Döppner, Thorsten Roland

[["dc.bibliographiccitation.firstpage","1297"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","STEM CELLS"],["dc.bibliographiccitation.lastpage","1310"],["dc.bibliographiccitation.volume","30"],["dc.contributor.author","Doeppner, T. R."],["dc.contributor.author","Ewert, T. A. S."],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Herz, J."],["dc.contributor.author","Zechariah, A."],["dc.contributor.author","Elali, A."],["dc.contributor.author","Ludwig, A.-K."],["dc.contributor.author","Giebel, B."],["dc.contributor.author","Nagel, F."],["dc.contributor.author","Dietz, G. P. H."],["dc.contributor.author","Weise, J."],["dc.contributor.author","Hermann, D. M."],["dc.contributor.author","Bähr, M."],["dc.date.accessioned","2017-09-07T11:48:52Z"],["dc.date.available","2017-09-07T11:48:52Z"],["dc.date.issued","2012"],["dc.description.abstract","Novel therapeutic concepts against cerebral ischemia focus on cell-based therapies in order to overcome some of the side effects of thrombolytic therapy. However, cell-based therapies are hampered because of restricted understanding regarding optimal cell transplantation routes and due to low survival rates of grafted cells. We therefore transplanted adult green fluorescence protein positive neural precursor cells (NPCs) either intravenously (systemic) or intrastriatally (intracerebrally) 6 hours after stroke in mice. To enhance survival of NPCs, cells were in vitro protein-transduced with TAT-heat shock protein 70 (Hsp70) before transplantation followed by a systematic analysis of brain injury and underlying mechanisms depending on cell delivery routes. Transduction of NPCs with TAT-Hsp70 resulted in increased intracerebral numbers of grafted NPCs after intracerebral but not after systemic transplantation. Whereas systemic delivery of either native or transduced NPCs yielded sustained neuroprotection and induced neurological recovery, only TAT-Hsp70-transduced NPCs prevented secondary neuronal degeneration after intracerebral delivery that was associated with enhanced functional outcome. Furthermore, intracerebral transplantation of TAT-Hsp70-transduced NPCs enhanced postischemic neurogenesis and induced sustained high levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor in vivo. Neuroprotection after intracerebral cell delivery correlated with the amount of surviving NPCs. On the contrary, systemic delivery of NPCs mediated acute neuroprotection via stabilization of the blood-brain-barrier, concomitant with reduced activation of matrix metalloprotease 9 and decreased formation of reactive oxygen species. Our findings imply two different mechanisms of action of intracerebrally and systemically transplanted NPCs, indicating that systemic NPC delivery might be more feasible for translational stroke concepts, lacking a need of in vitro manipulation of NPCs to induce long-term neuroprotection. STEM CELLS2012;30:12971310"],["dc.identifier.doi","10.1002/stem.1098"],["dc.identifier.gro","3142531"],["dc.identifier.isi","000304087300026"],["dc.identifier.pmid","22593021"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/8892"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","1066-5099"],["dc.title","Transduction of Neural Precursor Cells with TAT-Heat Shock Protein 70 Chaperone: Therapeutic Potential Against Ischemic Stroke after Intrastriatal and Systemic Transplantation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2044"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","STEM CELLS Translational Medicine"],["dc.bibliographiccitation.lastpage","2052"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Doeppner, Thorsten R."],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Hermann, Dirk M."],["dc.contributor.author","Giebel, Bernd"],["dc.date.accessioned","2018-04-23T11:49:28Z"],["dc.date.available","2018-04-23T11:49:28Z"],["dc.date.issued","2017"],["dc.description.abstract","Despite recent advances in stroke therapy, current therapeutic concepts are still limited. Thus, additional therapeutic strategies are in order. In this sense, the transplantation of stem cells has appeared to be an attractive adjuvant tool to help boost the endogenous regenerative capacities of the brain. Although transplantation of stem cells is known to