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Kai Diederich - One of the best experts on this subject based on the ideXlab platform.
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Functional Improvement after Photothrombotic Stroke in Rats Is Associated with Different Patterns of Dendritic Plasticity after G-CSF Treatment and G-CSF Treatment Combined with Concomitant or Sequential Constraint-Induced Movement Therapy.
PloS one, 2016Co-Authors: Katrin Frauenknecht, Kai Diederich, Wolf-rüdiger Schäbitz, Petra Leukel, Henrike Bauer, Clemens Sommer, Jens MinnerupAbstract:We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after Photothrombotic Stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-Stroke days 2 and 11); (iii) G-CSF (10 μg/kg G-CSF daily between post-Stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G-CSF) and (v) combined sequential group (CIMT between post-Stroke days 2 and 11; 10 μg/kg G-CSF daily between post-Stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri-lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after Stroke necessarily results in increased functional outcome into perspective.
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Progressive Cognitive Deficits in a Mouse Model of Recurrent Photothrombotic Stroke
Stroke, 2015Co-Authors: Antje Schmidt, Kai Diederich, Jan-kolja Strecker, Birgit Geng, Maike Hoppen, Thomas Duning, Wolf-rüdiger Schäbitz, Jens MinnerupAbstract:Background and Purpose—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 funct...
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Granulocyte colony-stimulating factor (G-CSF) treatment in combination with transplantation of bone marrow cells is not superior to G-CSF treatment alone after cortical Stroke in spontaneously hypertensive rats
Frontiers in cellular neuroscience, 2014Co-Authors: Kai Diederich, Antje Schmidt, Jan-kolja Strecker, Wolf-rüdiger Schäbitz, Carolin Beuker, Daniel-christoph Wagner, Johannes Boltze, Jens MinnerupAbstract:Granulocyte-colony stimulating factor (G-CSF) and bone marrow derived mononuclear cells (BM-MNC) have both been shown to improve functional outcome following experimental Stroke. These effects are associated with increased angiogenesis and neurogenesis. In the present study, we aimed to determine synergistic effects of G-CSF and BM-NMC treatment on long-term structural and functional recovery after Photothrombotic Stroke. To model the etiology of Stroke more closely, we used spontaneously hypertensive (SH) rats in our experiment. BM-MNC transplantation was initiated one hour after the onset of Photothrombotic Stroke. Repeated G-CSF treatment commenced immediately after BM-MNC treatment followed by daily injections for 5 consecutive days. The primary endpoint was functional outcome after ischemia. Secondary endpoints included analysis of neurogenesis and angiogenesis as well as determination of infarct size. G-CSF treated rats, either in combination with BM-MNC or alone showed improved somatosensory but not gross motor function following ischemia. No beneficial effect of BM-MNC monotherapy was found. Infarct volumes were comparable in all groups. In contrast to previous studies, which used healthy animals, post-Stroke neurogenesis and angiogenesis were not enhanced by G-CSF. In conclusion, the combination of G-CSF and BM-MNC was not more effective than G-CSF alone. The reduced efficacy of G-CSF treatment and the absence of any beneficial effect of BM-MNC transplantation might be directly attributed to hypertension-related morbidity.
