Abstract 43: Neuroprotective Effects of Inhibition of α5β1 Integrin Following Experimental Stroke: A Dual Center Pre-Clinical Study

Blood-brain barrier (BBB) dysfunction after ischemic stroke exacerbates brain damage by contributing to edema and inflammation. The β1 integrin receptor family may contribute to this dysfunction via alteration of BBB-forming tight junction proteins. We hypothesize that inhibition of the β1 integrin receptor subtype α5β1, which is acutely expressed in infarct and peri-infarct vasculature after experimental stroke, reduces BBB permeability, reduces infarct volume, and improves functional recovery. A randomized and blinded trial was conducted using transient middle cerebral artery occlusion (MCAO) in mice (60 min; n=8) and rats (90 min; n=15) in two independent laboratories. ATN-161 (α5β1 inhibitor; 1 mg/kg) was administered IV immediately upon reperfusion and on post-stroke day 1 and 2. Infarct volume was determined by cresyl violet (mice) and T 2 weighted MRI (rat) at day 3 post MCAO. Steady state contrast enhanced MRI was used to assess BBB breakdown in rats at day 3. ATN-161 resulted in a significant reduction in infarct volume in both mice and rats when measured at post-stroke day 3 (p<0.001). BBB permeability was decreased upon ATN-161 treatment in vivo as determined by reduced IgG and claudin-5 immunostaining in mice and reduced extent of Gadolinium enhanced MRI signal change in rats. Behavioral tests (open field, rotorod, sticky label and 28 point neuroscore), demonstrated significantly improved functional recovery in both mice and rats following treatment with ATN-161. Finally, in vitro studies where stroke was simulated using oxygen and glucose deprivation or TNF-α, ATN-161 (10 μM) treatment demonstrated decreased barrier permeability as measured by trans-endothelial cell electrical resistance, FITC-dextran permeability, and claudin-5 immunocytochemistry. Collectively, our results demonstrate that post-stroke inhibition of α5β1 integrin with the small peptide ATN-161 profoundly reduces infarct volume, improves functional outcome and decreases BBB permeability in both mice and rats using two different ischemic stroke models. Therefore, inhibition of α5β1 by ATN-161 could represent a novel stroke therapeutic target worthy of further investigation.

Download Full-text

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

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.596039 ◽

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.

Download Full-text

Abstract WP118: The Flavanol (-)-Epicatechin Improves Functional Recovery In Mice Subjected To Experimental Stroke

Stroke ◽

10.1161/str.44.suppl_1.awp118 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Christopher C Leonardo ◽

Sean Robbins ◽

Abdullah A Ahmad ◽

Sylvain Dore

Keyword(s):

Functional Recovery ◽

Transcriptional Activation ◽

Infarct Volume ◽

Epidemiological Studies ◽

Artery Occlusion ◽

Experimental Stroke ◽

Adhesive Tape ◽

Dietary Consumption ◽

Therapeutic Doses ◽

Cerebral Artery Occlusion

Background: Epidemiological studies indicate that flavanol consumption reduces the propensity to develop cerebrovascular disease. Available data suggest actions on multiple pro-inflammatory pathways, yet it remains unclear which pathways mediate functional recovery after stroke. Our goal is to begin identifying the mechanisms by which the flavanol (-)-epicatechin (EC) improves anatomical and functional outcomes. Based upon data from initial dose-response experiments, ongoing studies are investigating hypothesized protective pathways involving matrix metalloproteinase-mediated blood brain barrier protection and Nrf2 transcriptional activation. Methods: Male, 8-10wk old C57BL/6 mice were pretreated with EC 90m prior to permanent distal middle cerebral artery occlusion. Vehicle or EC was administered by oral gavage to mimic dietary consumption. Mice were evaluated 1, 4 and 7d post-stroke for performance on various sensorimotor tasks prior to histological assessments. Results: Initial experiments demonstrated that mice treated with 15mg/kg EC showed reduced latency to remove adhesive tape at 1d compared to vehicle controls (n=12, p<0.01). Similarly, immunoreactivity for the microglia/macrophage marker Iba1 was increased in the ipsilateral hemispheres of mice 7d after treatment with vehicle (p<0.01), whereas pretreatment with 15mg/kg blocked this effect (n=4). Mice treated with 15mg/kg also showed a trend toward reduced infarct volume relative to vehicle controls (n=5-9 per group). In subsequent reduced dosing studies, vehicle-treated mice again showed deficiencies in removing adhesive tape at 1d (n=8, p<0.01). Remarkably, mice treated with 15, 10 or 5mg/kg EC showed no deficits. Similarly, vehicle control mice showed grip strength impairments up to 7d (n=8, p<0.05) that were absent in all groups of EC-treated mice. Conclusions: Preventative administration of EC promotes functional recovery in mice subjected to experimental stroke. Investigations are underway to determine the pathways mediated by EC following administration at these therapeutic doses. Together, these data will provide insights into the potential for (-)-epicatechin as a clinical therapeutic.