induce beneficial outcome in (preclinical) stroke research, grafted cells do not replace lost tissue directly. Rather, these transplanted cells like neural progenitor cells or mesenchymal stem cells act in an indirect manner, among which the secretion of extracellular vesicles (EVs) appears to be one key factor. Indeed, the application of EVs in preclinical stroke studies suggests a therapeutic role, which appears to be noninferior in comparison to the transplantation of stem cells themselves. In this short review, we highlight some of the recent advances in the field of EVs as a therapeutic means to counter stroke."],["dc.identifier.doi","10.1002/sctm.17-0081"],["dc.identifier.gro","3142068"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13702"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","2157-6564"],["dc.title","Concise Review: Extracellular Vesicles Overcoming Limitations of Cell Therapies in Ischemic Stroke"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","429"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Acta Neuropathologica"],["dc.bibliographiccitation.lastpage","442"],["dc.bibliographiccitation.volume","122"],["dc.contributor.author","Doeppner, T. R."],["dc.contributor.author","Bretschneider, E."],["dc.contributor.author","Doehring, M."],["dc.contributor.author","Segura, I."],["dc.contributor.author","Sentürk, A."],["dc.contributor.author","Acker-Palmer, A."],["dc.contributor.author","Hasan, M. R."],["dc.contributor.author","Elali, A."],["dc.contributor.author","Hermann, D. M."],["dc.contributor.author","Bähr, M."],["dc.date.accessioned","2017-09-07T11:43:22Z"],["dc.date.available","2017-09-07T11:43:22Z"],["dc.date.issued","2011"],["dc.description.abstract","Cerebral ischemia stimulates endogenous neurogenesis. However, the functional relevance of this phenomenon remains unclear because of poor survival and low neuronal differentiation rates of newborn cells. Therefore, further studies on mechanisms regulating neurogenesis under ischemic conditions are required, among which ephrin-ligands and ephrin-receptors (Eph) are an interesting target. Although Eph/ephrin proteins like ephrin-B3 are known to negatively regulate neurogenesis under physiological conditions, their role in cerebral ischemia is largely unknown. We therefore studied neurogenesis, brain injury and functional outcome in ephrin-B3(-/-) (knockout) and ephrin-B3(+/+) (wild-type) mice submitted to cerebral ischemia. Induction of stroke resulted in enhanced cell proliferation and neuronal differentiation around the lesion site of ephrin-B3(-/-) compared to ephrin-B3(+/+) mice. However, prominent post-ischemic neurogenesis in ephrin-B3(-/-) mice was accompanied by significantly increased ischemic injury and motor coordination deficits that persisted up to 4 weeks. Ischemic injury in ephrin-B3(-/-) mice was associated with a caspase-3-dependent activation of the signal transducer and activator of transcription 1 (STAT1). Whereas inhibition of caspase-3 had no effect on brain injury in ephrin-B3(+/+) animals, infarct size in ephrin-B3(-/-) mice was strongly reduced, suggesting that aggravated brain injury in these animals might involve a caspase-3-dependent activation of STAT1. In conclusion, post-ischemic neurogenesis in ephrin-B3(-/-) mice is strongly enhanced, but fails to contribute to functional recovery because of caspase-3-mediated aggravation of ischemic injury in these animals. Our results suggest that ephrin-B3 might be an interesting target for overcoming some of the limitations of further cell-based therapies in stroke."],["dc.identifier.doi","10.1007/s00401-011-0856-5"],["dc.identifier.gro","3142655"],["dc.identifier.isi","000296506000004"],["dc.identifier.pmid","21779764"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/7316"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0001-6322"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject","Caspase-3; Cerebral ischemia; Endogenous neurogenesis; Ephrin-B3; Neural precursor cells; STAT1"],["dc.title","Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","57"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Restorative neurology and neuroscience"],["dc.bibliographiccitation.lastpage","64"],["dc.bibliographiccitation.volume","26"],["dc.contributor.author","Weise, Jens"],["dc.contributor.author","Doeppner, Thorsten