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Forced arm use is superior to voluntary training for motor recovery and brain plasticity after cortical ischemia in rats
Experimental & Translational Stroke Medicine, 2014Co-Authors: Armin Schneider, Kai Diederich, Andreas Rogalewski, Oliver Wafzig, Friederike Kirsch, Norbert Gretz, Carola Krüger, Claudia Pitzer, Rico Laage, Christian PlaasAbstract:Background and purpose Both the immobilization of the unaffected arm combined with physical therapy (forced arm use, FAU) and voluntary exercise (VE) as model for enriched environment are promising approaches to enhance recovery after Stroke. The genomic mechanisms involved in long-term plasticity changes after different means of rehabilitative training post-Stroke are largely unexplored. The present investigation explored the effects of these physical therapies on behavioral recovery and molecular markers of regeneration after experimental ischemia. Methods 42 Wistar rats were randomly treated with either forced arm use (FAU, 1-sleeve plaster cast onto unaffected limb at 8/10 days), voluntary exercise (VE, connection of a freely accessible running wheel to cage), or controls with no access to a running wheel for 10 days starting at 48 hours after Photothrombotic Stroke of the sensorimotor cortex. Functional outcome was measured using sensorimotor test before ischemia, after ischemia, after the training period of 10 days, at 3 and 4 weeks after ischemia. Global gene expression changes were assessed from the ipsi- and contralateral cortex and the hippocampus. Results FAU-treated animals demonstrated significantly improved functional recovery compared to the VE-treated group. Both were superior to cage control. A large number of genes are altered by both training paradigms in the ipsi- and contralateral cortex and the hippocampus. Overall, the extent of changes observed correlated well with the functional recovery obtained. One category of genes overrepresented in the gene set is linked to neuronal plasticity processes, containing marker genes such as the NMDA 2a receptor, PKC ζ, NTRK2, or MAP 1b. Conclusions We show that physical training after Photothrombotic Stroke significantly and permanently improves functional recovery after Stroke, and that forced arm training is clearly superior to voluntary running training. The behavioral outcomes seen correlate with patterns and extent of gene expression changes in all brain areas examined. We propose that physical training induces a fundamental change in plasticity-relevant gene expression in several brain regions that enables recovery processes. These results contribute to the debate on optimal rehabilitation strategies, and provide a valuable source of molecular entry points for future pharmacological enhancement of recovery.
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Citicoline Enhances Neuroregenerative Processes After Experimental Stroke in Rats
Stroke, 2012Co-Authors: Kai Diederich, Antje Schmidt, Jens Minnerup, Katrin Frauenknecht, Clemens Sommer, Barbara K. Schneider, Elena Altach, Verena Eggert, Wolf-rüdiger SchäbitzAbstract:Background and Purpose—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 ...
Jens Minnerup - One of the best experts on this subject based on the ideXlab platform.
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Functional Improvement after Photothrombotic Stroke in Rats Is Associated with Different Patterns of Dendritic Plasticity after G-CSF Treatment and G-CSF Treatment Combined with Concomitant or Sequential Constraint-Induced Movement Therapy.
PloS one, 2016Co-Authors: Katrin Frauenknecht, Kai Diederich, Wolf-rüdiger Schäbitz, Petra Leukel, Henrike Bauer, Clemens Sommer, Jens MinnerupAbstract:We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after Photothrombotic Stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-Stroke days 2 and 11); (iii) G-CSF (10 μg/kg G-CSF daily between post-Stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G-CSF) and (v) combined sequential group (CIMT between post-Stroke days 2 and 11; 10 μg/kg G-CSF daily between post-Stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri-lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after Stroke necessarily results in increased functional outcome into perspective.
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Progressive Cognitive Deficits in a Mouse Model of Recurrent Photothrombotic Stroke
Stroke, 2015Co-Authors: Antje Schmidt, Kai Diederich, Jan-kolja Strecker, Birgit Geng, Maike Hoppen, Thomas Duning, Wolf-rüdiger Schäbitz, Jens MinnerupAbstract:Background and Purpose—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 funct...
