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

Stroke ◽  
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.

scholarly journals 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

2018 ◽  
Vol 19 (12) ◽  
pp. 3782 ◽  
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.

Abstract 12: S-Nitrosylation Invokes Functional Recovery from Experimental Stroke through the Hypoxia-inducible Factor-1 alpha/Vascular Endothelial Growth Factor Pathway

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mushfiquddin Khan ◽  
Tajinder S Dhammu ◽  
Fumiyo Matsuda ◽  
Inderjit Singh ◽  
Avtar K Singh
Keyword(s):  
Functional Recovery ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Artery Occlusion ◽  
Tube Formation ◽  
Male Rats ◽  
Experimental Stroke ◽  
Capillary Endothelial Cells ◽  
Stimulation Of

Background: In stroke patients, the stimulation of neurorepair mechanisms is necessary to reduce morbidity and disability. Our studies on brain and spinal cord trauma show that an exogenous treatment with the S-nitrosylating agent S-nitrosoglutathione (GSNO) stimulates neurorepair and aids functional recovery. Using a rat model of cerebral ischemia reperfusion (IR), we tested the hypothesis that GSNO invokes the neurorepair process and improves neurobehavioral functions through the angiogenic HIF-1α/VEGF pathway. Methods: Stroke was induced by middle cerebral artery occlusion for 60 min followed by reperfusion in adult male rats. The injured animals were treated with vehicle (IR group, n=7), GSNO (0.25 mg/kg, GSNO group, n=7), and GSNO plus the HIF-1α inhibitor 2-mthoxyestradiol (0.25 mg/kg GSNO+5.0 mg/kg ME, GSNO+ME group, n=7). The groups were studied for 14 days to determine neurorepair mechanisms and functional recovery. Brain capillary endothelial cells were used to show that GSNO promotes angiogenesis and that GSNO-mediated induction of VEGF and the stimulation of angiogenesis are dependent on HIF-1α activity. Results: GSNO treatment of IR enhanced the expression of HIF-1α, VEGF, and PECAM-1. This GSNO treatment also led to increased expression of neurorepair mediators including BDNF. Increased expression of VEGF/BDNF and the degree of tube formation (angiogenesis) by GSNO were reduced in an endothelial cell culture model after the inhibition of HIF-1α by ME. ME treatment of the GSNO group also blocked not only GSNO’s effect of reduced infarct volume (p<0.05) and enhanced expression of PECAM-1but also its improvement of motor and neurological functions (p<0.001). Conclusions: GSNO shows therapeutic promise for stroke by stimulating the process of neurorepair and aiding functional recovery through the HIF-1α/VEGF/PECAM-1 dependent pathway.

scholarly journals Estradiol Attenuates Neuroprotective Benefits of Isoflurane Preconditioning in Ischemic Mouse Brain

2008 ◽  
Vol 28 (11) ◽  
pp. 1824-1834 ◽  
Author(s):  
Lan Wang ◽  
Hideto Kitano ◽  
Patricia D Hurn ◽  
Stephanie J Murphy
Keyword(s):  
Infarct Volume ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Ischemic Damage ◽  
Triphenyltetrazolium Chloride ◽  
Anesthetic Preconditioning ◽  
Infarction Volume ◽  
Male Specific ◽  
Cerebral Artery Occlusion