R."],["dc.contributor.author","Müller, T."],["dc.contributor.author","Wrede, Arne"],["dc.contributor.author","Schulz-Schaeffer, Walter J."],["dc.contributor.author","Zerr, Inga"],["dc.contributor.author","Witte, Otto W."],["dc.contributor.author","Bähr, M."],["dc.date.accessioned","2017-09-07T11:48:49Z"],["dc.date.available","2017-09-07T11:48:49Z"],["dc.date.issued","2008"],["dc.description.abstract","Purpose: The physiological function of the cellular prion protein (PrP(C)) is still unclear. A growing body of evidence suggests that PrP(C) has neuroprotective properties and that its deletion increases susceptibility to focal cerebral ischemia. The purpose of this study was to elucidate the role of PrP(C) overexpression in ischemic brain injury in vivo. Methods: PrP(C) overexpressing (TG35) and wild type (WT) mice were subjected to a 90-minute transient focal cerebral ischemia followed by infarct volume analysis 24 hours after lesion. To identify effects of PrP(C) overexpression on signalling pathways important for the regulation of ischemic cell death, we studied postischemic activation and expression of Akt and Erk1/2 using quantitative Western Blot analysis. Results: TG35 mice displayed significantly smaller infarct volumes and showed reduced early postischemic Erk1/2 phosphorylation, a pathway known to exacerbate neuronal injury following transient cerebral ischemia. In contrast, PrP(C) overexpression did not change postischemic Akt phosphorylation, which acts anti-apoptotic and is reduced in PrP(C) knockout animals. Conclusions: These results demonstrate that PrP(C) overexpression reduces deleterious Erk1/2 activation but does not affect Akt activation after transient cerebral ischemia, suggesting a role for distinct cytosolic signalling pathways in PrP(C) mediated neuroprotection."],["dc.identifier.gro","3143388"],["dc.identifier.isi","000256236700005"],["dc.identifier.pmid","18431006"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/896"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0922-6028"],["dc.title","Overexpression of cellular prion protein alters postischemic Erk1/2 phosphorylation but not Akt phosphorylation and protects against focal cerebral ischemia"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","6061"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Molecular neurobiology"],["dc.bibliographiccitation.lastpage","6073"],["dc.bibliographiccitation.volume","54"],["dc.contributor.author","Doeppner, Thorsten R."],["dc.contributor.author","Doehring, Maria"],["dc.contributor.author","Kaltwasser, Britta"],["dc.contributor.author","Majid, Arshad"],["dc.contributor.author","Lin, Fengyan"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Kilic, Ertugrul"],["dc.contributor.author","Hermann, Dirk M."],["dc.date.accessioned","2018-01-08T16:54:34Z"],["dc.date.available","2018-01-08T16:54:34Z"],["dc.date.issued","2017"],["dc.description.abstract","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 post-stroke, 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)-κB 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."],["dc.identifier.doi","10.1007/s12035-016-0137-3"],["dc.identifier.pmid","27699598"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/11571"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1559-1182"],["dc.title","Ischemic Post-Conditioning Induces Post-Stroke Neuroprotection via Hsp70-Mediated Proteasome Inhibition and Facilitates Neural Progenitor Cell Transplantation"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","567"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Molecular Neurobiology"],["dc.bibliographiccitation.lastpage","582"],["dc.bibliographiccitation.volume","56"],["dc.contributor.author","Doeppner, Thorsten R."],["dc.contributor.author","Herz, Josephine"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Tonchev, Anton B."],["dc.contributor.author","Stoykova, Anastassia"],["dc.date.accessioned","2020-12-10T14:14:28Z"],["dc.date.available","2020-12-10T14:14:28Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1007/s12035-018-1104-y"],["dc.identifier.eissn","1559-1182"],["dc.identifier.issn","0893-7648"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/71350"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","Zbtb20 Regulates Developmental Neurogenesis in the Olfactory Bulb and Gliogenesis After Adult Brain Injury"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e2024"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Doeppner, T. R."],["dc.contributor.author","Kaltwasser, B."],["dc.contributor.author","Schlechter, J."],["dc.contributor.author","Jaschke, J."],["dc.contributor.author","Kilic, E."