Increasing Neurogenesis with Fluoxetine, Simvastatin and Ascorbic Acid Leads to Functional Recovery in Ischemic Stroke

2015 ◽  
Vol 9 (2) ◽  
pp. 158-166 ◽  
Author(s):  
Adrian Corbett ◽  
Scott Sieber ◽  
Nicholas Wyatt ◽  
Jenna Lizzi ◽  
Tiffany Flannery ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Ischemic Stroke ◽  
Functional Recovery

Abstract WP105: An Effective Delayed Treatment for Ischemic Stroke Uses Fluoxetine and Simvastatin

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Adrian Corbett ◽  
Scott Sieber ◽  
Nicholas Wyatt ◽  
Jenna Lizzi ◽  
Tiffany Flannery ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Ischemic Stroke ◽  
Drug Treatment ◽  
Functional Recovery ◽  
Adult Neurogenesis ◽  
Fold Increase ◽  
Vehicle Control ◽  
Combination Drug ◽  
Stroke Treatment ◽  
Post Stroke

For more than 90% of ischemic stroke patients there exists no standardized drug treatment other than giving aspirin or beginning statin treatment for the prevention of future strokes. The purpose of this study was to develop a delayed pharmacological treatment for ischemic stroke, utilizing a combination of drugs that would enhance adult neurogenesis and brain-derived neurotrophic factor. An endothelin-induced stroke was produced in 10-12 month old rats, which have previously been trained on Montoya Staircase and Forelimb Asymmetry tests. Combination drug treatments were tested against vehicle controls, beginning 20-26 hours after stroke induction and continuing for 31 days. Functional tests were performed at various times post-stroke. Daily treatments of 5 mg/kg fluoxetine in combination with 0.5 mg/kg simvastatin and 20 mg/kg ascorbic acid produced a 19-fold increase in neurogenesis (P=0.001 compared to vehicle control), while fluoxetine alone produced a 10-fold increase in neurogenesis (P=0.007 compared to vehicle control). This combination drug treatment results in almost complete functional recovery as measured by Montoya Staircase (mean recovery to 85% of pre-stroke function, P=0.023) and Forelimb Asymmetry tests (mean recovery to 90% of pre-stroke function, P=0.041 and P= 0.05) in 10-12 month old stroked female Long Evans rats. Additional testing of 5 mg/kg fluoxetine and 20 mg/kg ascorbic acid drug combination as a delayed post-stroke treatment has only given half of the functional recovery seen when all three drugs are included, indicating that the statin is essential for full recovery. Fluoxetine is likely to be the other essential component of this combination treatment as it alone resulted in a significant increase in adult neurogenesis.

Role of S100β Glial Protein as a Serological Marker for Analysis of Acute Ischemic Stroke

2021 ◽  
pp. 251660852110112
Author(s):  
Kiran Buddharaju ◽  
Mahendra Javali ◽  
Anish Mehta ◽  
R Srinivasa ◽  
Purushottam Acharya
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Recovery ◽  
Protein Level ◽  
Serological Marker ◽  
Protein Levels ◽  
S100β Protein ◽  
Asymptomatic Volunteers ◽  
Scale Scores

Background: Stroke is a major cause of neurological disability, which can be often predicted with serological markers. Glial-derived S100β protein is a potential biomarker for cerebral ischemia and may be helpful in predicting the severity, outcome, and recovery of stroke. Aim: This study aimed to study the role of S100β glial protein as a serological marker in predicting the severity of acute ischemic stroke (AIS), outcome, and functional recovery after 1 month. Methods: A hospital-based prospective case control study included 43 consecutive patients, >18 years old, who were admitted with acute middle cerebral artery (MCA) territory infarcts within 72 h of onset of neurological deficits. Control group comprised of 43 age-matched asymptomatic volunteers. Independent t-test and chi square test were used to compare the means and evaluate the association between protein level and various parameters. P ≤ .05 was statistically significant. Results: S100β protein level in AIS patients was significantly higher compared to controls ( P < .05). Elevated serum S100β protein level was found to be associated with larger infarct volumes, higher National Institute Health Stroke Scale scores, and higher modified Rankin Scale scores at admission ( P < .05). Patients with higher S100β protein levels at admission had poor recovery at 1 month compared to patients having normal S100β protein levels. Conclusion: S100β protein levels at admission after an acute MCA territory infarct may be used as a reliable serological tool in predicting the severity, outcome, and functional recovery in stroke.

