Venkataramani, Vivek; Baehr, Mathias; Doeppner, Thorsten R.Systemic transplantation of oxygen-glucose deprivation (OGD)-preconditioned primary microglia enhances neurological recovery in rodent stroke models, albeit the underlying mechanisms have not been sufficiently addressed. Herein, we analyzed whether or not extracellular vesicles (EVs) derived from such microglia are the biological mediators of these observations and which signaling pathways are involved in the process. Exposing bEnd.3 endothelial cells (ECs) and primary cortical neurons to OGD, the impact of EVs from OGD-preconditioned microglia on angiogenesis and neuronal apoptosis by the tube formation assay and TUNEL staining was assessed. Under these conditions, EV treatment stimulated both angiogenesis and tube formation in ECs and repressed neuronal cell injury. Characterizing microglia EVs by means of Western blot analysis and other techniques revealed these EVs to be rich in TGF-beta 1. The latter turned out to be a key compound for the therapeutic potential of microglia EVs, affecting the Smad2/3 pathway in both ECs and neurons. EV infusion in stroke mice confirmed the aforementioned in vitro results, demonstrating an activation of the TGF-beta/Smad2/3 signaling pathway within the ischemic brain. Furthermore, enriched TGF-beta 1 in EVs secreted from OGD-preconditioned microglia stimulated M2 polarization of residing microglia within the ischemic cerebral environment, which may contribute to a regulation of an early inflammatory response in postischemic hemispheres. These observations are not only interesting from the mechanistic point of view but have an immediate therapeutic implication as well, since stroke mice treated with such EVs displayed a better functional recovery in the behavioral test analyses. Hence, the present findings suggest a new way of action of EVs derived from OGD-preconditioned microglia by regulating the TGF-beta/Smad2/3 pathway in order to promote tissue regeneration and neurological recovery in stroke mice.Öğe HMG-CoA reductase inhibition promotes neurological recovery, peri-lesional tissue remodeling, and contralesional pyramidal tract plasticity after focal cerebral ischemia(Frontiers Research Foundation, 2014) Kılıç, Ertuğrul; Reitmeir, Raluca; Kılıç, Ülkan; Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Kelestemur, Taha; Ethemoğlu, Muhsine Sinem; Öztürk, Gürkan; Hermann, Dirk M.3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are widely used for secondary stroke prevention. Besides their lipid-lowering activity, pleiotropic effects on neuronal survival, angiogenesis, and neurogenesis have been described. In view of these observations, we were interested whether HMG-CoA reductase inhibition in the post-acute stroke phase promotes neurological recovery, peri-lesional, and contralesional neuronal plasticity. We examined effects of the HMG-CoA reductase inhibitor rosuvastatin (0.2 or 2.0 mg/kg/day i.c.v.), administered starting 3 days after 30 min of middle cerebral artery occlusion for 30 days. Here, we show that rosuvastatin treatment significantly increased the grip strength and motor coordination of animals, promoted exploration behavior, and reduced anxiety. It was associated with structural remodeling of peri-lesional brain tissue, reflected by increased neuronal survival, enhanced capillary density, and reduced striatal and corpus callosum atrophy. Increased sprouting of contralesional pyramidal tract fibers crossing the midline in order to innervate the ipsilesional red nucleus was noticed in rosuvastatin compared with vehicle-treated mice, as shown by anterograde tract tracing experiments. Western blot analysis revealed that the abundance of HMG-CoA reductase was increased in the contralesional hemisphere at 14 and 28 days post-ischemia. Our data support the idea that HMG-CoA reductase inhibition promotes brain remodeling and plasticity far beyond the acute stroke phase, resulting in neurological recovery.Öğe HMG-CoA reductase inhibition promotes stroke recovery perilesional tissue remodeling and contralesional pyramidal tract plasticity(Wiley-Blackwell, 2014) Kılıç, Ertuğrul; Reitmeir, Raluca; Kılıç, Ülkan; Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Ethemoğlu, Sinem; Hermann, Dirk M.[Abstract Not Available]Öğe HMG-CoA reductase inhibition promotes stroke recovery perilesional tissue remodeling and contralesional pyramidal tract plasticity(Springer Heidelberg, 2014) Kılıç, Ertuğrul; Reitmeir, Raluca; Kılıç, Ülkan; Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Ethemoğlu, Sinem; Hermann, Dirk M.