Download Full-text

Abstract 1944: Atorvastatin Reduces Intracerebral Hemorrhage after Experimental Stroke

Circulation ◽

10.1161/circ.116.suppl_16.ii_418-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Hazem F Elewa ◽

Anna Kozak ◽

David Rychly ◽

Adviye Ergul ◽

Reginald Frye ◽

...

Keyword(s):

Ischemic Stroke ◽

Intracerebral Hemorrhage ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Methyl Cellulose ◽

The United States ◽

Experimental Stroke ◽

High Risk Population ◽

Protective Agent ◽

Oral Gavage

Ischemic stroke is a leading cause of death and disability in the United States and diabetes mellitus is the fastest growing risk factor for stroke. In addition, hyperglycemia, which is usually associated with diabetes, tends to worsen ischemia/reperfusion injury and to induce more oxidative stress damage. Preliminary data from our laboratory showed that diabetic animals (Goto-Kakizaki rats (GKs) are more susceptible to vascular damage leading to intracerebral hemorrhage. Many studies have indicated that statins possess neuroprotective properties even when administered after the onset of ischemia. However, the acute vascular effects of statins after ischemic stroke have not been studied to date. Objective: to evaluate the efficacy and magnitude of vascular protection of acute statin therapy in both GKs and their normoglycemic controls after experimental ischemic stroke. Methods: Male Wistar (W) and GK rats (270–305 g) underwent 3 hours of middle cerebral artery occlusion (MCAO) followed by reperfusion for 21 hours. Animals were randomized to receive either atorvastatin (15mg/Kg) or methyl cellulose (0.5%), administered by oral gavage, the first dose 5 minutes after reperfusion and the second dose after 12 hours. Brain tissue was analyzed for infarct volume and hemoglobin content. In another set of Wistar rats (n=3), atorvastatin (15mg/Kg) was administered by oral gavage to compare its pharmacokinetic profile with that of humans Results: Atorvastatin-treated groups had significantly lower hemoglobin (p=0.0156) and infarct volume (p=0.0132) compared to their controls. Atorvastatin peak concentration (27–77 ng/ml) in rats’ plasma was found to be similar to that seen after 80mg/day of atorvastatin in humans. Conclusion: Atorvastatin can be a novel vascular protective agent after acute ischemic stroke especially in a high risk population like diabetics. The mechanisms through which these effects are mediated are currently being investigated.

Download Full-text

Abstract TP111: Activation of the Brain Renin-Angiotensin System by Translational Approaches Following Stroke Onset Is Neuroprotective in a Rat Model of Ischemic Stroke

Stroke ◽

10.1161/str.44.suppl_1.atp111 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Douglas M Bennion ◽