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Granulocyte colony-stimulating factor (G-CSF) treatment in combination with transplantation of bone marrow cells is not superior to G-CSF treatment alone after cortical Stroke in spontaneously hypertensive rats
Frontiers in cellular neuroscience, 2014Co-Authors: Kai Diederich, Antje Schmidt, Jan-kolja Strecker, Wolf-rüdiger Schäbitz, Carolin Beuker, Daniel-christoph Wagner, Johannes Boltze, Jens MinnerupAbstract:Granulocyte-colony stimulating factor (G-CSF) and bone marrow derived mononuclear cells (BM-MNC) have both been shown to improve functional outcome following experimental Stroke. These effects are associated with increased angiogenesis and neurogenesis. In the present study, we aimed to determine synergistic effects of G-CSF and BM-NMC treatment on long-term structural and functional recovery after Photothrombotic Stroke. To model the etiology of Stroke more closely, we used spontaneously hypertensive (SH) rats in our experiment. BM-MNC transplantation was initiated one hour after the onset of Photothrombotic Stroke. Repeated G-CSF treatment commenced immediately after BM-MNC treatment followed by daily injections for 5 consecutive days. The primary endpoint was functional outcome after ischemia. Secondary endpoints included analysis of neurogenesis and angiogenesis as well as determination of infarct size. G-CSF treated rats, either in combination with BM-MNC or alone showed improved somatosensory but not gross motor function following ischemia. No beneficial effect of BM-MNC monotherapy was found. Infarct volumes were comparable in all groups. In contrast to previous studies, which used healthy animals, post-Stroke neurogenesis and angiogenesis were not enhanced by G-CSF. In conclusion, the combination of G-CSF and BM-MNC was not more effective than G-CSF alone. The reduced efficacy of G-CSF treatment and the absence of any beneficial effect of BM-MNC transplantation might be directly attributed to hypertension-related morbidity.
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Citicoline Enhances Neuroregenerative Processes After Experimental Stroke in Rats
Stroke, 2012Co-Authors: Kai Diederich, Antje Schmidt, Jens Minnerup, Katrin Frauenknecht, Clemens Sommer, Barbara K. Schneider, Elena Altach, Verena Eggert, Wolf-rüdiger SchäbitzAbstract:Background and Purpose—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 ...
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Effects of Neural Progenitor Cells on Sensorimotor Recovery and Endogenous Repair Mechanisms After Photothrombotic Stroke
Stroke, 2011Co-Authors: Jens Minnerup, Antje Schmidt, Kai Diederich, Jan-kolja Strecker, Henrike Bauer, Clemens Sommer, Jeong Beom Kim, Matthias Schilling, E. Bernd Ringelstein, Hans R. SchölerAbstract:Background and Purpose—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 as...
Anatoly B. Uzdensky - One of the best experts on this subject based on the ideXlab platform.
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Overexpression of HDAC6, but not HDAC3 and HDAC4 in the penumbra after Photothrombotic Stroke in the rat cerebral cortex and the neuroprotective effects of α-phenyl tropolone, HPOB, and sodium valproate.
Brain research bulletin, 2020Co-Authors: Svetlana Demyanenko, Valentina Dzreyan, Anatoly B. UzdenskyAbstract:Abstract Epigenetic processes play important roles in brain responses to ischemic injury. We studied effects of Photothrombotic Stroke (PTS, a model of ischemic Stroke) on the intracellular level and cellular localization of histone deacetylases HDAC3, HDAC4 and HDAC6 in the rat brain cortex, and tested the potential neuroprotector ability of their inhibitors. The background level of HDAC3, HDAC4 and HDAC6 in the rat cerebral cortex was relatively low. HDAC3 localized in the nuclei of some neurons and few astrocytes. HDAC4 was found in the neuronal cytoplasm. After PTS, their levels in penumbra did not change, but HDAC4 appeared in the nuclei of some cells. Its level in the cytoplasmic, but not nuclear fraction of penumbra decreased at 24, but not 4 h after PTS. HDAC6 was upregulated in neurons and astrocytes in the PTS-induced penumbra, especially in the nuclear fraction. Unlike HDAC3 and HDAC4, HDAC6 co-localized with TUNEL-positive apoptotic cells. Inhibitory analysis confirmed the involvement of HDAC6, but not HDAC3 and HDAC4 in neurodegeneration. HDAC6 inhibitor HPOB, HDAC2/8 inhibitor α-phenyl tropolone, and non-specific histone deacetylase inhibitor sodium valproate, but not HDAC3 inhibitor BRD3308, or HDAC4 inhibitor LMK235, decreased PTS-induced infarction volume in the mouse brain, reduced apoptosis, and recovered the motor behavior. HPOB also restored PTS-impaired acetylation of α-tubulin. α-phenyl tropolone restored acetylation of histone H4 in penumbra cells. These results suggest that histone deacetylases HDAC6 and HDAC2 are the possible molecular targets for anti-ischemic therapy, and their inhibitors α-phenyl tropolone, HBOP and sodium valproate can be considered as promising neuroprotectors.