[Abstract Not Available]Öğe Inhibition of fatty acid synthesis aggravates brain injury, reduces blood-brain barrier integrity and impairs neurological recovery in a murine stroke model(Frontiers Media SA, 2021) Janssen, Lisa; Ai, Xiaoyu; Zheng, Xuan; Wei, Wei; Çağlayan, Ahmet Burak; Kılıç, Ertuğrul; Wang, Ya-chao; Hermann, Dirk M.; Venkataramani, Vivek; Baehr, Mathias; Doeppner, Thorsten R.Inhibition of fatty acid synthesis (FAS) stimulates tumor cell death and reduces angiogenesis. When SH-SY5Y cells or primary neurons are exposed to hypoxia only, inhibition of FAS yields significantly enhanced cell injury. The pathophysiology of stroke, however, is not only restricted to hypoxia but also includes reoxygenation injury. Hence, an oxygen-glucose-deprivation (OGD) model with subsequent reoxygenation in both SH-SY5Y cells and primary neurons as well as a murine stroke model were used herein in order to study the role of FAS inhibition and its underlying mechanisms. SH-SY5Y cells and cortical neurons exposed to 10 h of OGD and 24 h of reoxygenation displayed prominent cell death when treated with the Acetyl-CoA carboxylase inhibitor TOFA or the fatty acid synthase inhibitor cerulenin. Such FAS inhibition reduced the reduction potential of these cells, as indicated by increased NADH(2)(+)/NAD(+) ratios under both in vitro and in vivo stroke conditions. As observed in the OGD model, FAS inhibition also resulted in increased cell death in the stroke model. Stroke mice treated with cerulenin did not only display increased brain injury but also showed reduced neurological recovery during the observation period of 4 weeks. Interestingly, cerulenin treatment enhanced endothelial cell leakage, reduced transcellular electrical resistance (TER) of the endothelium and contributed to poststroke blood-brain barrier (BBB) breakdown. The latter was a consequence of the activated NF-kappa B pathway, stimulating MMP-9 and ABCB1 transporter activity on the luminal side of the endothelium. In conclusion, FAS inhibition aggravated poststroke brain injury as consequence of BBB breakdown and NF-kappa B-dependent inflammation.Öğe Ischemic post-conditioning induces post-stroke neuroprotection via Hsp70-mediated proteasome inhibition and facilitates neural progenitor cell transplantation(Humana Press Inc, 2017) Doeppner, Thorsten R.; Doehring, Maria; Kaltwasser, Britta; Majid, Arshad; Lin, Fengyan; Bahr, Mathias; Kılıç, Ertuğrul; Hermann, Dirk M.In view of the failure of pharmacological therapies, alternative strategies promoting post-stroke brain repair are needed. Post-conditioning is a potentially promising therapeutic strategy, which induces acute neuroprotection against ischemic injury. To elucidate longer lasting actions of ischemic post-conditioning, mice were exposed to a 60-min stroke and post-conditioning by an additional 10-min stroke that was induced 10 min after reperfusion onset. Animals were sacrificed 24 h or 28 days post-stroke. Post-conditioning reduced infarct volume and neurological deficits 24 h poststroke, enhancing blood-brain barrier integrity, reducing brain leukocyte infiltration, and reducing oxidative stress. On the molecular level, post-conditioning yielded increased Hsp70 expression, whereas nuclear factor (NF)-kappa B and proteasome activities were decreased. Reduced infarct volume and proteasome inhibition were reversed by Hsp70 knockdown, suggesting a critical role of the Hsp70 proteasome pathway in ischemic post-conditioning. The survival-promoting effects of ischemic post-conditioning, however, were not sustainable as neuroprotection and neurological recovery were lost 28 days post-stroke. Although angioneurogenesis was not increased by post-conditioning, the favorable extracellular milieu facilitated intracerebral transplantation of neural progenitor cells 6 h post-stroke, resulting in persisted neuroprotection and neurological recovery. Thus, post-conditioning might support brain repair processes, but in view of its transient, neuroprotection is unlikely useful as stroke therapy in its current form.