Lauren Donnangelo ◽

David Pioquinto ◽

Robert Regenhardt ◽

Mohan K Raizada ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Volume ◽

Renin Angiotensin System ◽

Cerebral Infarct ◽

Intraventricular Administration ◽

Angiotensin System ◽

Renin Angiotensin ◽

Post Stroke ◽

Neurologic Deficits ◽

The Brain

Background: Toward discovering novel stroke therapies, recent research has shown that activation of the newly-discovered angiotensin converting enzyme 2/angiotensin-(1-7)/mas (ACE2/Ang-(1-7)/Mas) pathway, a counter-regulatory axis of the brain renin-angiotensin system, is neuroprotective in ischemic stroke in rats. Specifically, intraventricular administration of the novel ACE2 activator diminazine aceturate (DIZE) before and during an ischemic stroke decreases cerebral infarct and neurologic deficits. Efficacy must now be demonstrated using minimally-invasive methods if this therapy is to be translated to the care of human patients. In this study, we assessed the hypothesis that systemic administration of DIZE post ischemic stroke would be neuroprotective. Methods: Adult male Sprague-Dawley rats underwent ischemic stroke by endothelin-1 induced middle cerebral artery occlusion and were randomly divided into 2 groups (n=9-10/set): 1) intraperitoneal (IP) administrations of DIZE (7.5 mg/kg) at 4, 24, and 48 h after stroke; 2) IP administrations of 0.9% saline vehicle at the same time points. At 24 and 72 h after stroke, rats underwent blinded neurologic assessments. Immediately following the 72 h tests, animals were sacrificed, cerebral infarct volumes assessed by TTC staining, and IL-1β expression in the stroke region analyzed by rt-PCR. Data are expressed as mean ± SEM with significance inferred at p<0.05. Results: Mean infarct volume was significantly decreased by IP injections of DIZE (9.4% ± 4.35) as compared to control (22.8%±3.6, p=0.039). At 24 h post stroke, neurologic deficits (Garcia Scale) were significantly improved in the DIZE treated group (16.7±0.40) versus the saline group (15.22±0.57, p=0.037). Although DIZE tended to improve neurologic deficits 72 h post stroke, this trend was not significant. Finally, DIZE treatment significantly reduced mRNA expression of IL-1β (0.43 ± 0.14) in the cerebral cortical stroke region as compared to saline treatment (1.47±0.08, p=0.001). Conclusions: Our findings suggest that targeting the ACE2/Ang-(1-7)/Mas axis post stroke can improve function, decrease inflammation, and reduce infarct volume - a significant translational step in brain renin-angiotensin system research.

Download Full-text

The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke

Cellular Physiology and Biochemistry ◽

10.1159/000491661 ◽

2018 ◽

Vol 48 (1) ◽

pp. 42-53 ◽

Cited By ~ 6

Author(s):

Qingqing Wang ◽

Chengmei Lv ◽

Yongxin Sun ◽

Xu Han ◽

Shan Wang ◽

...

Keyword(s):

Ischemic Stroke ◽

Lipoic Acid ◽

Nuclear Translocation ◽

Infarct Volume ◽

Neurological Deficits ◽

Experimental Stroke ◽

Enzyme Linked Immunosorbent Assay ◽

M2 Phenotype

Background/Aims: Ischemic stroke results in increased cerebral infarction, neurological deficits and neuroinflammation. The underlying mechanisms involving the anti-inflammatory and neuroprotective properties of α-Lipoic acid (α-LA) remain poorly understood. Herein, we investigated the potential role of α-LA in a middle cerebral artery occlusion (MCAO) rat model and an in vitro lipopolysaccharide (LPS)-induced microglia inflammation model. Methods: In the in vivo study, infarct volume was examined by TTC staining and Garcia score was used to evaluate neurologic recovery. The cytokines were evaluated by enzyme-linked immunosorbent assay, and protein expression of microglia phenotype and NF-κB were measured using western blot. In the in vitro study, the expressions of microglia M1/M2 phenotype were evaluated using qRT-PCR, and immunofluorescence staining was used to assess the nuclear translocation of NF-κB. Results: Both 20 mg/kg and 40 mg/kg of α-LA alleviated infarct size, brain edema, and neurological deficits. Furthermore, α-LA induced the polarization of microglia to the M2 phenotype, modulated the expression of IL-1β, IL-6, TNF-α and IL-10, and attenuated the activation of NF-κB after MCAO. α-LA inhibited the expression of M1 markers, increased activation of the M2 markers, and suppressed the nuclear translocation of NF-κB in LPS-stimulated BV2 microglia. Conclusions: α-LA improved neurological outcome in experimental stroke via modulating microglia M1/M2 polarization. The potential mechanism of α-LA might be mediated by inhibition of NF-κB activation via regulating phosphorylation and nuclear translocation of p65.

