Saal, Kim-Ann

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","Pharmacology & Therapeutics"],["dc.bibliographiccitation.lastpage","21"],["dc.bibliographiccitation.volume","189"],["dc.contributor.author","Koch, Jan Christoph"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Roser, Anna-Elisa"],["dc.contributor.author","Saal, Kim-Ann"],["dc.contributor.author","Tönges, Lars"],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2020-12-10T15:20:44Z"],["dc.date.available","2020-12-10T15:20:44Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1016/j.pharmthera.2018.03.008"],["dc.identifier.issn","0163-7258"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/72778"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","ROCK inhibition in models of neurodegeneration and its potential for clinical translation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","13"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Brain Pathology"],["dc.bibliographiccitation.lastpage","25"],["dc.bibliographiccitation.volume","27"],["dc.contributor.author","Saal, Kim-Ann"],["dc.contributor.author","Galter, Dagmar"],["dc.contributor.author","Roeber, Sigrun"],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Tönges, Lars"],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2018-02-22T13:10:28Z"],["dc.date.available","2018-02-22T13:10:28Z"],["dc.date.issued","2017"],["dc.description.abstract","Causative treatment strategies for Parkinson's disease (PD) will have to address multiple underlying pathomechanisms to attenuate neurodegeneration. Additionally, the intrinsic regenerative capacity of the central nervous system is also an important factor contributing to restoration. Extracellular cues can limit sprouting and regrowth of adult neurons, but even aged neurons have a low intrinsic regeneration capacity. Whether this capacity has been lost or if growth inhibitory cues are increased during PD progression has not been resolved yet. In this study, we assessed the regenerative potential in the nigrostriatal system in post-mortem brain sections of PD patients compared to age-matched and young controls. Investigation of the expression pattern of the regeneration-associated protein GAP-43 suggested a lower regenerative capacity in nigral dopaminergic neurons of PD patients. Furthermore, the increase in protein expression of the growth-inhibitory protein ROCK2 in astrocytes and a similar trend in microglia, suggests an important role for ROCK2 in glial PD pathology, which is initiated already in normal aging. Considering the role of astro- and microglia in PD pathogenesis as well as beneficial effects of ROCK inhibition on neuronal survival and regeneration in neurodegenerative disease models, our data strengthens the importance of the ROCK pathway as a therapeutic target in PD."],["dc.identifier.doi","10.1111/bpa.12346"],["dc.identifier.pmid","26748453"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/12431"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.doi","10.1111/bpa.12346"],["dc.relation.eissn","1750-3639"],["dc.relation.issn","1015-6305"],["dc.title","Altered Expression of Growth Associated Protein-43 and Rho Kinase in Human Patients with Parkinson's Disease"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","217"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Glia"],["dc.bibliographiccitation.lastpage","232"],["dc.bibliographiccitation.volume","62"],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Günther, R."],["dc.contributor.author","Suhr, M."],["dc.contributor.author","Jansen, J."],["dc.contributor.author","Balck, A."],["dc.contributor.author","Saal, K.-A."],["dc.contributor.author","Barski, E."],["dc.contributor.author","Nientied, T."],["dc.contributor.author","Götz, A. A."],["dc.contributor.author","Koch, J.-C."],["dc.contributor.author","Mueller, B. K."],["dc.contributor.author","Weishaupt, J. H."],["dc.contributor.author","Sereda, M. W."],["dc.contributor.author","Hanisch, U.-K."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Lingor, P."],["dc.date.accessioned","2017-09-07T11:46:53Z"],["dc.date.available","2017-09-07T11:46:53Z"],["dc.date.issued","2014"],["dc.description.abstract","Disease progression in amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons (MN) and their axons, but is also influenced by neighboring cells such as astrocytes and microglial cells. The role of microglia in ALS is complex as it switches from an anti-inflammatory and neuroprotective phenotype in early disease to a proinflammatory and neurotoxic phenotype in later stages. Our previous studies in models of neurodegeneration identified rho kinase (ROCK) as a target, which can be manipulated to beneficially influence disease progression. Here, we examined the neuroprotective potential of the ROCK inhibitor Fasudil to target the central pathogenic features of ALS. Application of Fasudil to kainic acid-lesioned primary MN in vitro resulted in a strong prosurvival effect. In vivo, SOD1(G93A) mice benefited from oral treatment with Fasudil showing prolonged survival and improved motor function. These findings were correlated to an improved survival of motor neurons and a pronounced alteration of astroglial and microglial cell infiltration of the spinal cord under Fasudil treatment. Modeling a proinflammatory microglial phenotype by stimulation with LPS in vitro, Fasudil decreased the release of proinflammatory cytokines and chemokines TNF, Il6, CCL2, CCL3, and CCL5 while CXCL1 release was only transiently suppressed. In sciatic nerve motor axons, neuromuscular junction remodeling processes were increased. In conclusion, we provide preclinical and neurobiological evidence that inhibition of ROCK by the clinically approved small molecule inhibitor Fasudil may be a novel therapeutic approach in ALS combining both neuroprotection and immunomodulation for the cure of this devastating disease. GLIA 2014;62:217-232"],["dc.identifier.doi","10.1002/glia.22601"],["dc.identifier.gro","3142195"],["dc.identifier.isi","000328209300005"],["dc.identifier.pmid","24311453"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/5588"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1098-1136"],["dc.relation.issn","0894-1491"],["dc.title","Rho Kinase Inhibition Modulates Microglia Activation and Improves Survival in a Model of Amyotrophic Lateral Sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","150"],["dc.bibliographiccitation.journal","Neurobiology of Disease"],["dc.bibliographiccitation.lastpage","162"],["dc.bibliographiccitation.volume","73"],["dc.contributor.author","Saal, K.