Isoflurane preconditioning (IsoPC) neuroprotection in experimental stroke is male-specific. We determined whether estradiol alters ischemic outcomes in IsoPC brain and examined the role of estrogen receptors (ERs). Seven to 10 days before preconditioning, ovariectomized (OVX) mice were implanted with estradiol, vehicle, or ER subtype agonists. OVX ± estradiol, OVX ± vehicle, OVX ± ER agonists, and ER subtype wild-type (WT) and knockout (KO) mice were preconditioned for 4 h with sham anesthetic preconditioning (sham PC) or 1% IsoPC and recovered for 24 h. Mice then underwent 2 h of middle cerebral artery occlusion followed by 22 h of reperfusion. Infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride staining, with comparisons between IsoPC and corresponding sham PC for each treatment group. Decreased infarct injury was seen in IsoPC OVX ± vehicle, whereas estradiol in IsoPC OVX mice enhanced ischemic damage. In ER studies, increased infarct volumes were seen in IsoPC ERWT mice regardless of ER subtype. IsoPC in ERαKO mice had no effect on infarction volume but reduced only cortical ischemic damage in ERβKO mice. In OVX + ERβ agonist, IsoPC had no effect on infarction volume. In OVX + ER/α agonist, IsoPC increased cortical infarct volume. Estradiol depresses the brain's protective response to IsoPC and may exacerbate cortical ischemic injury mainly through an ERβ-dependent mechanism.

scholarly journals Effects of Tetramethylpyrazine on Functional Recovery and Neuronal Dendritic Plasticity after Experimental Stroke

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jun-Bin Lin ◽  
Chan-Juan Zheng ◽  
Xuan Zhang ◽  
Juan Chen ◽  
Wei-Jing Liao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Classical Model ◽  
Significant Negative Correlation ◽  
Artery Occlusion ◽  
Neurological Function ◽  
Experimental Stroke ◽  
Spine Density ◽  
Dendritic Plasticity ◽  
Cerebral Artery Occlusion

The 2,3,5,6-tetramethylpyrazine (TMP) has been widely used in the treatment of ischemic stroke by Chinese doctors. Here, we report the effects of TMP on functional recovery and dendritic plasticity after ischemic stroke. A classical model of middle cerebral artery occlusion (MCAO) was established in this study. The rats were assigned into 3 groups: sham group (sham operated rats treated with saline), model group (MCAO rats treated with saline) and TMP group (MCAO rats treated with 20 mg/kg/d TMP). The neurological function test of animals was evaluated using the modified neurological severity score (mNSS) at 3 d, 7 d, and 14 d after MCAO. Animals were euthanized for immunohistochemical labeling to measure MAP-2 levels in the peri-infarct area. Golgi-Cox staining was performed to test effect of TMP on dendritic plasticity at 14 d after MCAO. TMP significantly improved neurological function at 7 d and 14 d after ischemia, increased MAP-2 level at 14 d after ischemia, and enhanced spine density of basilar dendrites. TMP failed to affect the spine density of apical dendrites and the total dendritic length. Data analyses indicate that there was significant negative correlation between mNSS and plasticity measured at 14 d after MCAO. Thus, enhanced dendritic plasticity contributes to TMP-elicited functional recovery after ischemic stroke.

scholarly journals The R18 Polyarginine Peptide Is More Effective Than the TAT-NR2B9c (NA-1) Peptide When Administered 60 Minutes after Permanent Middle Cerebral Artery Occlusion in the Rat

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
D. Milani ◽  
N. W. Knuckey ◽  
R. S. Anderton ◽  
J. L. Cross ◽  
B. P. Meloni
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Statistical Significance ◽  
Dose Range ◽  
Artery Occlusion ◽  
Adhesive Tape ◽  
Significant Extent ◽  
Cerebral Artery Occlusion

We examined the dose responsiveness of polyarginine R18 (100, 300, and 1000 nmol/kg) when administered 60 minutes after permanent middle cerebral artery occlusion (MCAO). The TAT-NR2B9c peptide, which is known to be neuroprotective in rodent and nonhuman primate stroke models, served as a positive control. At 24 hours after MCAO, there was reduced total infarct volume in R18 treated animals at all doses, but this reduction only reached statistical significance at doses of 100 and 1000 nmol/kg. The TAT-NR2B9c peptide reduced infarct volume at doses of 300 and 1000 nmol/kg, but not to a statistically significant extent, while the 100 nmol/kg dose was ineffective. The reduction in infarct volume with R18 and TAT-NR2B9c peptide treatments was mirrored by improvements in one or more functional outcomes (namely, neurological score, adhesive tape removal, and rota-rod), but not to a statistically significant extent. These findings further confirm the neuroprotective properties of polyarginine peptides and for R18 extend its therapeutic time window and dose range, as well as demonstrating its greater efficacy compared to TAT-NR2B9c in a severe stroke model. The superior neuroprotective efficacy of R18 over TAT-NR2B9c highlights the potential of this polyarginine peptide as a lead candidate for studies in human stroke.

