scholarly journals Growth Hormone Promotes Motor Function after Experimental Stroke and Enhances Recovery-Promoting Mechanisms within the Peri-Infarct Area

2020 ◽  
Vol 21 (2) ◽  
pp. 606 ◽  
Author(s):  
Sonia Sanchez-Bezanilla ◽  
N. David Åberg ◽  
Patricia Crock ◽  
Frederick R. Walker ◽  
Michael Nilsson ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Proliferation ◽  
Motor Function ◽  
Stroke Recovery ◽  
Tissue Loss ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Post Stroke ◽  
Positive Effects ◽  
Infarct Area

Motor impairment is the most common and widely recognised clinical outcome after stroke. Current clinical practice in stroke rehabilitation focuses mainly on physical therapy, with no pharmacological intervention approved to facilitate functional recovery. Several studies have documented positive effects of growth hormone (GH) on cognitive function after stroke, but surprisingly, the effects on motor function remain unclear. In this study, photothrombotic occlusion targeting the motor and sensory cortex was induced in adult male mice. Two days post-stroke, mice were administered with recombinant human GH or saline, continuing for 28 days, followed by evaluation of motor function. Three days after initiation of the treatment, bromodeoxyuridine was administered for subsequent assessment of cell proliferation. Known neurorestorative processes within the peri-infarct area were evaluated by histological and biochemical analyses at 30 days post-stroke. This study demonstrated that GH treatment improves motor function after stroke by 50%–60%, as assessed using the cylinder and grid walk tests. Furthermore, the observed functional improvements occurred in parallel with a reduction in brain tissue loss, as well as increased cell proliferation, neurogenesis, increased synaptic plasticity and angiogenesis within the peri-infarct area. These findings provide new evidence about the potential therapeutic effects of GH in stroke recovery.

scholarly journals Post-Stroke Social Isolation Reduces Cell Proliferation in the Dentate Gyrus and Alters miRNA Profiles in the Aged Female Mice Brain

2020 ◽  
Vol 22 (1) ◽  
pp. 99
Author(s):  
Aleah Holmes ◽  
Yan Xu ◽  
Juneyoung Lee ◽  
Michael E. Maniskas ◽  
Liang Zhu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dentate Gyrus ◽  
Social Isolation ◽  
Census Data ◽  
Elderly Women ◽  
Stroke Recovery ◽  
Tissue Loss ◽  
Female Mice ◽  
Post Stroke ◽  
The Brain

Social isolation and loneliness are risk factors for stroke. Elderly women are more likely to be isolated. Census data shows that in homeowners over the age of 65, women are much more likely to live alone. However, the underlying mechanisms of the detrimental effects of isolation have not been well studied in older females. In this study, we hypothesized that isolation impairs post-stroke recovery in aged female mice, leading to dysregulated microRNAs (miRNAs) in the brain, including those previously shown to be involved in response to social isolation (SI). Aged C57BL/6 female mice were subjected to a 60-min middle cerebral artery occlusion and were randomly assigned to either single housing (SI) or continued pair housing (PH) immediately after stroke for 15 days. SI immediately after stroke led to significantly more brain tissue loss after stroke and higher mortality. Furthermore, SI significantly delayed motor and sensory recovery and worsened cognitive function, compared to PH. A decrease in cell proliferation was seen in the dentate gyrus of SI mice assessed by bromodeoxyuridine (BrdU) labeling. miRNAome data analysis revealed changes in several miRNAs in the brain, such as miR-297a-3p and miR-200c-3p, which are known to regulate pathways involved in cell proliferation. In conclusion, our data suggest that SI can lead to a poor post-stroke recovery in aged females and dysregulation of miRNAs and reduced hippocampal cell proliferation.

Abstract P757: Social Isolation After Stroke Reduces Cell Proliferation and Alters Brain MiRNA Profiles in the Aged Female Mice

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Aleah Holmes ◽  
Yan Xu ◽  
Juneyoung Lee ◽  
Liang Zhu ◽  
Venugopal Reddy Venna ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Social Isolation ◽  
Elderly Women ◽  
Epidemiological Studies ◽  
Stroke Recovery ◽  
Tissue Loss ◽  
Adhesive Tape ◽  
Female Mice ◽  
Post Stroke ◽  
Hippocampal Cell

