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  • 1
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. 7 ( 2012-07), p. 1931-1940
    Abstract: The neuroprotective potential of citicoline in acute ischemic stroke has been shown in many experimental studies and, although the exact mechanisms are still unknown, a clinical Phase III trial is currently underway. Our present study was designed to check whether citicoline also enhances neuroregeneration after experimental stroke. Methods— Forty Wistar rats were subjected to photothrombotic stroke and treated either with daily injections of citicoline (100 mg/kg) or vehicle for 10 consecutive days starting 24 hours after ischemia induction. Sensorimotor tests were performed after an adequate training period at Days 1, 10, 21, and 28 after stroke. Then brains were removed and analyzed for infarct size, glial scar formation, neurogenesis, and ligand binding densities of excitatory and inhibitory neurotransmitter receptors. Results— Animals treated with citicoline showed a significantly better neurological outcome at Days 10, 21, and 28 after ischemia, which could not be attributed to differences in infarct volumes or glial scar formation. However, neurogenesis in the dentate gyrus, subventricular zone, and peri-infarct area was significantly increased by citicoline. Furthermore, enhanced neurological outcome after citicoline treatment was associated with a shift toward excitation in the perilesional cortex. Conclusions— Our present data demonstrate that, apart from the well-known neuroprotective effects in acute ischemic stroke, citicoline also possesses a substantial neuroregenerative potential. Thanks to its multimodal effects, easy applicability, and history as a well-tolerated drug, promising possibilities of neurological treatment including chronic stroke open up.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
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  • 2
    In: Frontiers in Behavioral Neuroscience, Frontiers Media SA, Vol. 11 ( 2017-03-16)
    Type of Medium: Online Resource
    ISSN: 1662-5153
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2017
    detail.hit.zdb_id: 2452960-6
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  • 3
    In: Annals of Neurology, Wiley, Vol. 83, No. 5 ( 2018-05), p. 1003-1015
    Abstract: Neurological recovery after stroke mainly depends on the location of the lesion. A substantial portion of strokes affects the brainstem. However, patterns of neural plasticity following brainstem ischemia are almost unknown. Methods Here, we established a rat brainstem ischemia model that resembles key features of the human disease and investigated mechanisms of neural plasticity, including neurogenesis and axonal sprouting as well as secondary neurodegeneration. Results Spontaneous functional recovery was accompanied by a distinct pattern of axonal sprouting, for example, an increased bilateral fiber outgrowth from the corticorubral tract to the respective contralesional red nucleus suggesting a compensatory role of extrapyramidal pathways after damage to pyramid tracts within the brainstem. Using different markers for DNA replication, we showed that the brainstem displays a remarkable ability to undergo specific plastic cellular changes after injury, highlighting a yet unknown pattern of neurogenesis. Neural progenitor cells proliferated within the dorsal brainstem and migrated toward the lesion, whereas neurogenesis in classic neurogenic niches, the subventricular zone of the lateral ventricle and the hippocampus, remained, in contrast to what is known from hemispheric stroke, unaffected. These beneficial changes were paralleled by long‐term degenerative processes, that is, corticospinal fiber loss superior to the lesion, degeneration of spinal tracts, and a decreased neuron density within the ipsilesional substantia nigra and the contralesional red nucleus that might have limited further functional recovery. Interpretation Our findings provide knowledge of elementary plastic adaptions after brainstem stroke, which is fundamental for understanding the human disease and for the development of new treatments. Ann Neurol 2018;83:1003–1015
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2037912-2
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  • 4
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Stroke Vol. 46, No. 4 ( 2015-04), p. 1127-1131
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. 4 ( 2015-04), p. 1127-1131