Öğe Knockdown of NEAT1 prevents post-stroke lipid droplet agglomeration in microglia by regulating autophagy(Springer Science and Business Media Deutschland GmbH, 2024) Pan, Yongli; Xin, Wenqiang; Wei, Wei; Tatenhorst, Lars; Graf, Irina; Popa-Wagner, Aurel; Gerner, Stefan T.; Huber, Sabine E.; Kılıç, Ertuğrul; Hermann, Dirk M.; Bähr, Mathias; Huttner, Hagen B.; Doeppner, Thorsten RolandBackground: Lipid droplets (LD), lipid-storing organelles containing neutral lipids like glycerolipids and cholesterol, are increasingly accepted as hallmarks of inflammation. The nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA with over 200 nucleotides, exerts an indispensable impact on regulating both LD agglomeration and autophagy in multiple neurological disorders. However, knowledge as to how NEAT1 modulates the formation of LD and associated signaling pathways is limited. Methods: In this study, primary microglia were isolated from newborn mice and exposed to oxygen-glucose-deprivation/reoxygenation (OGD/R). To further explore NEAT1-dependent mechanisms, an antisense oligonucleotide (ASO) was adopted to silence NEAT1 under in vitro conditions. Studying NEAT1-dependent interactions with regard to autophagy and LD agglomeration under hypoxic conditions, the inhibitor and activator of autophagy 3-methyladenine (3-MA) and rapamycin (RAPA) were used, respectively. In a preclinical stroke model, mice received intraventricular injections of ASO NEAT1 or control vectors in order to yield NEAT1 knockdown. Analysis of readout parameters included qRT-PCR, immunofluorescence, western blot assays, and behavioral tests. Results: Microglia exposed to OGD/R displayed a temporal pattern of NEAT1 expression, peaking at four hours of hypoxia followed by six hours of reoxygenation. After effectively silencing NEAT1, LD formation and autophagy-related proteins were significantly repressed in hypoxic microglia. Stimulating autophagy in ASO NEAT1 microglia under OGD/R conditions by means of RAPA reversed the downregulation of LD agglomeration and perilipin 2 (PLIN2) expression. On the contrary, application of 3-MA promoted repression of both LD agglomeration and expression of the LD-associated protein PLIN2. Under in vivo conditions, NEAT1 was significantly increased in mice at 24 h post-stroke. Knockdown of NEAT1 significantly alleviated LD agglomeration and inhibited autophagy, resulting in improved cerebral perfusion, reduced brain injury and increased neurological recovery. Conclusion: NEAT1 is a key player of LD agglomeration and autophagy stimulation, and NEAT1 knockdown provides a promising therapeutic value against stroke. Graphical abstract: [Figure not available: see fulltext.].Öğe Lentivirally administered glial cell line-derived neurotrophic factor promotes post-ischemic neurological recovery, brain remodeling and contralesional pyramidal tract plasticity by regulating axonal growth inhibitors and guidance proteins(Academic Press Inc Elsevier Science, 2020) Beker, Merve; Çağlayan, Ahmet Burak; Beker, Mustafa Çağlar; Altunay, Serdar; Karaçay, Reyda; Dalay, Arman; Altıntaş, Mehmet Özgen; Torun Köse, Gamze; Hermann, Dirk M.; Kılıç, ErtuğrulOwing to its potent longterm neuroprotective and neurorestorative properties, glial cell line-derived neurotrophic factor (GDNF) is currently studied in neurodegenerative disease clinical trials. However, little is known about the longterm effect of GDNF on neurological recovery, brain remodeling and neuroplasticity in the post-acute phase of ischemic stroke. In a comprehensive set of experiments, we examined the effects of lentiviral GDNF administration after ischemic stroke. GDNF reduced neurological deficits, neuronal injury, blood-brain barrier permeability in the acute phase in mice. As compared with control, enhanced motor-coordination and spontaneous locomotor activity were noted in GDNF-treated mice, which were associated with increased microvascular remodeling, increased neurogenesis and reduced glial scar formation in the peri-infarct tissue. We observed reduced brain atrophy and increased plasticity of contralesional pyramidal tract axons that crossed the midline in order to innervate denervated neurons in the ipsilesional red and facial nuclei. Contralesional axonal plasticity by GDNF was associated with decreased abundance of the axonal growth inhibitors brevican and versican in contralesional and ipsilesional brain tissue, reduced abundance of the growth repulsive guidance molecule ephrin b1 in contralesional brain tissue, increased abundance of the midline growth repulsive protein Slit1 in contralesional brain tissue and reduced abundance of Slit1's receptor Robo2 in ipsilesional brain tissue. These data indicate that GDNF potently induces longterm neurological recovery, peri-infarct brain remodeling and contralesional neuroplasticity, which are associated with the fine-tuned regulation of axonal growth inhibitors and guidance molecules that facilitate the growth of contralesional corticofugal axons in the direction to the ipsilesional hemisphere.