Background: Social isolation (SI) and loneliness are risk factors for stroke. Epidemiological studies have shown that women tend to have a higher risk of stroke at later age and elderly women are more likely to be isolated. The mechanisms underlying the detrimental effects of SI have not been well studied in older females. We hypothesized that SI in aged female mice would lead to impaired post-stroke recovery and could lead to differential regulation of microRNAs (miRNAs). Methods: In this study, aged C57BL/6N female mice were subjected to a 60-minute middle cerebral artery occlusion (MCAO) and were randomly assigned to either single housing (SI) or continued pair housing (PH) immediately after stroke for 15 days. Infarct size, mortality and recovery was assessed using open field, the adhesive-tape removal task and the Y-maze test. MiRNAs were comprehensively analyzed by miRNAome analysis on stroke brain, and changes in hippocampal cell proliferation was assessed from perfused brain sections. Results: Importantly, SI immediately after stroke led to significantly larger tissue loss and higher mortality in aged females, it also significantly delayed motor/sensory recovery in the adhesive removal test and impaired overall locomotor activity. In addition, these mice also demonstrated worse post-stroke cognitive function. In parallel, brains of these mice showed reduced miR-297a-3p expression and increased miR-18a-3p and miR-200c-3p expression with SI compared to PH cohort and reduced hippocampal cell proliferation. Conclusion: The results from this study suggest that SI after stroke can increase mortality and significantly impair post-stroke recovery in aged female mice. These worse outcomes are in parallel to the significant changes in several miRNAs and reduced hippocampal cell proliferation.

Abstract WP108: Co-transplantation of NPCs and EPCs Synergistically Promotes Brain Recovery After Ischemia-reperfusion Injury in Mice

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Jinju Wang ◽  
Xiaotang Ma ◽  
Shuzhen Chen ◽  
Xiang Xiao ◽  
Ji Bihl ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Motor Function ◽  
Ischemia Reperfusion Injury ◽  
Synergistic Effects ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Therapeutic Effects ◽  
Gene Expressions ◽  
Protein Ratio ◽  
Infarct Area

Introduction: The promising of neuron progenitor cells (NPCs) or endothelial progenitor cells (EPCs) for treating ischemic stroke has been recognized. In this study, we determined the therapeutic effects of NPC and EPC co-transplantation and the underlying mechanisms in a mouse model of ischemia-reperfusion (I-R) stroke. Methods: NPCs and EPCs were generated from human inducible pluripotent stem cells. C57BL/6 adult mice were subjected to middle cerebral artery occlusion (MCAO; 90 min) followed by reperfusion (30 min), and treated with (n=10/group): 1) PBS; 2) EPCs; 3) NPCs; 4) EPCs+NPCs (1:1 ratio); 5) EPCs+NPCs (1:1 ratio)+LY294002 (1μM). Cells (3x105/2μl PBS) were injected into ipsilateral striatum at 2 sites (1μl/site). Bromodeoxyuridine (BrdU, 65 mg/g/day, i.p.) was injected to label the new generated cells. Mice were sacrificed at days 2 and 10. Motor function (Rotarod test and neurologic deficit score), infarct volume, cerebral microvascular density (cMVD), neurogenesis and angiogenesis, and gene expressions of the PI3K/Akt pathway were evaluated. Results: Co-transplantation of EPCs and NPCs exhibited synergistic effects on improving motor function, increasing cMVD in the peri-infarct area, and decreasing infarct volume at days 2 and 10 (refer to table). Moreover, neurogenesis (Brdu+NeuN+) and angiogenesis (Brdu+CD31+) in the peri-infarct area were largely enhanced in the co-transplantation group at day 10 (refer to table). In addition, the protein ratio of p-Akt/Akt was increased in the brain in the co-transplantation group (p<0.05). These effects were significantly reduced by LY294002 administration. Conclusion: Co-transplantation of NPCs and EPCs synergistically increases cMVD, promotes angiogenesis and neurogenesis, and improves functional outcome in I-R injured mice. Activation of the PI3K/Akt signal pathway contributes to the synergistic effects of NPCs and EPCs.

scholarly journals β-Oscillations Reflect Recovery of the Paretic Upper Limb in Subacute Stroke

2020 ◽  
Vol 34 (5) ◽  
pp. 450-462 ◽  
Author(s):  
Chih-Wei Tang ◽  
Fu-Jung Hsiao ◽  
Po-Lei Lee ◽  
Yun-An Tsai ◽  
Ya-Fang Hsu ◽  
...  
Keyword(s):  
Motor Function ◽  
Upper Limb ◽  
Primary Motor Cortex ◽  
Hand Movement ◽  
Stroke Recovery ◽  
Stroke Survivors ◽  
Healthy Controls ◽  
Functional Changes ◽  
Post Stroke ◽  
Subacute Stroke