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The Expression and Localization of Histone Acetyltransferases HAT1 and PCAF in Neurons and Astrocytes of the Photothrombotic Stroke-Induced Penumbra in the Rat Brain Cortex
Molecular neurobiology, 2020Co-Authors: Svetlana Demyanenko, Valentina Dzreyan, Anatoly B. UzdenskyAbstract:Stroke is one of the leading reasons of human death. Ischemic penumbra that surrounds the Stroke-induced infarction core is potentially salvageable, but molecular mechanisms of its formation are poorly known. Histone acetylation induces chromatin decondensation and stimulates gene expression. We studied the changes in the levels and localization of histone acetyltransferases HAT1 and PCAF in penumbra after Photothrombotic Stroke (PTS, a Stroke model). In PTS, laser irradiation induces local occlusion of cerebral vessels after photosensitization by Rose Bengal. HAT1 and PCAF are poorly expressed in normal cortical neurons and astrocytes, but they are overexpressed 4–24 h after PTS. Their predominant localization in neuronal nuclei did not change after PTS, but their levels in the astrocyte nuclei significantly increased. Western blotting showed the increase of HAT1 and PCAF levels in the cytoplasmic fraction of the PTS-induced penumbra. In the nuclear fraction, PCAF level did not change, and HAT1 was overexpressed only at 24 h post-PTS. PTS-induced upregulation of HAT1 and PCAF in the penumbra was mainly associated with overexpression in the cytoplasm of neurons and especially astrocytes. HAT1 and PCAF did not co-localize with TUNEL-positive cells that indicated their nonparticipation in PTS-induced apoptosis.
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The Neuroprotective Effect of the HDAC2/3 Inhibitor MI192 on the Penumbra After Photothrombotic Stroke in the Mouse Brain.
Molecular neurobiology, 2019Co-Authors: Svetlana Demyanenko, V V Nikul, Anatoly B. UzdenskyAbstract:Unilateral Photothrombotic Stroke caused tissue infarct in the mouse cerebral cortex. The injury of the cerebral cortex impaired the mouse motor activity, in particular the functional asymmetry in forelimb use. In the peri-infarct cortical tissue outside the infarct core cell apoptosis occurred at 4 and 7 days after PTS. The downregulation of acetylated α-tubulin, a marker of stable microtubules, showed the destruction of neurites, axons, and dendrites in injured neurons. However, the upregulation of GAP43 indicates the stimulation of neurite growth that was possibly aimed at the recovery of the cortical tissue in the damaged cerebral hemisphere. Application of MI-192, an inhibitor of histone deacetylases HDAC2 and HDAC3, demonstrated the neuroprotective activity in the mouse brain subjected to Photothrombotic Stroke. It reduced the volume of the PTS-induced infarction core in the mouse brain, partly restored the functional symmetry in the forelimb use, decreased the level of PTS-induced apoptosis and acetylation of α-tubulin characteristic for stable microtubules, and increased the expression of GAP-43 in the cerebral cortex of the damaged hemisphere. These data point to the involvement of HDAC2 and HDAC3 in the Photothrombotic injury of the mouse brain not only in the infarction core but also outside it. The application of MI192 after PTS reduced or eliminated these negative effects and exerted the neuroprotective effect on the mouse brain. It may be a promising neuroprotector agent for anti-Stroke therapy.