scholarly journals Impact of Post-Stroke Recanalization on General and Upper Limb Functioning: A Prospective, Observational Study

2021 ◽  
Vol 13 (1) ◽  
pp. 46-58
Author(s):  
João Paulo Branco ◽  
Filipa Rocha ◽  
João Sargento-Freitas ◽  
Gustavo C. Santo ◽  
António Freire ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Observational Study ◽  
Acute Ischemic Stroke ◽  
Upper Limb ◽  
Functional Recovery ◽  
Prospective Observational Study ◽  
Positive Impact ◽  
Rehabilitation Program ◽  
Patient Functioning ◽  
The Impact

The objective of this study is to assess the impact of recanalization (spontaneous and therapeutic) on upper limb functioning and general patient functioning after stroke. This is a prospective, observational study of patients hospitalized due to acute ischemic stroke in the territory of the middle cerebral artery (n = 98). Patients completed a comprehensive rehabilitation program and were followed-up for 24 weeks. The impact of recanalization on patient functioning was evaluated using the modified Rankin Scale (mRS) and Stroke Upper Limb Capacity Scale (SULCS). General and upper limb functioning improved markedly in the first three weeks after stroke. Age, gender, and National Institutes of Health Stroke Scale (NIHSS) score at admission were associated with general and upper limb functioning at 12 weeks. Successful recanalization was associated with better functioning. Among patients who underwent therapeutic recanalization, NIHSS scores ≥16.5 indicate lower general functioning at 12 weeks (sensibility = 72.4%; specificity = 78.6%) and NIHSS scores ≥13.5 indicate no hand functioning at 12 weeks (sensibility = 83.8%; specificity = 76.5%). Recanalization, either spontaneous or therapeutic, has a positive impact on patient functioning after acute ischemic stroke. Functional recovery occurs mostly within the first 12 weeks after stroke, with greater functional gains among patients with successful recanalization. Higher NIHSS scores at admission are associated with worse functional recovery.

Chemogenetic activation of glutamatergic neurons in the motor cortex promotes functional recovery after ischemic stroke in rats

2019 ◽  
Vol 359 ◽  
pp. 81-88 ◽  
Author(s):  
Ke-hui Hu ◽  
Yang-an Li ◽  
Wei Jia ◽  
Guang-yan Wu ◽  
Lin Sun ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Motor Cortex ◽  
Functional Recovery ◽  
Glutamatergic Neurons

scholarly journals ANTIOXIDANT STATUS IN VARIOUS PATHOGENIC SUBTYPES OF ISCHEMIC STROKE IN ACUTE PERIOD

2016 ◽  
Vol 1 (6) ◽  
pp. 76-81
Author(s):  
Лукьянова ◽  
Yuliya Lukyanova
Keyword(s):  
Ascorbic Acid ◽  
Ischemic Stroke ◽  
Antioxidant Capacity ◽  
Antioxidant Status ◽  
Control Group ◽  
Blood Levels ◽  
Cell Recovery ◽  
Stroke Subtype ◽  
Acute Period ◽  
Group 5

The aim of the study was to detect significant biochemical changes in antioxidant status during acute period of ischemic stroke in its various pathogenic subtypes in patients aged 45–74years. The most important results were blood levels of ascorbic acid, malondialdehyde and free/ oxidized glutathione ratio. Cardioembolic stroke was associated with: the reduced ascorbic acid level of 62–74% comparable to control group; 5-times increased malondialdehyde level at the end of the first week of the disease; and also 50% decreasing of cell antioxidant capacity comparable to control group and other stroke subtypes. In lacunary stroke minimal changes in antioxidant status were measured, possibly because of small size of brain damage. Positive clinical dynamics was followed by decreasing of free glutathione levels. It could be related with its previous significant expenditure in process of cell recovery in penumbra area. In case of favorable outcome all of the markers return to the levels which were comparable to control group. The differences in the dynam-ics of the cells antioxidant capacity and consumption of native antioxidants, the time from the onset of the disease, the severity of the clinical picture, depending on the stroke subtype, were revealed. Further research of this problem may help to create new methods of diagnostics and selective pharmacological correction of this pathology.

