Abstract WP110: Identification and Validation of a Unique Mirna Target Mir-141-3p in Post Stroke Socially Isolated Aged Mice

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Rajkumar Verma ◽  
Louise D McCullough
Keyword(s):  
Social Isolation ◽  
Post Treatment ◽  
Stroke Recovery ◽  
Motor Deficits ◽  
Dependent Manner ◽  
Total Rna ◽  
Post Stroke ◽  
Mrna Targets ◽  
Socially Isolated

Introduction: MicroRNAs (miRNAs) are a class of short non-coding RNAs that have been identified as a powerful interventional tool for many diseases, including stroke. Very recent studies have found that microRNAs also mediate aspects of social interaction. Social environments can directly influence miRNA expression, which then triggers a plethora of downstream gene changes. Social isolation (SI) impairs stroke recovery and leads to inflammation. We hypothesize that miRNAs are involved in the detrimental effects of post-stroke social isolation. Methods: Eighteen-month-old male C57BL/6 mice were pair housed (PH) for two weeks prior to stroke and randomly assigned to various housing conditions (ST-ISO or ST-PH) immediately after stroke (ST). Mice were sacrificed either at 3, 7 or 14 days after 60-minute right MCAO or sham surgery (n=4-6/group) and perilesional frontal cortex was isolated for miRNA analysis. Total RNA was isolated using either Qiagen miRNeasy® Mini Kit/ miRVANA miRNA isolation kit (Ambion, Life technologies). Whole miRNOme analysis of total RNA isolated from brain tissue was performed using miRCURY LNA TM Universal RT microRNA. Post-treatment with an ‘in vivo ready’ antagomir of miR-141-3p (7mg/kg i.v/day x 3 days; n=4/group) was given through lateral tail veins. Results: Using whole miRNOme analysis of approx. 800 miRNA, we found miR-141-3p was a unique miRNA whose expression was significantly upregulated in a time dependent manner up to day 14 after stroke. The post treatment with an ‘in vivo ready’ antogomir of miR-141-3p reduced the isolation-induced increase in miR-141-3p to levels almost equal to that of pair-housed controls. Post- treatment significantly reduced mortality (by 21% as compared to -ve control) and sensory motor deficits after stroke. mRNA targets analysis study using qPCR confirmed the significant (p<0.05 vs Neg Control ) upregulation of target several genes like arg-1, ccl22 and TGFbr1, markers of M2 type microglial activation, after antogomir treatment. Summary: The present data suggests the unique role of miR-141-3p in post stroke isolation. Temporal expression profiling studies suggest its validation as a potential targets. Post treatment data confirms the in vivo feasibility of miRNA modulation after stroke.

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.

scholarly journals Micro RNA 181c-5p: A promising target for post-stroke recovery in socially isolated mice

2020 ◽  
Vol 715 ◽  
pp. 134610 ◽  
Author(s):  
Maria Antony ◽  
Victoria Scranton ◽  
Pranay Srivastava ◽  
Rajkumar Verma
Keyword(s):  
Micro Rna ◽  
Stroke Recovery ◽  
Post Stroke ◽  
Promising Target ◽  
Socially Isolated

scholarly journals Social isolation impacts late-life socio-cognitive decline in APP/PS1 mice

2019 ◽  
Author(s):  
Eva Rens ◽  
Rudi D’Hooge ◽  
Ann Van der Jeugd
Keyword(s):  
Social Isolation ◽  
Short Term Memory ◽  
Social Recognition ◽  
Long Term Memory ◽  
Dependent Manner ◽  
Term Memory ◽  
Y Maze ◽  
The Social ◽  
Socially Isolated

AbstractIn this study the effects of social isolation (SI) were investigated in APP/PS1 mice. It was found that SI during adolescence has an impact on anxiogenic behaviour, such that isolated animals tend to explore a threatening environment less than non-isolated animals as assessed with the EPM test, and that this holds for both AD and non-AD mice. While no evidence was found for any differences in short-term memory as assessed by the Y-maze, long-term memory seemed to be affected in a context-dependent manner. Object memory as assessed with the NOR test was affected in APP/PS1 mice compared to WT mice, but this deficit was not induced or influenced by SI. When it comes to social recognition memory however, we found that SI exacerbated the social memory deficit in AD mice, and even induced a deficit in WTs. Associative fear memory as assessed with the PA test suggested that WTs perform better when group housed, and APP/PS1 mice better when socially isolated. The link between isolation and AD, or cognition in general, may be more complex than initially thought. The effect of isolation may not be the same for AD versus non-AD subjects.