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Expression of Histone Deacetylases HDAC1 and HDAC2 and Their Role in Apoptosis in the Penumbra Induced by Photothrombotic Stroke
Molecular neurobiology, 2019Co-Authors: Svetlana Demyanenko, Valentina Dzreyan, M. A. Neginskaya, Anatoly B. UzdenskyAbstract:In ischemic Stroke, vascular occlusion rapidly induces tissue infarct. Over the ensuing hours, damage spreads to adjacent tissue and forms transition zone (penumbra), which is potentially salvageable. Epigenetic regulation of chromatin structure controls gene expression and protein synthesis. We studied the expression of histone deacetylases HDAC1 and HDAC2 in the penumbra at 4 or 24 h after Photothrombotic Stroke (PTS) in the rat brain cortex. PTS increased the expression of HDAC1 and HDAC2 in penumbra and caused the redistribution of HDAC1 but not HDAC2 from the neuronal nuclei to cytoplasm. In astrocytes, HDAC1 expression and localization did not change. In neurons, HDAC2 localized exclusively in nuclei, but in astrocytes, it was also observed in processes. PTS induced neuronal apoptosis in the penumbra. TUNEL-stained apoptotic neurons co-localized with HDAC2 but not HDAC1. These data suggest that HDAC2 may represent the potential target for anti-Stroke therapy and its selective inhibition may be a promising strategy for the protection of the penumbra tissue after ischemic Stroke.
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Epigenetic Alterations Induced by Photothrombotic Stroke in the Rat Cerebral Cortex: Deacetylation of Histone h3, Upregulation of Histone Deacetylases and Histone Acetyltransferases.
International journal of molecular sciences, 2019Co-Authors: Svetlana Demyanenko, Anatoly B. UzdenskyAbstract:Ischemic penumbra that surrounds a Stroke-induced infarction core is potentially salvageable; however, mechanisms of its formation are not well known. Covalent modifications of histones control chromatin conformation, gene expression and protein synthesis. To study epigenetic processes in ischemic penumbra, we used Photothrombotic Stroke (PTS), a Stroke model in which laser irradiation of the rat brain cortex photosensitized by Rose Bengal induces local vessel occlusion. Immunoblotting and immunofluorescence microscopy showed decrease in acetylation of lysine 9 in histone H3 in penumbra at 1, 4 or 24 h after PTS. This was associated with upregulation of histone deacetylases HDAC1 and HDAC2, but not HDAC4, which did not localize in the nuclei. HDAC2 was found in cell nuclei, HDAC4 in the cytoplasm and HDAC1 both in nuclei and cytoplasm. Histone acetyltransferases HAT1 and PCAF (p300/CBP associated factor) that acetylated histone H3 synthesis were also upregulated, but lesser and later. PTS increased localization of HDAC2 and HAT1 in astroglia. Thus, the cell fate in PTS-induced penumbra is determined by the balance between opposite tendencies leading either to histone acetylation and stimulation of gene expression, or to deacetylation and suppression of transcriptional processes and protein biosynthesis. These epigenetic proteins may be the potential targets for anti-Stroke therapy.
Malgorzata Kossut - One of the best experts on this subject based on the ideXlab platform.
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Functional assessment of sensory functions after Photothrombotic Stroke in the barrel field of mice.
Behavioural brain research, 2013Co-Authors: Monika Liguz-lecznar, Renata Zakrzewska, Katarzyna Daniszewska, Malgorzata KossutAbstract:Motor, sensory and cognitive deficits are common impairments observed in human Stroke as well as in animal Stroke models. Using a battery of behavioural tests we assessed sensorimotor deficits after Photothrombotic Stroke localized within or beyond cortical representation of mouse sensory vibrissae. We found restricted, modality specific behavioural consequences in the acute post-Stroke period. Among incorporated tests, adhesive removal test, novelty exploration test and sensory labyrinth task were sensitive to the somatosensory cortical deficits. Injured animals explored new objects significantly longer, they also needed distinctly more time to contact and to remove the adhesive tape placed on whiskers contralateral to the infarct. Moreover, we observed that after Stroke animals were unable to solve the sensory labyrinth depending only upon tactile sensation from whiskers with injured cortical representation. Spontaneous recovery could be observed within the first post-Stroke week for adhesive tape removal and within 14 days for labyrinth performance. However, for the novel object exploration we did not observed the recovery for the period of 18 days after Stroke. Moreover, new object exploration test performance differed between the somatosensory and visual cortical impairments. We suggest that those three tests might be valuable in assessing the usefulness of therapies designed to support brain repair after experimental Stroke.