Download Full-text

MiR-29a Knockout Aggravates Neurological Damage by Pre-polarizing M1 Microglia in Experimental Rat Models of Acute Stroke

Frontiers in Genetics ◽

10.3389/fgene.2021.642079 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fangfang Zhao ◽

Haiping Zhao ◽

Junfen Fan ◽

Rongliang Wang ◽

Ziping Han ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Stroke ◽

Molecular Mechanisms ◽

Infarct Volume ◽

Glutamate Release ◽

Artery Occlusion ◽

Experimental Stroke ◽

Neurological Damage ◽

Stroke Patients ◽

Rat Models

ObjectiveBy exploring the effects of miR-29a-5p knockout on neurological damage after acute ischemic stroke, we aim to deepen understanding of the molecular mechanisms of post-ischemic injury and thus provide new ideas for the treatment of ischemic brain injury.MethodsmiR-29a-5p knockout rats and wild-type SD rats were subjected to transient middle cerebral artery occlusion (MCAO). miR-29a levels in plasma, cortex, and basal ganglia of ischemic rats, and in plasma and neutrophils of ischemic stroke patients, as well as hypoxic glial cells were detected by real-time PCR. The infarct volume was detected by TTC staining and the activation of astrocytes and microglia was detected by western blotting.ResultsThe expression of miR-29a-5p was decreased in parallel in blood and brain tissue of rat MCAO models. Besides, miR-29a-5p levels were reduced in the peripheral blood of acute stroke patients. Knockout of miR-29a enhanced infarct volume of the MCAO rat model, and miR-29a knockout showed M1 polarization of microglia in the MCAO rat brain. miR-29a knockout in rats after MCAO promoted astrocyte proliferation and increased glutamate release.ConclusionKnockout of miR-29a in rats promoted M1 microglial polarization and increased glutamate release, thereby aggravating neurological damage in experimental stroke rat models.

Download Full-text

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

The Medical and Ecological Problems ◽

10.31718/mep.2021.25.3-4.02 ◽

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.

Download Full-text

Early and Sustained Increases in Leukotriene B4 Levels Are Associated with Poor Clinical Outcome in Ischemic Stroke Patients

Neurotherapeutics ◽

10.1007/s13311-019-00787-4 ◽

2019 ◽

Vol 17 (1) ◽

pp. 282-293 ◽

Cited By ~ 2

Author(s):

Su Jing Chan ◽

Mary P. E. Ng ◽

Hui Zhao ◽

Geelyn J. L. Ng ◽

Chuan De Foo ◽

...

Keyword(s):

Ischemic Stroke ◽

Middle Cerebral Artery ◽

Cerebral Artery ◽

Infarct Volume ◽

Prognostic Significance ◽

Leukotriene B4 ◽

Stroke Patients ◽

Middle Cerebral Artery Infarction ◽

Post Stroke ◽

Stroke Models

Abstract Leukotriene B4 (LTB4) has been implicated in ischemic stroke pathology. We examined the prognostic significance of LTB4 levels in patients with acute middle cerebral artery (MCA) infarction and their mechanisms in rat stroke models. In ischemic stroke patients with middle cerebral artery infarction, plasma LTB4 levels were found to increase rapidly, roughly doubling within 24 h when compared to initial post-stroke levels. Further analyses indicate that poor functional recovery is associated with early and more sustained increase in LTB4 rather than the peak levels. Results from studies using a rat embolic stroke model showed increased 5-lipoxygenase (5-LOX) expression in the ipsilateral infarcted cortex compared with sham control or respective contralateral regions at 24 h post-stroke with a concomitant increase in LTB4 levels. In addition, neutrophil influx was also observed in the infarcted cortex. Double immunostaining indicated that neutrophils express 5-LOX and leukotriene A4 hydrolase (LTA4H), highlighting the pivotal contributions of neutrophils as a source of LTB4. Importantly, rise in plasma LTB4 levels corresponded with an increase in LTB4 amount in the infarcted cortex, thereby supporting the use of plasma as a surrogate for brain LTB4 levels. Pre-stroke LTB4 loading increased brain infarct volume in tMCAO rats. Conversely, administration of the 5-LOX-activating protein (FLAP) inhibitor BAY-X1005 or B-leukotriene receptor (BLTR) antagonist LY255283 decreased the infarct volume by a similar extent. To conclude, targeted interruption of the LTB4 pathway might be a viable treatment strategy for acute ischemic stroke.

Download Full-text

Abstract TP282: Eotaxin Shows a Sex-specific Association With Positive Ischemic Stroke Outcomes and Post-stroke Peripheral Leukocyte Activation

Stroke ◽

10.1161/str.47.suppl_1.tp282 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Meaghan Roy-O'Reilly ◽

Sarah Conway ◽

Ilene Staff ◽

Gilbert Fortunado ◽

Madeline Levy ◽

...