    Abstract: In spite of its high disease burden, there is no specific treatment for multi-infarct dementia. The preclinical evaluation of candidate drugs is limited because an appropriate animal model is lacking. Therefore, we aimed to evaluate whether a mouse model of recurrent photothrombotic stroke is suitable for the preclinical investigation of multi-infarct dementia. Methods— Recurrent photothrombotic cortical infarcts were induced in 25 adult C57BL/6 mice. Twenty-five sham-operated animals served as controls. The object recognition test and the Morris water maze test were performed 〉 6 weeks to assess cognitive deficits. Afterward, histological analyses were performed to characterize histopathologic changes associated with recurrent photothrombotic infarcts. Results— After the first infarct, the object recognition test showed a trend toward an impaired formation of recognition memories ( P =0.08), and the Morris Water Maze test revealed significantly impaired spatial learning and memory functions ( P 〈 0.05). After recurrent infarcts, the object recognition test showed significant recognition memory deficits ( P 〈 0.001) and the Morris water maze test demonstrated persisting spatial learning and memory deficits ( P 〈 0.05). Histological analyses revealed remote astrogliosis in the hippocampus. Conclusions— Our results show progressive cognitive deficits in a mouse model of recurrent photothrombotic stroke. The presented model resembles the clinical features of human multi-infarct dementia and enables the investigation of its pathophysiological mechanisms and the evaluation of treatment strategies.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467823-8
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  • 5
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 47, No. 3 ( 2016-03), p. 852-862
    Abstract: Bone marrow cell (BMC)–based therapies, either the transplantation of exogenous cells or stimulation of endogenous cells by growth factors like the granulocyte colony–stimulating factor (G-CSF), are considered a promising means of treating stroke. In contrast to large preclinical evidence, however, a recent clinical stroke trial on G-CSF was neutral. We, therefore, aimed to investigate possible synergistic effects of co-administration of G-CSF and BMCs after experimental stroke in mice to enhance the efficacy compared with single treatments. Methods— We used an animal model for experimental stroke as paradigm to study possible synergistic effects of co-administration of G-CSF and BMCs on the functional outcome and the pathophysiological mechanism. Results— G-CSF treatment alone led to an improved functional outcome, a reduced infarct volume, increased blood vessel stabilization, and decreased overall inflammation. Surprisingly, the combination of G-CSF and BMCs abrogated G-CSFs’ beneficial effects and resulted in increased hemorrhagic infarct transformation, altered blood–brain barrier, excessive astrogliosis, and altered immune cell polarization. These increased rates of infarct bleeding were mainly mediated by elevated matrix metalloproteinase-9–mediated blood–brain barrier breakdown in G-CSF- and BMCs-treated animals combined with an increased number of dilated and thus likely more fragile vessels in the subacute phase after cerebral ischemia. Conclusions— Our results provide new insights into both BMC-based therapies and immune cell biology and help to understand potential adverse and unexpected side effects.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467823-8
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  • 6
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. 1 ( 2014-01), p. 239-247
    Abstract: Although several studies have shown beneficial effects of training in animal stroke models, the most effective training strategy and the optimal time to initiate training have not been identified. The present meta-analysis was performed to compare the efficacy of different training strategies and to determine the optimal time window for training in animal stroke models. Methods— We searched the literature for studies analyzing the efficacy of training in animal models of ischemic stroke. Training was categorized into forced physical training, voluntary physical training, constraint-induced movement therapy, and skilled reaching training. Two reviewers independently extracted data on study quality, infarct size, and neurological outcome. Data were pooled by means of a meta-analysis. Results— Thirty-five studies with 〉 880 animals were included. A meta-analysis of all treatments showed that training reduced the infarct volume by 14% (95% confidence interval, 2%–25%) and improved the cognitive function by 33% (95% confidence interval, 8%–50%), the neuroscore by 13.4% (95% confidence interval, 1.5%–25.3%), and the running function by 6.6% (95% confidence interval, 1.4%–11.9%). Forced physical training reduced the infarct volume and enhanced the running function most effectively, whereas skilled reaching training improved the limb function most effectively. A meta-regression illustrated that training was particularly efficacious when initiated between 1 and 5 days after stroke onset. Conclusions— Our meta-analysis confirms that training reduces the infarct volume and improves the functional recovery in animal stroke models. Forced physical training and skilled reaching training were identified as particularly effective training strategies. The efficacy of training is time dependent.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467823-8