Prolonged release of VEGF and Ang1 from intralesionally implanted hydrogel promotes perilesional vascularization and functional recovery after experimental ischemic stroke

2022 ◽  
pp. 0271678X2110699
Author(s):  
Pavel Yanev ◽  
Geralda AF van Tilborg ◽  
Annette van der Toorn ◽  
Xiangmei Kong ◽  
Ann M Stowe ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Release Kinetics ◽  
Chronic Phase ◽  
Stroke Recovery ◽  
Intralesional Injection ◽  
Prolonged Release ◽  
Post Stroke ◽  
In Situ Forming

Injectable hydrogels can generate and support pro-repair environments in injured tissue. Here we used a slow-releasing drug carrying in situ-forming hydrogel to promote post-stroke recovery in a rat model. Release kinetics were measured in vitro and in vivo with MRI, using gadolinium-labeled albumin (Galbumin), which demonstrated prolonged release over multiple weeks. Subsequently, this hydrogel was used for long-term delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) (Gel VEGF + Ang1, n = 14), in a photothrombotically induced cortical stroke lesion in rats. Control stroke animals were intralesionally injected with saline (Saline, n = 10), non-loaded gel (Gel, n = 10), or a single bolus of VEGF + Ang1 in saline (Saline VEGF + Ang1, n = 10). MRI was executed to guide hydrogel injection. Functional recovery was assessed with sensorimotor function tests, while tissue status and vascularization were monitored by serial in vivo MRI. Significant recovery from sensorimotor deficits from day 28 onwards was only measured in the Gel VEGF + Ang1 group. This was accompanied by significantly increased vascularization in the perilesional cortex. Histology confirmed (re)vascularization and neuronal sparing in perilesional areas. In conclusion, intralesional injection of in situ-forming hydrogel loaded with pro-angiogenic factors can support prolonged brain tissue regeneration and promote functional recovery in the chronic phase post-stroke.

scholarly journals GAT3 selective substrate l-isoserine upregulates GAT3 expression and increases functional recovery after a focal ischemic stroke in mice

2017 ◽  
Vol 39 (1) ◽  
pp. 74-88 ◽  
Author(s):  
Maria EK Lie ◽  
Emma K Gowing ◽  
Nina B Johansen ◽  
Nils Ole Dalby ◽  
Louise Thiesen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Surface Expression ◽  
Tonic Inhibition ◽  
Stroke Recovery ◽  
Gaba Uptake ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Post Stroke ◽  
Long Term Treatment

Ischemic stroke triggers an elevation in tonic GABA inhibition that impairs the ability of the brain to form new structural and functional cortical circuits required for recovery. This stroke-induced increase in tonic inhibition is caused by impaired GABA uptake via the glial GABA transporter GAT3, highlighting GAT3 as a novel target in stroke recovery. Using a photothrombotic stroke mouse model, we show that GAT3 protein levels are decreased in peri-infarct tissue from 6 h to 42 days post-stroke. Prior studies have shown that GAT substrates can increase GAT surface expression. Therefore, we aimed to assess whether the GAT3 substrate, L-isoserine, could increase post-stroke functional recovery. L-Isoserine (38 µM or 380 µM) administered directly into the infarct from day 5 to 32 post-stroke, significantly increased motor performance in the grid-walking and cylinder tasks in a concentration-dependent manner, without affecting infarct volumes. Additionally, L-isoserine induced a lasting increase in GAT3 expression in peri-infarct regions accompanied by a small decrease in GFAP expression. This study is the first to show that a GAT3 substrate can increase GAT3 expression and functional recovery after focal ischemic stroke following a delayed long-term treatment. We propose that enhancing GAT3-mediated uptake dampens tonic inhibition and promotes functional recovery after stroke.