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Matrix metalloproteinase inhibition counteracts impairment of cortical experience-dependent plasticity after Photothrombotic Stroke.
The European journal of neuroscience, 2011Co-Authors: Anita Cybulska-klosowicz, D Nowicka, Monika Liguz-lecznar, Malgorzata Kossut, M. Ziemka-nalecz, Jolanta Skangiel-kramskaAbstract:Matrix metalloproteinases (MMPs) are fine modulators of brain plasticity and pathophysiology. The inhibition of MMPs shortly after ischaemic Stroke reduces the infarct size and has beneficial effects on post-Stroke behavioural recovery. Our previous studies have shown that Photothrombotic cortical Stroke disrupts use-dependent plasticity in the neighbouring cortex. The aim of the present study was to check whether the inhibition of MMPs after photothrombosis rescued the plastic capacity of the barrel cortex. To induce plasticity in adult mice, a unilateral deprivation of all vibrissae except row C was applied. The deprivation started immediately after Stroke and lasted 7 days. This procedure, in control (non-Stroke) animals, results in an enlargement of functional representation of the spared row, as shown with [(14)C]2-deoxyglucose uptake mapping. In mice with Stroke induced by photothrombosis in the vicinity of the barrel cortex, vibrissae deprivation did not result in an enlargement of the cortical representation of the spared row C of vibrissae, which confirmed our previous results. However, when mice were injected with the broad-spectrum inhibitor of MMPs FN-439 (10 mg/kg, i.v.) immediately before a Stroke, an enlargement of the representation of the spared row similar to the enlargement found in sham mice was observed. These results indicate the involvement of MMPs in the impairment of use-dependent plasticity in the vicinity of an ischaemic lesion.
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Remapping of the somatosensory cortex after a Photothrombotic Stroke: dynamics of the compensatory reorganization.
Neuroscience, 2009Co-Authors: J.a. Jablonka, Otto W. Witte, Kalina Burnat, Malgorzata KossutAbstract:Abstract Although Stroke can affect cerebral structure and function, the brain has a potential for plasticity thanks to which some degree of function can be restored. The pathways of such recovery are of great interest, since the dynamics of rewiring of the injured brain may become the basis for designing appropriate strategies of rehabilitation. We investigated the spontaneous plasticity of cortical somatosensory representations following a focal unilateral Stroke in the barrel cortex of rats. Ischemic lesions were produced with the Photothrombotic technique in the cortical representation of vibrissae. Functional activation of the brain in response to the stimulation of vibrissae with destroyed cortical representation was monitored through the 2 months post-Stroke survival period with [14C] 2-deoxyglucose (2DG) autoradiographic brain mapping (1, 7, 28, 56 days after the Stroke). 2DG uptake was measured on autoradiograms of tangential sections in several regions of somatosensory cortex and in motor, auditory and prefrontal cortex. Behavioral deficit was assessed by the gap-crossing test 3, 28, 56 days after the Stroke. Changes in the activation pattern of the intact hemisphere and non-vibrissal somatosensory representations of the lesioned hemisphere evolved during the observation period. Full recovery of the behavioral function was reached 2 months after the Stroke and at the same time, new foci of activation were observed in the lesioned hemisphere. At that time, hyperactivation of the somatosensory areas in the intact hemisphere subsided. The new activation foci located in representations of anterior vibrissae, front paw and hind paw were specific for the vibrissae stimulation and were most probably a new functional representation of the vibrissae. We demonstrated spatial and temporal remodeling of the brain induced by cortical Stroke, leading to vicariation of function.