Keyword(s):

Ischemic Stroke ◽

T Cell Activation ◽

Whole Blood ◽

Experimental Stroke ◽

Stroke Severity ◽

Stroke Outcomes ◽

Post Stroke ◽

Age Related ◽

Specific Association ◽

Peripheral Leukocytes

Background and Purpose: Eotaxin, a TH2 chemokine, has been shown to increase in mouse brain and plasma following experimental stroke. While eotaxin has been associated with age-related deficits in neurogenesis, little is known about its role in ischemic injury. Hypothesis: We tested the hypothesis that serum eotaxin levels are associated with long-term stroke outcome, with follow up mechanistic studies in a mouse model of ischemic stroke. Methods: Serum was taken from patients (n=158) 24 hours after ischemic stroke onset. Levels of serum eotaxin were quantified by ELISA, then analyzed for outcome association. For murine studies, animals (n=14) underwent 90-minute middle cerebral artery occlusion and were sacrificed at 24 hours, with sham surgery mice serving as controls. Blood was incubated with or without eotaxin (100 ng/ml) and stained for leukocyte markers and CD62L (L-selectin). Results: Although eotaxin protein levels were not significantly different between sexes, a multivariate analysis controlling for age, stroke severity and cardiovascular risk factors revealed a male-specific association between higher eotaxin levels at 24 hours post-stroke and a positive functional outcome at three months (p=.010). Analysis of peripheral leukocytes isolated from both sham and stroke mice revealed that addition of eotaxin to whole blood significantly increased the activation of myeloid cells in both in male (p=.0031) and female (p=.0048) animals, as measured by shedding of L-selectin. Further experiments demonstrated that shedding of L-selectin on CD8+ T-cells after treatment of whole blood with eotaxin was significant only in female animals (p=.0008). Conclusion: In conclusion, the results of this study suggest that eotaxin has a sex-specific association with improved stroke outcomes. Murine studies demonstrate that eotaxin causes activation of peripheral leukocytes (as measured by loss of L-selectin), with a sexually dimorphic effect on CD8+ T-cell activation that may alter the character of the post-stroke immune response and support a pro-recovery inflammatory phenotype in males. This research underscores the importance of studying both sexes in future ischemic inflammatory research.

Download Full-text

Intracerebral Delivery of Brain-Derived Neurotrophic Factor Using HyStem®-C Hydrogel Implants Improves Functional Recovery and Reduces Neuroinflammation in a Rat Model of Ischemic Stroke

International Journal of Molecular Sciences ◽

10.3390/ijms19123782 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3782 ◽

Cited By ~ 10

Author(s):

Kristine Ravina ◽

Denise Briggs ◽

Sezen Kislal ◽

Zuha Warraich ◽

Tiffany Nguyen ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Recovery ◽

Neurotrophic Factor ◽

Infarct Volume ◽

Brain Derived Neurotrophic Factor ◽

Artery Occlusion ◽

Sensorimotor Function ◽

Neural Repair ◽

Adhesive Removal ◽

Cerebral Artery Occlusion

Ischemic stroke is a leading cause of death and disability worldwide. Potential therapeutics aimed at neural repair and functional recovery are limited in their blood-brain barrier permeability and may exert systemic or off-target effects. We examined the effects of brain-derived neurotrophic factor (BDNF), delivered via an extended release HyStem®-C hydrogel implant or vehicle, on sensorimotor function, infarct volume, and neuroinflammation, following permanent distal middle cerebral artery occlusion (dMCAo) in rats. Eight days following dMCAo or sham surgery, treatments were implanted directly into the infarction site. Rats received either vehicle, BDNF-only (0.167 µg/µL), hydrogel-only, hydrogel impregnated with 0.057 µg/µL of BDNF (hydrogel + BDNFLOW), or hydrogel impregnated with 0.167 µg/µL of BDNF (hydrogel + BDNFHIGH). The adhesive removal test (ART) and 28-point Neuroscore (28-PN) were used to evaluate sensorimotor function up to two months post-ischemia. The hydrogel + BDNFHIGH group showed significant improvements on the ART six to eight weeks following treatment and their behavioral performance was consistently greater on the 28-PN. Infarct volume was reduced in rats treated with hydrogel + BDNFHIGH as were levels of microglial, phagocyte, and astrocyte marker immunoexpression in the corpus striatum. These data suggest that targeted intracerebral delivery of BDNF using hydrogels may mitigate ischemic brain injury and restore functional deficits by reducing neuroinflammation.

Download Full-text