scholarly journals Delayed Administration of Angiotensin Receptor (AT2R) Agonist C21 Improves Survival and Preserves Sensorimotor Outcomes in Female Diabetic Rats Post-Stroke through Modulation of Microglial Activation

2021 ◽  
Vol 22 (3) ◽  
pp. 1356
Author(s):  
LaDonya Jackson-Cowan ◽  
Wael Eldahshan ◽  
Selin Dumanli ◽  
Guangkuo Dong ◽  
Sarah Jamil ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Young Female ◽  
Artery Occlusion ◽  
Diabetic Rats ◽  
Stroke Recovery ◽  
Fine Motor ◽  
Post Stroke ◽  
The Impact

About 70% of stroke victims present with comorbid diseases such as diabetes and hypertension. The integration of comorbidities in pre-clinical experimental design is important in understanding the mechanisms involved in the development of stroke injury and recovery. We recently showed that administration of compound C21, an angiotensin II type 2 receptor agonist, at day 3 post-stroke improved sensorimotor outcomes by lowering neuroinflammation in diabetic male animals. In the current study, we hypothesized that a delayed administration of C21 would also lower chronic inflammation post-stroke in diabetic female animals. Young female diabetic rats were subjected to 1 h of middle cerebral artery occlusion (MCAO). Three days post-stroke, rats were administered C21 or vehicle in drinking water at a dose of 0.12 mg/kg/day for 4 weeks. The impact of C21 on microglial polarization was analyzed by flow cytometry in vivo and in vitro. Compound 21 treatment improved fine motor skills after MCAO through modulation of the microglia/macrophage inflammatory properties. In addition, C21 increased M2 polarization and reduced the M1:M2 ratio in vitro. In conclusion, delayed administration of C21 downregulates post-stroke inflammation in female diabetic animals. C21 may be a useful therapeutic option to lower neuro-inflammation and improve the post-stroke recovery in diabetes.

scholarly journals Post-Treatment with Erinacine A, a Derived Diterpenoid of H. erinaceus, Attenuates Neurotoxicity in MPTP Model of Parkinson’s Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 137 ◽  
Author(s):  
Kam-Fai Lee ◽  
Shui-Yi Tung ◽  
Chih-Chuan Teng ◽  
Chien-Heng Shen ◽  
Meng Chiao Hsieh ◽  
...  
Keyword(s):  
Cell Death ◽  
Substantia Nigra ◽  
Neuronal Survival ◽  
Post Treatment ◽  
Signal Molecules ◽  
Dependent Manner ◽  
Treatment Regimens ◽  
Cell Death Pathways ◽  
Erinacine A

Hericium erinaceus, a valuable pharmaceutical and edible mushroom, contains potent bioactive compounds such as H. erinaceus mycelium (HEM) and its derived ethanol extraction of erinacine A, which have been found to regulate physiological functions in our previous study. However, HEM or erinacine A with post-treatment regimens also shows effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, but its mechanisms remain unknown. By using annexin-V–fluorescein-isothiocyanate (FITC)/propidium iodide staining and a 2’,7’ –dichlorofluorescin diacetate (DCFDA) staining assay, the cell death, cell viability, and reactive oxygen species (ROS) of 1-methyl-4-phenylpyridinium (MMP+)-treated Neuro-2a (N2a) cells with or without erinacine A addition were measured, respectively. Furthermore, signaling molecules for regulating the p21/GADD45 cell death pathways and PAKalpha, p21 (RAC1) activated kinase 1 (PAK1) survival pathways were also detected in the cells treated with MPP+ and erinacine A by Western blots. In neurotoxic animal models of MPTP induction, the effects of HEM or erinacine A and its mechanism in vivo were determined by measuring the TH-positive cell numbers and the protein level of the substantia nigra through a brain histological examination. Our results demonstrated that post-treatment with erinacine A was capable of preventing the cytotoxicity of neuronal cells and the production of ROS in vitro and in vivo through the neuroprotective mechanism for erinacine A to rescue the neurotoxicity through the disruption of the IRE1α/TRAF2 interaction and the reduction of p21 and GADD45 expression. In addition, erinacine A treatment activated the conserved signaling pathways for neuronal survival via the phosphorylation of PAK1, AKT, LIM domain kinase 2 (LIMK2), extracellular signal-regulated kinases (ERK), and Cofilin. Similar changes in the signal molecules also were found in the substantia nigra of the MPTP, which caused TH+ neuron damage after being treated with erinacine A in the post-treatment regimens in a dose-dependent manner. Taken together, our data indicated a novel mechanism for post-treatment with erinacine A to protect from neurotoxicity through regulating neuronal survival and cell death pathways.