Abstract WP105: Tissue Plasminogen Activator (tPA) is Essential for Functional Recovery After Stroke by Promoting Axonal Outgrowth

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Shubei Ma
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Recovery ◽  
Stroke Recovery ◽  
White Matter Integrity ◽  
Blue Staining ◽  
Tissue Plasminogen

Objectives: Stroke is the leading cause of long term neurological disability with limited therapeutic options. Human recombinant tissue plasminogen activator (tPA) is currently the only FDA approved drug for the thrombolytic treatment of ischemic stroke. Emerging evidence suggests that the effects of tPA in ischemic brain may extend beyond its thrombolytic activity. In this study, we investigated the role of tPA in long term stroke recovery. Methods: Cortical infarct was induced by distal middle cerebral artery occlusion (dMCAO) in tPA knockout (KO) and wild type (WT) mice. Sensorimotor functions were evaluated at 3-35 days after dMCAO. White matter integrity was assessed by luxol fast blue staining, immunohistochemistry for SMI-32, and diffusion tensor imaging (DTI). The neuronal tracer biotinylated dextran amine (BDA) was used to label the corticorubral tract and the corticospinal tract. For rescue experiment, tPA (2mg/kg) was delivered intranasally to tPA KO mice once a day for 14 days starting 6h after dMCAO. Results: Infarct volume was comparable between tPA KO and WT mice after dMCAO. Sensorimotor deficits after dMCAO were exacerbated in tPA KO mice than WT mice. tPA KO mice also showed more severe demyelination in post-stroke white matter and reduced axonal sprouting at 35 days after dMCAO compared to WT mice. DTI studies revealed deteriorated white matter integrity in tPA KO mice, as manifested by decreased fractional anisotropy. Intranasal delivery of tPA after dMCAO rescued the neurological phenotype shown by tPA KO mice. Conclusion: Endogenous tPA promotes white matter integrity and is essential for functional recovery after ischemic stroke. tPA may be a novel neurorestorative therapy for stroke recovery.

Abstract TP96: Functional Recovery and White Matter Repair After Exosomes Administration in Different Experimental Animal Models of Stroke

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Laura Otero Ortega ◽  
María Gutiérrez Fernández ◽  
Berta Rodríguez Frutos ◽  
Jaime Ramos Cejudo ◽  
Irene Lorenzo Llorente ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Functional Recovery ◽  
Brain Plasticity ◽  
Trophic Factors ◽  
Lesion Volume ◽  
Axonal Sprouting ◽  
Control Groups ◽  
Myelin Formation ◽  
White Matter Repair

Introduction: Extracellular vesicles such as exosomes has opened a new field of research. Exosomes are able to transfer DNAs, mRNAs, microRNAs, non-coding RNAs, proteins, trophic factors and lipids associated with brain plasticity enhancement after stroke. Aim: To investigate white matter repair after exosomes administration in two experimental models of subcortical stroke: ischemic and hemorrhage. Material/Methods: Subcortical ischemic stroke was induced by Endothelin-1 and Collagenase IV was used to induce subcortical hemorrhagic stroke into striatum. Intravenous exosomes or saline only were administrated at 24h after cerebral infarct as treatment. Exosomes were isolated from culture of adipose mesenchymal stem cell and they were characterized by Nanoshight, Electronic microscope, Western blot and Immunofluorescence. Proteins contained into exosomes were analyzed by Orbitrab. We analyzed functional recovery by Rotarod, beam walking and Rogers tests. Lesion volume and tract connectivity were studied by magnetic resonance image. Anterograde and retrograde tracers were used to analyze axonal sprouting. Myelin formation was analyzed by cryomielin. Results: Proteomics analysis of exosomes identified more than 1400 proteins, many of them involved in intercellular communication. DiI labeled-Exosomes were detected in brain and peripheral organs (liver, lung and spleen). After 28 days, treated groups showed smaller functional deficit compared to control groups in both hemorrhagic and ischemic models. Moreover, treated group showed an increase in tract connectivity at 7 and 28 days compared to control groups. Also, animals which received exosomes showed an increase axonal sprouting and myelin formation at 28 days after stroke in both hemorrhagic and ischemic stroke. The treated groups also showed higher levels of white matter-associated markers in the injured area than the control groups. Conclusion: White matter integrity in different subcortical strokes is in part restored by exosomes treatment, probably mediated by repair molecular factors implicated in axonal sprouting, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery in both kinds of strokes.