Öğe Lithium modulates miR-1906 levels of mesenchymal stem cell-derived extracellular vesicles contributing to poststroke neuroprotection by toll-like receptor 4 regulation(Wiley, 2021) Haupt, Matteo; Zheng, Xuan; Kuang, Yaoyun; Lieschke, Simone; Janssen, Lisa; Bosche, Bert; Jin, Fengyan; Hein, Katharina; Kılıç, Ertuğrul; Venkataramani, Vivek; Hermann, Dirk M.; Bahr, Mathias; Doeppner, Thorsten R.Lithium is neuroprotective in preclinical stroke models. In addition to that, poststroke neuroregeneration is stimulated upon transplantation of mesenchymal stem cells (MSCs). Preconditioning of MSCs with lithium further enhances the neuroregenerative potential of MSCs, which act by secreting extracellular vesicles (EVs). The present work analyzed, whether MSC preconditioning with lithium modifies EV secretion patterns, enhancing the therapeutic potential of such derived EVs (Li-EVs) in comparison with EVs enriched from native MSCs. Indeed, Li-EVs significantly enhanced the resistance of cultured astrocytes, microglia, and neurons against hypoxic injury when compared with controls and to native EV-treated cells. Using a stroke mouse model, intravenous delivery of Li-EVs increased neurological recovery and neuroregeneration for as long as 3 months in comparison with controls and EV-treated mice, albeit the latter also showed significantly better behavioral test performance compared with controls. Preconditioning of MSCs with lithium also changed the secretion patterns for such EVs, modifying the contents of various miRNAs within these vesicles. As such, Li-EVs displayed significantly increased levels of miR-1906, which has been shown to be a new regulator of toll-like receptor 4 (TLR4) signaling. Li-EVs reduced posthypoxic and postischemic TLR4 abundance, resulting in an inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling pathway, decreased proteasomal activity, and declined both inducible NO synthase and cyclooxygenase-2 expression, all of which culminating in reduced levels of poststroke cerebral inflammation. Conclusively, the present study for the first time demonstrates an enhanced therapeutic potential of Li-EVs compared with native EVs, interfering with a novel signaling pathway that yields both acute neuroprotection an enhanced neurological recovery.Öğe Lithium promotes long-term neurological recovery after spinal cord injury in mice by enhancing neuronal survival, gray and white matter remodeling, and long-distance axonal regeneration(Frontiers Media S.A., 2022) Balçıkanlı, Zeynep; Çulha, İrem; Dilsiz, Pelin; Aydın, Mehmet Şerif; Ateş, Nilay; Beker, Mustafa Çağlar; Baltacı, Saltuk Buğra; Koç, Halil İbrahim; Yiğitbaşı, Ahmet; Gündoğar, Mustafa; Doeppner, Thorsten Roland; Hermann, Dirk M.Spinal cord injury (SCI) induces neurological deficits associated with long-term functional impairments. Since the current treatments remain ineffective, novel therapeutic options are needed. Besides its effect on bipolar mood disorder, lithium was reported to have neuroprotective activity in different neurodegenerative conditions, including SCI. In SCI, the effects of lithium on long-term neurological recovery and neuroplasticity have not been assessed. We herein investigated the effects of intraperitoneally administered lithium chloride (LiCl) on motor coordination recovery, electromyography (EMG) responses, histopathological injury and remodeling, and axonal plasticity in mice exposed to spinal cord transection. At a dose of 0.2, but not 2.0 mmol/kg, LiCl enhanced motor coordination and locomotor activity starting at 28 days post-injury (dpi), as assessed by a set of behavioral tests. Following electrical stimulation proximal to the hemitransection, LiCl at 0.2 mmol/kg decreased the latency and increased the amplitude of EMG responses in the denervated hindlimb at 56 dpi. Functional recovery was associated with reduced gray and white matter atrophy rostral and caudal to the hemitransection, increased neuronal survival and reduced astrogliosis in the dorsal and ventral horns caudal to the hemitransection, and increased regeneration of long-distance axons proximal and distal to the lesion site in mice receiving 0.2 mmol/kg, but not 2 mmol/kg LiCl, as assessed by histochemical and immunohistochemical studies combined with anterograde tract tracing. Our results indicate that LiCl induces long-term neurological recovery and neuroplasticity following SCI.