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Hermann, D. M."],["dc.contributor.author","Weise, J."],["dc.date.accessioned","2017-09-07T11:54:49Z"],["dc.date.available","2017-09-07T11:54:49Z"],["dc.date.issued","2015"],["dc.description.abstract","Although cellular prion protein (PrPc) has been suggested to have physiological roles in neurogenesis and angiogenesis, the pathophysiological relevance of both processes remain unknown. To elucidate the role of PrPc in post-ischemic brain remodeling, we herein exposed PrPc wild type (WT), PrPc knockout (PrP -/-) and PrPc overexpressing (PrP+/+) mice to focal cerebral ischemia followed by up to 28 days reperfusion. Improved neurological recovery and sustained neuroprotection lasting over the observation period of 4 weeks were observed in ischemic PrP+/+ mice compared with WT mice. This observation was associated with increased neurogenesis and angiogenesis, whereas increased neurological deficits and brain injury were noted in ischemic PrP-/- mice. Proteasome activity and oxidative stress were increased in ischemic brain tissue of PrP -/- mice. Pharmacological proteasome inhibition reversed the exacerbation of brain injury induced by PrP -/-, indicating that proteasome inhibition mediates the neuroprotective effects of PrPc. Notably, reduced proteasome activity and oxidative stress in ischemic brain tissue of PrP+/+ mice were associated with an increased abundance of hypoxia-inducible factor 1 alpha and PACAP-38, which are known stimulants of neural progenitor cell (NPC) migration and trafficking. To elucidate effects of PrPc on intracerebral NPC homing, we intravenously infused GFP(+) NPCs in ischemic WT, PrP -/- and PrP+/+ mice, showing that brain accumulation of GFP+ NPCs was greatly reduced in PrP -/- mice, but increased in PrP+/+ animals. Our results suggest that PrPc induces post-ischemic long-term neuroprotection, neurogenesis and angiogenesis in the ischemic brain by inhibiting proteasome activity."],["dc.identifier.doi","10.1038/cddis.2015.365"],["dc.identifier.gro","3141770"],["dc.identifier.isi","000368172400023"],["dc.identifier.pmid","26673668"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12863"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/879"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10 / Funder: TUBITAK [2221]; German Research Council [HE3173/2-2, HE3173/3-1]"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","Cell signalling; Ischaemia; Proteasome; Stroke"],["dc.title","Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","914"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Journal of Cerebral Blood Flow & Metabolism"],["dc.bibliographiccitation.lastpage","926"],["dc.bibliographiccitation.volume","37"],["dc.contributor.author","Kaltwasser, Britta"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Doeppner, Thorsten R."],["dc.contributor.author","Sanchez-Mendoza, Eduardo H."],["dc.contributor.author","Caglayan, Ahmet B."],["dc.contributor.author","Hermann, Dirk M."],["dc.date.accessioned","2020-12-10T18:38:25Z"],["dc.date.available","2020-12-10T18:38:25Z"],["dc.date.issued","2016"],["dc.description.abstract","Lithium promotes acute poststroke neuronal survival, which includes mechanisms that are not limited to GSK3β 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 (1 mg/kg bolus followed by 2 mg/kg/day over up to 7 days) was intraperitoneally administered starting 0-9 h after reperfusion onset. Delivery of lithium no later than 6 h 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 GSK3β 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."],["dc.identifier.doi","10.1177/0271678X16647738"],["dc.identifier.eissn","1559-7016"],["dc.identifier.issn","0271-678X"],["dc.identifier.pmid","27126323"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77307"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.status","final"],["dc.relation.eissn","1559-7016"],["dc.title","Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3β