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.

scholarly journals Ambroxol Upregulates Glucocerebrosidase Expression to Promote Neural Stem Cells Differentiation Into Neurons Through Wnt/β-Catenin Pathway After Ischemic Stroke

2021 ◽  
Vol 13 ◽  
Author(s):  
Hongfei Ge ◽  
Chao Zhang ◽  
Yang Yang ◽  
Weixiang Chen ◽  
Jun Zhong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Infarct Volume ◽  
Basic Knowledge ◽  
Brain Disorders ◽  
Potential Mechanism ◽  
Stroke Patients ◽  
Stroke Treatment ◽  
Post Stroke

Ischemic stroke has been becoming one of the leading causes resulting in mortality and adult long-term disability worldwide. Post-stroke pneumonia is a common complication in patients with ischemic stroke and always associated with 1-year mortality. Though ambroxol therapy often serves as a supplementary treatment for post-stroke pneumonia in ischemic stroke patients, its effect on functional recovery and potential mechanism after ischemic stroke remain elusive. In the present study, the results indicated that administration of 70 mg/kg and 100 mg/kg enhanced functional recovery by virtue of decreasing infarct volume. The potential mechanism, to some extent, was due to promoting NSCs differentiation into neurons and interfering NSCs differentiation into astrocytes through increasing GCase expression to activate Wnt/β-catenin signaling pathway in penumbra after ischemic stroke, which advanced basic knowledge of ambroxol in regulating NSCs differentiation and provided a feasible therapy for ischemic stroke treatment, even in other brain disorders in clinic.

Abstract T P228: Ischemic Stroke Results in Increased Activity of the Neuroprotective Angiotensin Converting Enzyme 2 in Rat Brain and Serum

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Douglas M Bennion ◽  
Emily Haltigan ◽  
Alexander J Irwin ◽  
Daniel L Purich ◽  
Colin Sumners
Keyword(s):  
Cerebral Cortex ◽  
Ischemic Stroke ◽  
Angiotensin Converting Enzyme ◽  
Rat Cerebral Cortex ◽  
Mrna Levels ◽  
Converting Enzyme ◽  
Stroke Treatment ◽  
Angiotensin Converting Enzyme 2 ◽  
Post Stroke ◽  
Rebound Increase

Background: Recent studies show that pharmacological induction of the angiotensin converting enzyme 2/angiotensin-(1-7)/mas [ACE2-Ang-(1-7)-Mas] axis, a protective pathway of the renin angiotensin system, elicits neuroprotection in ischemic stroke. However, endogenous levels and activity of the components of this axis in the brain and serum following stroke are not well established. Here, we assessed the post-stroke activity and expression of ACE2 in rat cerebral cortex and serum after ischemic stroke in rats, in the absence or presence of an ACE2 activator. Methods: Sprague Dawley rats underwent sham surgery or endothelin-1-induced middle cerebral artery occlusion (ET-1 MCAO). Activity of ACE2 was analyzed within serum and cerebral cortical tissue samples using a fluorometric assay, and mRNA levels were assessed by qRT-PCR. In an additional experiment, rats received daily intraperitoneal administration of diminazene aceturate (DIZE), a putative ACE2 activator, or vehicle after ET-1 MCAO. Data are normalized to corresponding control values and expressed as means ± SEM with a significance of p<0.05. Results: ACE2 activity levels were significantly increased in ischemic brain cortex at 4, 12, and 24 h after a stroke (4h: 237.1±46.1%; 12h: 212.4±12.8%; 24h: 191.6±19.1%) versus rats with sham strokes. Paradoxically, there was a significant decrease in ACE2 mRNA levels in the ischemic cortex at 24h (0.71±0.1) compared to shams (1.0±0.08). After decreasing in activity at 4h after stroke, serum ACE2 activity was increased at 24h in stroked rats (96.08±9.4%) versus shams (70.80±7.1%). Post-stroke treatment with DIZE (7.5 mg/kg) resulted in significantly increased ACE2 activity in serum (213.7±49.8%) versus controls, two days following stroke. Conclusions: Activity of the protective enzyme ACE2 is increased in rat cerebral cortex following stroke, with a rebound increase in serum activity. Post-stroke treatment with an ACE2 activator resulted in significantly increased ACE2 activity in serum. These results suggest that stroke therapeutics designed to target the ACE2/Ang-(1-7)/Mas axis may act in synergy with endogenous changes in the acute post-stroke setting, lending promise to their further study as potential neuroprotective agents.