-A."],["dc.contributor.author","Koch, J. C."],["dc.contributor.author","Tatenhorst, L."],["dc.contributor.author","Szegő, É. M."],["dc.contributor.author","Ribas, V. T."],["dc.contributor.author","Michel, U."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Tönges, L."],["dc.contributor.author","Lingor, P."],["dc.date.accessioned","2017-09-07T11:45:21Z"],["dc.date.available","2017-09-07T11:45:21Z"],["dc.date.issued","2015"],["dc.description.abstract","Parkinson's disease (PD) is a neurodegenerative disorder with prominent neuronal cell death in the substantia nigra (SN) and other parts of the brain. Previous studies in models of traumatic and neurodegenerative CNS disease showed that pharmacological inhibition of Rho-associated kinase (ROCK), a molecule involved in inhibitory signaling in the CNS, by small-molecule inhibitors improves neuronal survival and increases regeneration. Most small-molecule inhibitors, however, offer only limited target specificity and also inhibit other kinases, including both ROCK isoforms. To establish the role of the predominantly brain-expressed ROCK2 isoform in models of regeneration and PD, we used adeno-associated viral vectors (MV) to specifically knockdown ROCK2 in neurons. Rat primary midbrain neurons (PMN) were transduced with MV expressing short-hairpin-RNA (shRNA) against ROCK2 and LIM-domain kinase 1 (LIMK1), one of the downstream targets of ROCK2. While knock-down of ROCK2 and LIMK1 both enhanced neurite regeneration in a traumatic scratch lesion model, only ROCK2-shRNA protected PMN against 1-methyl-4-phenylpyridinium (MPP+) toxicity. Moreover, AAV.ROCK2-shRNA increased levels of the pro-survival markers Bcl-2 and phospho-Erk1. In vivo, AAV.ROCK2-shRNA vectors were injected into the ipsilateral SN and a unilateral 6-OHDA striatal lesion was performed. After four weeks, behavioral, immunohistochemical and biochemical alterations were investigated. Downregulation of ROCK2 protected dopaminergic neurons in the SN from 6-OHDA-induced degeneration and resulted in significantly increased TH-positive neuron numbers. This effect, however, was confined to nigral neuronal somata as striatal terminal density, dopamine and metabolite levels were not significantly preserved. Interestingly, motor behavior was improved in the ROCK2-shRNA treated animals compared to control after four weeks. Our studies thus confirm ROCK2 as a promising therapeutic target in models of PD and demonstrate that neuronspecific inhibition of ROCK2 promotes survival of lesioned dopaminergic neurons. (C) 2015 Elsevier Inc All rights reserved."],["dc.identifier.doi","10.1016/j.nbd.2014.09.013"],["dc.identifier.gro","3141993"],["dc.identifier.isi","000346328100014"],["dc.identifier.pmid","25283984"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/3357"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1095-953X"],["dc.relation.issn","0969-9961"],["dc.title","AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson's disease in vitro and in vivo"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","770"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Journal of Neuropathology and Experimental Neurology"],["dc.bibliographiccitation.lastpage","779"],["dc.bibliographiccitation.volume","73"],["dc.contributor.author","Tatenhorst, Lars"],["dc.contributor.author","Tönges, Lars"],["dc.contributor.author","Saal, Kim-Ann"],["dc.contributor.author","Koch, J. C."],["dc.contributor.author","Szegő, Éva M."],["dc.contributor.author","Bähr, Mathias"],["dc.contributor.author","Lingor, Paul"],["dc.date.accessioned","2018-04-23T11:47:28Z"],["dc.date.available","2018-04-23T11:47:28Z"],["dc.date.issued","2014"],["dc.description.abstract","Chronic degeneration of nigrostriatal projections, followed by nigral dopaminergic cell death, is a key feature of Parkinson disease (PD). This study examines the neuroprotective potential of the rho kinase inhibitor fasudil in the 6-hydroxydopamine (6-OHDA) mouse model of PD in vivo. C57Bl/6 mice were lesioned by striatal stereotactic injections with 4 mu g of 6-OHDA and treated with fasudil 30 or 100 mg/kg body weight via drinking water. Motor behavior was tested biweekly; histologic and biochemical analyses were performed at 4 and 12 weeks after lesion. Motor behavior was severely impaired after 6-OHDA lesion and was not improved by fasudil treatment. Fasudil 100 mg/kg did not significantly increase the number of dopaminergic cells in the substantia nigra after 12 weeks versus lesion controls. Interestingly, however, high-performance liquid chromatography analysis of dopamine metabolites revealed that striatal levels of 3,4-dihydroxyphenylacetic acid were significantly increased after 12 weeks, suggesting a regenerative response. In contrast to recent findings in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin model, fasudil effects seem limited in this severe 6-OHDA model of PD. Nevertheless, high therapeutic concentrations of fasudil are suggestive of a proregenerative potential for dopaminergic neurons, making further evaluations of rho kinase inhibition as a proregenerative therapeutic strategy in PD promising."],["dc.identifier.doi","10.1097/nen.0000000000000095"],["dc.identifier.gro","3142078"],["dc.identifier.isi","000339386600004"],["dc.identifier.pmid","25003236"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/4367"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1554-6578"],["dc.relation.issn","0022-3069"],["dc.relation.issn","0022-3069"],["dc.title","Rho Kinase Inhibition by Fasudil in the Striatal 6-Hydroxydopamine Lesion Mouse Model of Parkinson Disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","no"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]