Öğe Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3 beta inhibition-independent pathways(Sage Publication Inc., 2017) Doeppner, Thorsten Roland; Kaltwasser, Britta; Sanchez-Mendoza, Eduardo H.; Çağlayan, Ahmet Burak; Baehr, Mathias; Hermann, Dirk M.Lithium promotes acute poststroke neuronal survival, which includes mechanisms that are not limited to GSK3 inhibition. However, whether lithium induces long-term neuroprotection and enhanced brain remodeling is unclear. Therefore, mice were exposed to transient middle cerebral artery occlusion and lithium (1mg/kg bolus followed by 2mg/kg/day over up to 7 days) was intraperitoneally administered starting 0-9h after reperfusion onset. Delivery of lithium no later than 6h reduced infarct volume on day 2 and decreased brain edema, leukocyte infiltration, and microglial activation, as shown by histochemistry and flow cytometry. Lithium-induced neuroprotection persisted throughout the observation period of 56 days and was associated with enhanced neurological recovery. Poststroke angioneurogenesis and axonal plasticity were also enhanced by lithium. On the molecular level, lithium increased miR-124 expression, reduced RE1-silencing transcription factor abundance, and decreased protein deubiquitination in cultivated cortical neurons exposed to oxygen-glucose deprivation and in brains of mice exposed to cerebral ischemia. Notably, this effect was not mimicked by pharmacological GSK3 inhibition. This study for the first time provides efficacy data for lithium in the postacute ischemic phase, reporting a novel mechanism of action, i.e. increased miR-124 expression facilitating REST degradation by which lithium promotes postischemic neuroplasticity and angiogenesis.Öğe Long-term treatment with chloroquine increases lifespan in middle-aged male mice possibly via autophagy modulation, proteasome inhibition and glycogen metabolism(Impact Journals LLC, 2022) Doeppner, Thorsten R.; Coman, Cristin; Burdusel, Daiana; Ancuta, Diana Larisa; Brockmeier, Ulf; Pirici, Daniel Nicolae; Kuang Yaoyun; Hermann, Dirk M.; Popa Wagner, AurelPrevious studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. Since spermidine increases autophagy, we asked if treatment with chloroquine, an inhibitor of autophagy, would shorten the lifespan of mice. Recently, chloroquine has intensively been discussed as a treatment option for COVID-19 patients. To rule out unfavorable long-term effects on longevity, we examined the effect of chronic treatment with chloroquine given in the drinking water on the lifespan and organ pathology of male middle-aged NMRI mice. We report that, surprisingly, daily treatment with chloroquine extended the median life span by 11.4% and the maximum life span of the middle-aged male NMRI mice by 11.8%. Subsequent experiments show that the chloroquine-induced lifespan elevation is associated with dose-dependent increase in LC3B-II, a marker of autophagosomes, in the liver and heart that was confirmed by transmission electron microscopy. Quite intriguingly, chloroquine treatment was also associated with a decrease in glycogenolysis in the liver suggesting a compensatory mechanism to provide energy to the cell. Accumulation of autophagosomes was paralleled by an inhibition of proteasome-dependent proteolysis in the liver and the heart as well as with decreased serum levels of insulin growth factor binding protein-3 (IGFBP3), a protein associated with longevity. We propose that inhibition of proteasome activity in conjunction with an increased number of autophagosomes and decreased levels of IGFBP3 might play a central role in lifespan extension by chloroquine in male NMRI mice.Öğe Nanodrugs for the treatment of ischemic stroke: A systematic review(MDPI, 2023) Ruscu, Mihai; Cercel, Andreea; Kılıç, Ertuğrul; Çatalın, Boğdan; Gresita, Andrei; Hermann, Dirk M.; Albu, Carmen Valeria; Popa-Wagner, AurelIschemic stroke, a significant neurovascular disorder, currently lacks effective restorative medication. However, recently developed nanomedicines bring renewed promise for alleviating ischemia’s effects and facilitating the healing of neurological and physical functions. The aim of this systematic review was to evaluate the efficacy of nanotherapies in animal models of stroke and their potential impact on future stroke therapies. We also assessed the scientific quality of current research focused on nanoparticle-based treatments for ischemic stroke in animal models. We summarized the effectiveness of nanotherapies in these models, considering multiple factors such as their anti-inflammatory, antioxidant, and angiogenetic properties, as well as their safety and biodistribution. We conclude that the application of nanomedicines may reduce infarct size and improve neurological function post-stroke without causing significant organ toxicity.