scholarly journals ЗАСТОСУВАННЯ Α-ГЛІЦЕРИЛФОСФОРИЛХОЛІНУ В СХЕМІ КОМПЛЕКСНОГО ЛІКУВАННЯ ДЛЯ ФУНКЦІОНАЛЬНОГО ВІДНОВЛЕННЯ ПІСЛЯ МОЗКОВОГО ПІВКУЛЬОВОГО ІШЕМІЧНОГО ІНСУЛЬТУ

2021 ◽  
Vol 25 (3-4) ◽  
pp. 8-13
Author(s):  
О.О. Пушко ◽  
Н.В. Литвиненко
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Vascular Diseases ◽  
Comprehensive Treatment ◽  
Post Stroke ◽  
Rehabilitation Programs ◽  
Comprehensive Therapy ◽  
Progressive Growth ◽  
Active Rehabilitation ◽  
Combination Of Methods

The article considers the influence of α-glycerylphosphorylcholine in the scheme of comprehensive therapy on the dynamics of functional recovery in patients with cerebral hemispheric ischemic stroke. Against the background of the progressive growth of acute cerebral infarction, the problem of timely care is relevant. Timely treatment of stroke, based on evidence-based medicine, along with early activation and rehabilitation of patients is designed to reduce mortality and subsequent disability of patients. Given that cholinergic insufficiency and structural and functional damage of neurons play an important role in the pathogenesis of post-stroke disorders, the use of medicines for their correction, in particular α-glycerylphosphorylcholine, is justified. Choline alfoscerate, a precursor of acetylcholine and phosphatidylcholine, is broken down by enzymes into choline and glycerophosphate when ingested, and the choline thus obtained is able to improve neuronal functionality in patients with neurodegenerative and vascular diseases. The study revealed a significantly better recovery of impaired motor and cognitive functions after cerebral hemispheric stroke under the influence of comprehensive therapeutic and rehabilitation measures using active rehabilitation methods in conjunction with α-glycerylphosphorylcholine. The results obtained during the study allow us to report the advantage of a combination of methods of active rehabilitation and the use of the pharmacological agent α-glycerylphosphorylcholine. The feasibility and efficacy of α-glycerylphosphorylcholine are related to its ability to reduce motor and cognitive deficits after ischemic stroke. The scheme of comprehensive treatment of patients in acute and restorative periods of cerebral hemispheric ischemic stroke with the use of α-glycerylphosphorylcholine helps to increase the effectiveness of functional recovery after an acute cerebral accident, and can be used in the use of therapeutic and rehabilitation programs for patients after cerebral hemispheric ischemic stroke to reduce the post-stroke deficit.

scholarly journals Lipids and Lipid Mediators Associated with the Risk and Pathology of Ischemic Stroke

2020 ◽  
Vol 21 (10) ◽  
pp. 3618 ◽  
Author(s):  
Anna Kloska ◽  
Marcelina Malinowska ◽  
Magdalena Gabig-Cimińska ◽  
Joanna Jakóbkiewicz-Banecka
Keyword(s):  
Fatty Acids ◽  
Ischemic Stroke ◽  
Brain Tissue ◽  
Lipid Mediators ◽  
Normal Brain ◽  
Stroke Treatment ◽  
Post Stroke ◽  
Increased Risk ◽  
Risk Biomarkers ◽  
And Function