Abstract WP291: Diabetes Impairs Long-term Functional Recovery in an Embolic Stroke Model in Sex Independent Manner

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Sherif Hafez ◽  
John Paul Valenzuela ◽  
Rebecca Ward ◽  
Guangkuo Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Hemorrhagic Transformation ◽  
Cognitive Outcome ◽  
Embolic Stroke ◽  
Neurological Deficits ◽  
Independent Manner ◽  
Male And Female ◽  
The Impact

Ischemic stroke is a leading cause of death and disability. Diabetes not only increases the risk of stroke, it also worsens the outcomes, increases the risk of hemorrhagic transformation (HT) and impairs recovery after stroke. It is well established that young females are more protected and show better outcomes than males after stroke. However, the impact of diabetes on long term recovery after stroke in both sexes was not clear. Accordingly, this study tested the hypothesis that diabetes impairs long term functional recovery after ischemic stroke in a sex independent manner. Methods: Diabetes was induced in male and female Wistar rats using high fat diet and low dose streptozotocin (30 mg/Kg). After 8 weeks of diabetes, animals were subjected to embolic stroke. Male and female Wistar normoglycemic age matched rats were used as controls. Motor (composite score: 14 best outcome and adhesive removal-ART) and cognitive (novel object recognition, NOR) deficits were assessed at day1, 3, 7 and 14. Results: Female control animals had better outcomes compared to the males. Mortality was higher in diabetic animals, especially in males. The neurological deficits were greater in diabetic animals with no difference between males and females. Conclusion: Diabetes impaired functional and cognitive outcome and recovery after ischemic stroke in a sex independent manner.

Abstract 47: Age of Donor of Human Mesenchymal Stem Cells Drastically Affects Structural and Functional Recovery After Cell Therapy Following Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Susumu Yamaguchi ◽  
Nobutaka Horie ◽  
Katsuya Satoh ◽  
Yoichi Morofuji ◽  
Tsuyoshi Izumo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Migration ◽  
Ischemic Stroke ◽  
Functional Recovery ◽  
Human Mesenchymal Stem Cells ◽  
Trophic Factor ◽  
Donor Age ◽  
Vessel Maturation ◽  
Factor Secretion

Background and purpose: Cell transplantation therapy holds great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is uncertain. We investigate regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischemic stroke. Methods: The value of platelet-derived growth factor (PDGF)-BB secreted from human mesenchymal stem cells (hMSC) was analyzed regarding in two age groups; young (20-30 years) and old (57-65 years) in vitro. Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion, and received young or old hMSC trans-arterially at 24 h after stroke. Functional recovery was assessed with modified neurological severity score (mNSS). Structural recovery was assessed on neovascularization and endogenous cell migration as well as trophic factor secretion. Results: The value of PDGF-BB was significantly higher in young hMSC (40.47±4.29 pg/ml/10 4 cells) than that in old hMSC (25.35±3.16 pg/ml/10 4 cells; P =0.02) and negatively correlated with age ( P =0.048, r=-0.79, Spearman). Rats treated with young hMSC (3.7±0.6) showed better behavior recovery in mNSS with prevention of brain atrophy than that with control (6.1±0.5) or old (5.2±0.7) at D21 ( P <0.01). The number of RECA-1 and PDGFR-β double positive vessels in rat with young hMSC (113±48.6/mm 2 ) was higher than that in control (61.5±35.9/mm 2 ) or old (76.9±36.9/mm 2 ) suggesting vessel maturation ( P <0.01). Interestingly, migration of neural stem/progenitor cells expressing Musashi-1 positively correlated with astrocyte process alignment ( P <0.01, r=0.27; Spearman), which was more pronounced in young hMSC ( P <0.05). Conclusions: Aging of hMSC may be the critical factor which affects outcome of cell therapy, and transplantation of young hMSC could provide better functional recovery by vessel maturation and endogenous cell migration potentially due to dominance of trophic factor secretion.

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