Background. Recovery of upper limb function post-stroke can be partly predicted by initial motor function, but the mechanisms underpinning these improvements have yet to be determined. Here, we sought to identify neural correlates of post-stroke recovery using longitudinal magnetoencephalography (MEG) assessments in subacute stroke survivors. Methods. First-ever, subcortical ischemic stroke survivors with unilateral mild to moderate hand paresis were evaluated at 3, 5, and 12 weeks after stroke using a finger-lifting task in the MEG. Cortical activity patterns in the β-band (16-30 Hz) were compared with matched healthy controls. Results. All stroke survivors (n=22; 17 males) had improvements in action research arm test (ARAT) and Fugl-Meyer upper extremity (FM-UE) scores between 3 and 12 weeks. At 3 weeks post-stroke the peak amplitudes of the movement-related ipsilesional β-band event-related desynchronization (β-ERD) and synchronization (β-ERS) in primary motor cortex (M1) were significantly lower than the healthy controls (p<0.001) and were correlated with both the FM-UE and ARAT scores (r=0.51-0.69, p<0.017). The decreased β-ERS peak amplitudes were observed both in paretic and non-paretic hand movement particularly at 3 weeks post-stroke, suggesting a generalized disinhibition status. The peak amplitudes of ipsilesional β-ERS at week 3 post-stroke correlated with the FM-UE score at 12 weeks (r=0.54, p=0.03) but no longer significant when controlling for the FM-UE score at 3 weeks post-stroke. Conclusions. Although early β-band activity does not independently predict outcome at 3 months after stroke, it mirrors functional changes, giving a potential insight into the mechanisms underpinning recovery of motor function in subacute stroke.

scholarly journals The Asparaginyl Endopeptidase Legumain after Experimental Stroke

2010 ◽  
Vol 30 (10) ◽  
pp. 1756-1766 ◽  
Author(s):  
Taku Ishizaki ◽  
Agnes Erickson ◽  
Enida Kuric ◽  
Mehrdad Shamloo ◽  
Ikuko Hara-Nishimura ◽  
...  
Keyword(s):  
Immune Cell ◽  
Infarct Volume ◽  
Recovery Period ◽  
Gene Array ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Post Stroke ◽  
Asparaginyl Endopeptidase ◽  
Infarct Area ◽  
Deficient Mice

Various proteases in the brain contribute to ischemic brain injury. We investigated the involvement of the asparaginyl endopeptidase legumain after experimental stroke. On the basis of gene array studies and in situ hybridizations, we observed an increase of legumain expression in the peri-infarct area of rats after transient occlusion of the middle cerebral artery (MCAO) for 120 mins with a maximum expression at 24 and 48 h. Immunohistochemical analyses revealed the expression of legumain in Iba1+ microglial cells and glial fibrillary acidic protein-positive astrocytes of the peri-infarct area in mice after MCAO. Post-stroke recovery was also studied in aged legumain-deficient mice (45 to 58 weeks old). Legumain-deficient mice did not show any differences in physiologic parameters compared with respective littermates before, during MCAO (45 mins), and the subsequent recovery period of 8 days. Moreover, legumain deficiency had no effect on mortality, infarct volume, and the neurologic deficit determined by the rotating pole test, a standardized grip strength test, and the pole test. However, a reduced number of invading CD74+ cells in the ischemic hemisphere indicates an involvement in post-stroke inflammation. We conclude that legumain is not essential for the functional deficit after MCAO but may be involved in mechanisms of immune cell invasion.

scholarly journals Corticosterone Administration Alters White Matter Tract Structure and Reduces Gliosis in the Sub-Acute Phase of Experimental Stroke

2021 ◽  
Vol 22 (13) ◽  
pp. 6693
Author(s):  
Katarzyna Zalewska ◽  
Rebecca J. Hood ◽  
Giovanni Pietrogrande ◽  
Sonia Sanchez-Bezanilla ◽  
Lin Kooi Ong ◽  
...  
Keyword(s):  
White Matter ◽  
Biochemical Analysis ◽  
Stroke Recovery ◽  
Tissue Loss ◽  
Experimental Stroke ◽  
White Matter Tract ◽  
Ipsilateral Hemisphere ◽  
Post Stroke ◽  
Sham Surgery ◽  
Prolonged Stress

White matter tract (WMT) degeneration has been reported to occur following a stroke, and it is associated with post-stroke functional disturbances. White matter pathology has been suggested to be an independent predictor of post-stroke recovery. However, the factors that influence WMT remodeling are poorly understood. Cortisol is a steroid hormone released in response to prolonged stress, and elevated levels of cortisol have been reported to interfere with brain recovery. The objective of this study was to investigate the influence of corticosterone (CORT; the rodent equivalent of cortisol) on WMT structure post-stroke. Photothrombotic stroke (or sham surgery) was induced in 8-week-old male C57BL/6 mice. At 72 h, mice were exposed to standard drinking water ± CORT (100 µg/mL). After two weeks of CORT administration, mice were euthanised and brain tissue collected for histological and biochemical analysis of WMT (particularly the corpus callosum and corticospinal tract). CORT administration was associated with increased tissue loss within the ipsilateral hemisphere, and modest and inconsistent WMT reorganization. Further, a structural and molecular analysis of the WMT components suggested that CORT exerted effects over axons and glial cells. Our findings highlight that CORT at stress-like levels can moderately influence the reorganization and microstructure of WMT post-stroke.