Stroke is a severe neurological disorder in humans that results from an interruption of the blood supply to the brain. Worldwide, stoke affects over 100 million people each year and is the second largest contributor to disability. Dyslipidemia is a modifiable risk factor for stroke that is associated with an increased risk of the disease. Traditional and non-traditional lipid measures are proposed as biomarkers for the better detection of subclinical disease. In the central nervous system, lipids and lipid mediators are essential to sustain the normal brain tissue structure and function. Pathways leading to post-stroke brain deterioration include the metabolism of polyunsaturated fatty acids. A variety of lipid mediators are generated from fatty acids and these molecules may have either neuroprotective or neurodegenerative effects on the post-stroke brain tissue; therefore, they largely contribute to the outcome and recovery from stroke. In this review, we provide an overview of serum lipids associated with the risk of ischemic stroke. We also discuss the role of lipid mediators, with particular emphasis on eicosanoids, in the pathology of ischemic stroke. Finally, we summarize the latest research on potential targets in lipid metabolic pathways for ischemic stroke treatment and on the development of new stroke risk biomarkers for use in clinical practice.

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 W P86: Photo-stimulation of the Striatum Promotes Functional Recovery and Neurogenesis after Focal Ischemic Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mingke Song ◽  
Osama Mohamad ◽  
Xiaohuan Gu ◽  
Shipeng Wei ◽  
Ling Wei ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Functional Recovery ◽  
Focal Cerebral Ischemia ◽  
Blue Laser ◽  
Control Group ◽  
Stroke Treatment ◽  
Adhesive Removal ◽  
The Brain ◽  
Stimulation Of

Introduction and Purpose: The striatum region of the brain supports self-repair process after experimental cerebral ischemia. Optogenetics is a temporally and spatially precise method to manipulate targeted neuronal populations. We tested whether optogenetic technique can be translated into stroke treatment by photo-stimulation of the striatum after focal cerebral ischemia. Methods: Adult male channelrhodopsin-2 (ChR2) transgenic mice were utilized, taking the advantage of that the cation channel ChR2 is abundantly expressed in the striatum. Before stroke, mice were trained 5 times per day for 3 days with a modified adhesive removal test. Mice were then subjected to the ischemic insult targeting the right sensorimotor (barrel) cortex. Four days after stroke, optical fibers were implanted into the striatum and fixed with a cannula on the skull. In control group, stoke mice received optical fiber implantation but without photo-stimulation. In treatment group, daily photo-stimulation pulses (473 nm blue laser) were started at 5 days after stroke and sustained for 8 days. The adhesive removal test on forepaws was performed 3, 10, 17, 24, and 31 days after stroke. Results: The impaired forepaw sensorimotor function in these two groups progressively recovered over the timeline. Stroke mice treated with photo-stimulation showed significantly better recovery assessed 31 days after stroke compared to stroke control. Our study also shows that the activity of neurogenesis in the brain was augmented by photo-stimulation, which may be responsible for enhanced functional recovery. Conclusions: Optogenetic stimulation of the striatum promotes functional recovery and neurogenesis after focal ischemic stroke.

Abstract TMP41: High-sensitivity C-Reactive Protein and Depression in Patients With Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Irene Katzan ◽  
Nicolas Thompson ◽  
Ahmed Itrat
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Responses ◽  
Fold Increase ◽  
Time Interval ◽  
Hscrp Level ◽  
Treatment Interventions ◽  
Post Stroke ◽  
Post Stroke Depression ◽  
New Treatment ◽  
Statin Use