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  • 7
    In: Frontiers in Cellular Neuroscience, Frontiers Media SA, Vol. 7 ( 2014)
    Type of Medium: Online Resource
    ISSN: 1662-5102
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2014
    detail.hit.zdb_id: 2452963-1
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  • 8
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Stroke Vol. 45, No. suppl_1 ( 2014-02)
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. suppl_1 ( 2014-02)
    Abstract: Introduction: The peptide hormone Ghrelin is known as the ligand of the growth hormone secretagogue receptor and affects pituitary hormone secretion, gastrointestinal function and the cardiovascular and immune system. Recently it has been shown that Ghrelin also influences key mechanisms of the CNS. Ghrelin crosses the blood-brain barrier and binds to hippocampal neurons thereby promoting dendritic spine synapse formation and proliferation of progenitor cells. These finings led to the assumption that Ghrelin might exert neuroprotective and neuroregenerative effects in the brain. We assessed the hypothesis that a chronic pharmacological stimulation with Ghrelin promotes mechanisms of long term post-stroke neuroregeneration thereby improving functional and structural regeneration. Methods: In order to examine long term neuroregenerative effects, Ghrelin (40 μg/kg/d) was administered starting 24 hours after photothrombotic ischemia until the end of the experiment via osmotic pumps. Functional recovery was assessed by the adhesive tape removal test and the cylinder test performed weekly for 4 weeks. Cognitive function was analysed using the Morris water maze test. Brains were removed 4 weeks after ischemia. Post-ischemic neurogenesis was quantified in the subventricular zone (SVZ) and dentate gyrus (DG) using antibodies against Bromodeoxyuridine and Doublecortin. Results: Treatment with Ghrelin improved motoric and cognitive recovery following photothrombotic stroke. In close apposition to the enhanced functional recovery, the pharmacological stimulation with Ghrelin significantly increased the generation of newborn hippocampal neurons in the SVZ as well as in the DG of the hippocampus. Conclusion: In the present study, we demonstrated that chronic treatment with Ghrelin promotes the structural and functional recovery following ischemia. The recently discovered neurotrophic properties and the effects on post-stroke recovery demonstrated in this study substantiate the potential of Ghrelin as a promising agent for the neuroregenerative treatment of ischemic stroke.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467823-8
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  • 9
    Online Resource
    Online Resource
    Elsevier BV ; 2017
    In:  Neurochemistry International Vol. 107 ( 2017-07), p. 117-126
    In: Neurochemistry International, Elsevier BV, Vol. 107 ( 2017-07), p. 117-126
    Type of Medium: Online Resource
    ISSN: 0197-0186
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 1500654-2
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  • 10
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. 6 ( 2011-06), p. 1757-1763
    Abstract: Intravenous neural progenitor cell (NPC) treatment was shown to improve functional recovery after experimental stroke. The underlying mechanisms, however, are not completely understood so far. Here, we investigated the effects of systemic NPC transplantation on endogenous neurogenesis and dendritic plasticity of host neurons. Methods— Twenty-four hours after photothrombotic ischemia, adult rats received either 5 million NPC or placebo intravenously. Behavioral tests were performed weekly up to 4 weeks after ischemia. Endogenous neurogenesis, dendritic length, and dendritic branching of cortical pyramid cells and microglial activation were quantified. Results— NPC treatment led to a significantly improved sensorimotor function measured by the adhesive removal test. The dendritic length and the amount of branch points were significantly increased after NPC transplantation, whereas endogenous neurogenesis was decreased compared to placebo therapy. Decreased endogenous neurogenesis was associated with an increased number of activated microglial cells. Conclusions— Our findings suggest that an increased dendritic plasticity might be the structural basis of NPC-induced functional recovery. The decreased endogenous neurogenesis after NPC treatment seems to be mediated by microglial activation.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1467823-8
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