scholarly journals Targeting GABAC Receptors Improves Post-Stroke Motor Recovery

2021 ◽  
Vol 11 (3) ◽  
pp. 315
Author(s):  
Petra S. van Nieuwenhuijzen ◽  
Kim Parker ◽  
Vivian Liao ◽  
Josh Houlton ◽  
Hye-Lim Kim ◽  
...  
Keyword(s):  
Infarct Size ◽  
Motor Function ◽  
Treatment Options ◽  
Motor Recovery ◽  
Stroke Recovery ◽  
Xenopus Laevis Oocytes ◽  
Reactive Astrogliosis ◽  
Delayed Treatment ◽  
Post Stroke ◽  
Gabac Receptors

Ischemic stroke remains a leading cause of disability worldwide, with limited treatment options available. This study investigates GABAC receptors as novel pharmacological targets for stroke recovery. The expression of ρ1 and ρ2 mRNA in mice were determined in peri-infarct tissue following photothrombotic motor cortex stroke. (R)-4-amino-cyclopent-1-enyl butylphosphinic acid (R)-4-ACPBPA and (S)-4-ACPBPA were assessed using 2-elecotrode voltage electrophysiology in Xenopus laevis oocytes. Stroke mice were treated for 4 weeks with either vehicle, the α5-selective negative allosteric modulator, L655,708, or the ρ1/2 antagonists, (R)-4-ACPBPA and (S)-4-ACPBPA respectively from 3 days post-stroke. Infarct size and expression levels of GAT3 and reactive astrogliosis were determined using histochemistry and immunohistochemistry respectively, and motor function was assessed using both the grid-walking and cylinder tasks. After stroke, significant increases in ρ1 and ρ2 mRNAs were observed on day 3, with ρ2 showing a further increase on day 7. (R)- and (S)-4-ACPBPA are both potent antagonists at ρ2 and only weak inhibitors of α5β2γ2 receptors. Treatment with either L655,708, (S)-4-ACPBPA (ρ1/2 antagonist; 5 mM only), or (R)-4-ACPBPA (ρ2 antagonist; 2.5 and 5 mM) from 3 days after stroke resulted in a significant improvement in motor recovery on the grid-walking task, with L655,708 and (R)-4-ACPBPA also showing an improvement in the cylinder task. Infarct size was unaffected, and only (R)-4-ACPBPA significantly increased peri-infarct GAT3 expression and decreased the level of reactive astrogliosis. Importantly, inhibiting GABAC receptors affords significant improvement in motor function after stroke. Targeting the ρ-subunit could provide a novel delayed treatment option for stroke recovery.

scholarly journals Cell Proliferation in the Piriform Cortex of Rats with Motor Cortex Ablation Treated with Growth Hormone and Rehabilitation

2021 ◽  
Author(s):  
Margarita Heredia ◽  
Virginia Sánchez-Robledo ◽  
Inés Gómez ◽  
José María Criado ◽  
Antonio de la Fuente ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Proliferation ◽  
Brain Injury ◽  
Motor Cortex ◽  
Motor Function ◽  
Piriform Cortex ◽  
Male Rats ◽  
Motor Deficit ◽  
Gh Treatment ◽  
The Brain

Traumatic brain injury represents one of the main health problems in developed countries. Growth Hormone (GH) and rehabilitation have been claimed to significantly contribute to the recovery of lost motor function after acquired brain injury, but the mechanisms by which this occurs are not well understood. In this work, we have investigated cell proliferation in the piriform cortex (PC) of adult rats with ablation of the frontal motor cortex treated with GH and rehabilitation, in order to evaluate if this region of the brain, related to the sense of smell, could be involved in benefits of GH treatment. Male rats were either ablated the frontal motor cortex in the dominant hemisphere or sham-operated and treated with GH or vehicle at 35 days post-injury (dpi) for five days. At 36 dpi, all rats received daily injections of bromodeoxyuridine (BrdU) for 4 days. We assessed motor function through the paw-reaching-for-food task. GH treatment and rehabilitation at 35 dpi significantly improved the motor deficit caused by the injury and promoted an increase of cell proliferation in the PC ipsilateral to the injury, which could be involved in the improvement observed. Cortical ablation promoted greater number of BrdU+ cells in the piriform cortex that was maintained long-term, which could be involved in the compensatory mechanisms of the brain after injury.

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