Background: Depression is common in patients after stroke and is associated with worse outcomes Recognition of the causal factors contributing to post-stroke depression may lead to new treatment interventions. Ischemic stroke produces inflammatory responses and there is data to suggest that inflammation may promote depression. The objective of this analysis is to determine the association of hsCRP levels with depression in patients with ischemic stroke. Methods: We performed a retrospective cohort study of patients with ischemic stroke seen in a cerebrovascular clinic who completed a PHQ-9 depression screen and had a hsCRP level drawn between 28 days before or within 7 days after the PHQ-9 screen. Multivariate linear regression was performed:- the dependent variable was PHQ-9 score, the independent variable was log-transformed hsCRP. Additional covariates included age, sex, race (White vs. Black/Other), time since stroke (≤ 3 months vs. > 3 months), mRS score (0-2 vs. 3-5) and statin use at time of hsCRP draw (yes vs. no). Results: Between Feb 3, 2009 and March 14, 2014, 803 patients were seen in the cerebrovascular clinic with a diagnosis of ischemic stroke who had hscrp level. Of these, 220 patients had a hSCRP drawn within the prespecified time interval from PHQ9 screen. Mean age was 60.7 years, 43.2% were female and 78.6% were White. There was a significant independent association between hsCRP value and PHQ-9 score; For each 5-fold increase in hsCRP, the average PHQ-9 score increased by 1.22 points (95% CI 0.38 - 2.06, P = 0.005). Other variables independently associated with PHQ-9 score were: mRS > 2 (OR = 3.39, 95% CI 1.40 - 5.38), female (OR=-1.72 95% CI -3.11 - -0.32), and statin use (OR=-1.91, 95% CI -3.34 - -0.47). Conclusions: hsCRP level was independently associated with depressive symptoms. Understanding the association between inflammatory markers and depression following ischemic stroke may lead to the development of improved methods to predict post-stroke depression and new treatment interventions

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.

Abstract TMP121: Gender Differences in Functional Outcomes After Acute Ischemic Stroke: The Role of White Matter Structural Integrity

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Mark Etherton ◽  
Ona Wu ◽  
Pedro Cougo ◽  
Anne-Katrin Giese ◽  
Lisa Cloonan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Ischemic Stroke ◽  
Functional Recovery ◽  
Stroke Subtype ◽  
Post Stroke ◽  
Significant Difference ◽  
Acute Infarct ◽  
Underlying Mechanisms ◽  
Microstructural Integrity

Background: Women are known to have worse post-stroke outcomes; however, the underlying mechanisms remain unclear. We evaluated sex-specific clinical and neuroimaging characteristics linked to cerebrovascular brain health in association with functional recovery after acute ischemic stroke (AIS). Methods: We reviewed 316 AIS patients with acute MRI (<48 hours from symptom onset) and modified Rankin scale score (mRS) assessed at 3-6 months post-stroke. Acute infarct volume on diffusion-weighted imaging (DWIv) and white matter hyperintensity volume (WMHv) on FLAIR sequences were determined using a validated semi-automated method. Mean diffusivity (MD) and fractional anisotropy (FA) of normal appearing white matter (NAWM) were derived from the contralesional hemisphere. Wilcoxon rank sum, Spearman correlation, and Fisher’s exact tests were used at p-value <0.05, as appropriate. Results: Women comprised 41.1% of this AIS cohort, and as compared to men, they were older (68 vs. 62.8 years, p = 0.002), had higher prevalence of atrial fibrillation (21.5% vs. 12.4%, p = 0.04), and less tobacco use (21.1% vs. 36.3%, p = 0.03). There was no statistically significant difference between men and women in admission stroke severity, TOAST stroke subtype distribution, DWIv or WMHv. However, women were significantly less likely to have a favorable outcome (mRS <2), as compared to men (53.7% vs. 68.5%, p = 0.01). Both FA (ρ -0.18, p=0.04) and MD (ρ 0.28, p=0.002) values in NAWM correlated with follow-up mRS in women, but only MD (ρ 0.26, p=0.0004) in men. Conclusion: Despite no differences in admission NIHSS, acute infarct size, WMH burden or stroke subtype, women with AIS had significantly worse post-stroke outcomes in our cohort. Our findings suggest that microstructural integrity, as assessed by NAWM diffusivity anisotropy measurements, may represent a neuroimaging correlate of worse outcomes in women. The correlation between markers of white matter microstructural integrity and long-term mRS provides insight into the underlying mechanisms of disease that may influence functional recovery after stroke.

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