inhibition-independent pathways"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Cellular Neuroscience"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","Janssen, Lisa"],["dc.contributor.author","Ai, Xiaoyu"],["dc.contributor.author","Zheng, Xuan"],["dc.contributor.author","Wei, Wei"],["dc.contributor.author","Caglayan, Ahmet B."],["dc.contributor.author","Kilic, Ertugrul"],["dc.contributor.author","Wang, Ya-chao"],["dc.contributor.author","Hermann, Dirk M."],["dc.contributor.author","Venkataramani, Vivek"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Doeppner, Thorsten R."],["dc.date.accessioned","2021-10-01T09:58:18Z"],["dc.date.available","2021-10-01T09:58:18Z"],["dc.date.issued","2021"],["dc.description.abstract","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-κB 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-κB-dependent inflammation."],["dc.description.abstract","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-κB 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-κB-dependent inflammation."],["dc.identifier.doi","10.3389/fncel.2021.733973"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/90034"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1662-5102"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Inhibition of Fatty Acid Synthesis Aggravates Brain Injury, Reduces Blood-Brain Barrier Integrity and Impairs Neurological Recovery in a Murine Stroke Model"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1187"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Journal of Cerebral Blood Flow & Metabolism"],["dc.bibliographiccitation.lastpage","1196"],["dc.bibliographiccitation.volume","29"],["dc.contributor.author","Doeppner, T. R."],["dc.contributor.author","Nagel, F."],["dc.contributor.author","Dietz, G. P. H."],["dc.contributor.author","Weise, J."],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Schwarting, S."],["dc.contributor.author","Bähr, M."],["dc.date.accessioned","2017-09-07T11:47:27Z"],["dc.date.available","2017-09-07T11:47:27Z"],["dc.date.issued","2009"],["dc.description.abstract","Cerebral ischemia stimulates endogenous neurogenesis within the subventricular zone and the hippocampal dentate gyrus of the adult rodent brain. However, such newly generated cells soon die after cerebral ischemia. To enhance postischemic survival of neural precursor cells (NPC) and long-lasting neural regeneration, we applied the antiapoptotic chaperone heat shock protein 70 (Hsp70) fused to a cell-penetrating peptide derived from the HIV TAT to ensure delivery across the blood-brain barrier and the cell membrane. After transient focal cerebral ischemia in mice, TAT-Hsp70 was intravenously injected concomitant with reperfusion and additionally on day 14 after stroke. TAT-Hsp70 treatment resulted in smaller infarct size (27.1 +/- 9.0 versus 109.0 +/- 14.0 and 88.5 +/- 26.0 mm(3) in controls) and in functional improvement as assessed by the rota rod, tight rope, and water maze tests when compared with saline-and TAT-hemagglutinin- treated controls. In addition, postischemic survival of endogenous doublecortin (Dcx)-positive NPC was improved within the lesioned striatum of TAT-Hsp70-treated animals for up to 4 weeks after stroke without changing overall cell proliferation of BrdU(+) cells. Thus, TAT-Hsp70 treatment after stroke may be a promising tool to act neuroprotective and improve postischemic functional outcome, and also to increase survival of endogenous NPC after stroke. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1187-1196; doi: 10.1038/jcbfm.2009.44; published online 22 April 2009"],["dc.identifier.doi","10.1038/jcbfm.2009.44"],["dc.identifier.gro","3143110"],["dc.identifier.isi","000266451700013"],["dc.identifier.pmid","19384335"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/588"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10 / Funder: BMBF [1362910]"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0271-678X"],["dc.title","TAT-Hsp70-mediated neuroprotection and increased survival of neuronal precursor cells after focal cerebral ischemia in mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]