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Focal Stroke in the barrel cortex of rats enhances ipsilateral response to vibrissal input
Acta neurobiologiae experimentalis, 2006Co-Authors: J.a. Jablonka, Malgorzata KossutAbstract:Brain injury triggers spontaneous plasticity, often resulting in considerable restoration of function. To investigate mechanisms of this compensatory plasticity we followed changes in the brain's pattern of activation evoked by stimulation of vibrissae, after a focal cortical Stroke which destroyed the cortical representation of vibrissae, the barrel cortex. The pattern of brain activation was visualized with [ 14 C]-2-doexyglucose (2DG) autoradiography in rats 7 days after Photothrombotic Stroke. During isotope incorporation, vibrissae contralateral to Stroke were stimulated. In control rats this stimulation activates the barrel cortex and the second somatosensory cortex in the contralateral hemisphere. Seven days after Stroke in the barrel cortex, significant increases in activation were found in ipsilateral, uninjured hemisphere in the barrel cortex and anterior vibrissae representation, and also in regions not specifically connected to vibrissae stimulation, such as motor and auditory cortex. Shortly after cortical Stroke, the intact hemisphere shows higher metabolic activation in several cortical regions, possibly due to abnormal interactions with the injured hemisphere.
Osamu Miyamoto - One of the best experts on this subject based on the ideXlab platform.
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Rehabilitative skilled forelimb training enhances axonal remodeling in the corticospinal pathway but not the brainstem-spinal pathways after Photothrombotic Stroke in the primary motor cortex.
PloS one, 2017Co-Authors: Naohiko Okabe, Naoyuki Himi, Emi Maruyama-nakamura, Norito Hayashi, Kazuhiko Narita, Osamu MiyamotoAbstract:Task-specific rehabilitative training is commonly used for chronic Stroke patients. Axonal remodeling is believed to be one mechanism underlying rehabilitation-induced functional recovery, and significant roles of the corticospinal pathway have previously been demonstrated. Brainstem-spinal pathways, as well as the corticospinal tract, have been suggested to contribute to skilled motor function and functional recovery after brain injury. However, whether axonal remodeling in the brainstem-spinal pathways is a critical component for rehabilitation-induced functional recovery is not known. In this study, rats were subjected to Photothrombotic Stroke in the caudal forelimb area of the primary motor cortex and received rehabilitative training with a skilled forelimb reaching task for 4 weeks. After completion of the rehabilitative training, the retrograde tracer Fast blue was injected into the contralesional lower cervical spinal cord. Fast blue-positive cells were counted in 32 brain areas located in the cerebral cortex, hypothalamus, midbrain, pons, and medulla oblongata. Rehabilitative training improved motor performance in the skilled forelimb reaching task but not in the cylinder test, ladder walk test, or staircase test, indicating that rehabilitative skilled forelimb training induced task-specific recovery. In the histological analysis, rehabilitative training significantly increased the number of Fast blue-positive neurons in the ipsilesional rostral forelimb area and secondary sensory cortex. However, rehabilitative training did not alter the number of Fast blue-positive neurons in any areas of the brainstem. These results indicate that rehabilitative skilled forelimb training enhances axonal remodeling selectively in the corticospinal pathway, which suggests a critical role of cortical plasticity, rather than brainstem plasticity, in task-specific recovery after subtotal motor cortex destruction.
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Experimental design.
2017Co-Authors: Naohiko Okabe, Naoyuki Himi, Emi Maruyama-nakamura, Norito Hayashi, Kazuhiko Narita, Osamu MiyamotoAbstract:(A) After completion of skill acquisition training, rats received Photothrombotic Stroke (PT) in the CFA. Rat with rehabilitative training (PT + Rehab) carried out a skilled forelimb reaching task 100 times per day, 5 days per week for 4 weeks. Fast blue was injected 3 to 4 days after final behavioral testing. (B) Fast blue was injected into the lower cervical spinal cord (C7-8) in the contralesional side. Orange areas indicate forelimb areas (divided into RFA and CFA). Black circles indicate infarct induced by photothrombosis.