scholarly journals Translational effects of robot-mediated therapy in subacute stroke patients: an experimental evaluation of upper limb motor recovery

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5544 ◽  
Author(s):  
Eduardo Palermo ◽  
Darren Richard Hayes ◽  
Emanuele Francesco Russo ◽  
Rocco Salvatore Calabrò ◽  
Alessandra Pacilli ◽  
...  
Keyword(s):  
Upper Limb ◽  
Effective Means ◽  
Post Treatment ◽  
Motor Deficits ◽  
Stroke Patients ◽  
Optoelectronic System ◽  
Clinical Scales ◽  
Post Stroke ◽  
Subacute Stroke ◽  
Kinematic Assessment

Robot-mediated therapies enhance the recovery of post-stroke patients with motor deficits. Repetitive and repeatable exercises are essential for rehabilitation following brain damage or other disorders that impact the central nervous system, as plasticity permits to reorganize its neural structure, fostering motor relearning. Despite the fact that so many studies claim the validity of robot-mediated therapy in post-stroke patient rehabilitation, it is still difficult to assess to what extent its adoption improves the efficacy of traditional therapy in daily life, and also because most of the studies involved planar robots. In this paper, we report the effects of a 20-session-rehabilitation project involving the Armeo Power robot, an assistive exoskeleton to perform 3D upper limb movements, in addition to conventional rehabilitation therapy, on 10 subacute stroke survivors. Patients were evaluated through clinical scales and a kinematic assessment of the upper limbs, both pre- and post-treatment. A set of indices based on the patients’ 3D kinematic data, gathered from an optoelectronic system, was calculated. Statistical analysis showed a remarkable difference in most parameters between pre- and post-treatment. Significant correlations between the kinematic parameters and clinical scales were found. Our findings suggest that 3D robot-mediated rehabilitation, in addition to conventional therapy, could represent an effective means for the recovery of upper limb disability. Kinematic assessment may represent a valid tool for objectively evaluating the efficacy of the rehabilitation treatment.

scholarly journals NK cells clear α-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of α-synucleinopathy

2020 ◽  
Vol 117 (3) ◽  
pp. 1762-1771 ◽  
Author(s):  
Rachael H. Earls ◽  
Kelly B. Menees ◽  
Jaegwon Chung ◽  
Claire-Anne Gutekunst ◽  
Hyun Joon Lee ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Biological Fluids ◽  
Lewy Body Dementia ◽  
Motor Deficits ◽  
Dependent Manner

The pathological hallmark of synucleinopathies, including Lewy body dementia and Parkinson’s disease (PD), is the presence of Lewy bodies, which are primarily composed of intracellular inclusions of misfolded α-synuclein (α-syn) among other proteins. α-Syn is found in extracellular biological fluids in PD patients and has been implicated in modulating immune responses in the central nervous system (CNS) and the periphery. Natural killer (NK) cells are innate effector lymphocytes that are present in the CNS in homeostatic and pathological conditions. NK cell numbers are increased in the blood of PD patients and their activity is associated with disease severity; however, the role of NK cells in the context of α-synucleinopathies has never been explored. Here, we show that human NK cells can efficiently internalize and degrade α-syn aggregates via the endosomal/lysosomal pathway. We demonstrate that α-syn aggregates attenuate NK cell cytotoxicity in a dose-dependent manner and decrease the release of the proinflammatory cytokine, IFN-γ. To address the role of NK cells in PD pathogenesis, NK cell function was investigated in a preformed fibril α-syn–induced mouse PD model. Our studies demonstrate that in vivo depletion of NK cells in a preclinical mouse PD model resulted in exacerbated motor deficits and increased phosphorylated α-syn deposits. Collectively, our data provide a role of NK cells in modulating synuclein pathology and motor symptoms in a preclinical mouse model of PD, which could be developed into a therapeutic for PD and other synucleinopathies.

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