scholarly journals Intranasal Administration of PACAP Is an Efficient Delivery Route to Reduce Infarct Volume and Promote Functional Recovery After Transient and Permanent Middle Cerebral Artery Occlusion

2021 ◽  
Vol 11 ◽  
Author(s):  
Asma Cherait ◽  
Julie Maucotel ◽  
Benjamin Lefranc ◽  
Jérôme Leprince ◽  
David Vaudry
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Functional Recovery ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Systemic Exposure ◽  
Artery Occlusion ◽  
Bioactive Molecules ◽  
Cerebral Artery Occlusion

Intranasal (IN) administration appears to be a suitable route for clinical use as it allows direct delivery of bioactive molecules to the central nervous system, reducing systemic exposure and sides effects. Nevertheless, only some molecules can be transported to the brain from the nasal cavity. This led us to compare the efficiency of an IN, intravenous (IV), and intraperitoneal (IP) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) after transient or permanent middle cerebral artery occlusion (MCAO) in C57BL/6 mice. The results show that the neuroprotective effect of PACAP is much more efficient after IN administration than IV injection while IP injection had no effect. IN administration of PACAP reduced the infarct volume when injected within 6 h after the reperfusion and improved functional recovery up to at least 1 week after the ischemia.

scholarly journals Neuroprotective mechanisms of erythropoietin in a rat stroke model

2020 ◽  
Vol 11 (1) ◽  
pp. 48-59
Author(s):  
Martin Juenemann ◽  
Tobias Braun ◽  
Nadine Schleicher ◽  
Mesut Yeniguen ◽  
Patrick Schramm ◽  
...  
Keyword(s):  
Blood Flow ◽  
Infarct Size ◽  
Cerebral Edema ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Lesion Volume ◽  
Ischemic Lesion ◽  
Human Erythropoietin ◽  
Male Wistar Rats ◽  
Cerebral Artery Occlusion

AbstractObjectiveThis study was designed to investigate the indirect neuroprotective properties of recombinant human erythropoietin (rhEPO) pretreatment in a rat model of transient middle cerebral artery occlusion (MCAO).MethodsOne hundred and ten male Wistar rats were randomly assigned to four groups receiving either 5,000 IU/kg rhEPO intravenously or saline 15 minutes prior to MCAO and bilateral craniectomy or sham craniectomy. Bilateral craniectomy aimed at elimination of the space-consuming effect of postischemic edema. Diagnostic workup included neurological examination, assessment of infarct size and cerebral edema by magnetic resonance imaging, wet–dry technique, and quantification of hemispheric and local cerebral blood flow (CBF) by flat-panel volumetric computed tomography.ResultsIn the absence of craniectomy, EPO pretreatment led to a significant reduction in infarct volume (34.83 ± 9.84% vs. 25.28 ± 7.03%; p = 0.022) and midline shift (0.114 ± 0.023 cm vs. 0.083 ± 0.027 cm; p = 0.013). We observed a significant increase in regional CBF in cortical areas of the ischemic infarct (72.29 ± 24.00% vs. 105.53 ± 33.10%; p = 0.043) but not the whole hemispheres. Infarct size-independent parameters could not demonstrate a statistically significant reduction in cerebral edema with EPO treatment.ConclusionsSingle-dose pretreatment with rhEPO 5,000 IU/kg significantly reduces ischemic lesion volume and increases local CBF in penumbral areas of ischemia 24 h after transient MCAO in rats. Data suggest indirect neuroprotection from edema and the resultant pressure-reducing and blood flow-increasing effects mediated by EPO.

MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat

2002 ◽  
Vol 283 (3) ◽  
pp. H1005-H1011 ◽  
Author(s):  
Katsuyoshi Shimizu ◽  
Zsombor Lacza ◽  
Nishadi Rajapakse ◽  
Takashi Horiguchi ◽  
James Snipes ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Ischemia Reperfusion Injury ◽  
Neuronal Damage ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Sham Treatment ◽  
Cerebral Artery Occlusion

We investigated effects of diazoxide, a selective opener of mitochondrial ATP-sensitive K+ (mitoKATP) channels, against brain damage after middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (0.4 or 2 mM in 30 μl saline) or saline (sham) was infused into the right lateral ventricle 15 min before MCAO. Neurological score was improved 24 h later in the animals treated with 2 mM diazoxide (13.8 ± 0.7, n = 13) compared with sham treatment (9.5 ± 0.2, n = 6, P < 0.01). The total percent infarct volume (MCAO vs. contralateral side) of sham treatment animals was 43.6 ± 3.6% ( n = 12). Treatment with 2 mM diazoxide reduced the infarct volume to 20.9 ± 4.8% ( n = 13, P < 0.05). Effects of diazoxide were prominent in the cerebral cortex. The protective effect of diazoxide was completely prevented by the pretreatment with 5-hydroxydecanoate (100 mM in 10 μl saline), a selective blocker of mitoKATP channels ( n = 6). These results indicate that selective opening of the mitoKATP channel has neuroprotective effects against ischemia-reperfusion injury in the rat brain.

Abstract WMP41: Neuronal Sirt1 is Required for Resveratrol Preconditioning Induced Ischemic Tolerance

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Kevin B Koronowski ◽  
Isa Saul ◽  
Zachary Balmuth-Loris ◽  
Miguel Perez-Pinzon
Keyword(s):  
Knockout Mouse ◽  
Infarct Volume ◽  
Hypoxia Inducible Factor ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Tamoxifen Treatment ◽  
Neurological Score ◽  
Transcription Factor Activation ◽  
Cerebral Artery Occlusion

Introduction: Our previous work demonstrates that resveratrol, a naturally occurring polyphenol, protects against cerebral ischemia when administered 2 or 14 days prior to injury. Resveratrol activates Sirt1, an NAD + -dependent deacylase that regulates cellular metabolism. It has been postulated that neuronal Sirt1 directly mediates this neuroprotection but it remains to be empirically tested. Objective: The objective of this study was to generate an inducible, neuronal-specific Sirt1 knockout mouse and determine whether neuronal Sirt1 is necessary for resveratrol-induced ischemic tolerance. Methods: Twenty to twenty-five gram neuronal-specific Sirt1 knockout mice (Sirt1neu-/-) and WTs were induced with tamoxifen. Mice were randomized for 1) western blot; 2) resveratrol preconditioning (RPC; 10 mg/kg resveratrol i.p.) or vehicle (1.5% DMSO; 0.9% saline) treatment 2 days prior to 60 minute middle cerebral artery occlusion (MCAo); 3) untargeted primary metabolomics by GC-TOF-MS; or 4) transcription factor activation profiling. Twenty-four hours following MCAo, neurological score was used to assess functional outcome and infarct volume was quantified by TTC staining. Results: Tamoxifen treatment removed WT Sirt1 protein from major brain regions but not from heart (Figure 1A, n=3). In WT, RPC reduced infarct volume by 43.7% and improved neurological score by nearly 3 points, however these effects were lost in Sirt1neu-/- (Figure 1B, n=5-9). Compared to WT, metabolic profiles from Sirt1neu-/- displayed significantly altered glycolysis metabolites (Figure 1C, n=8). Activation of hypoxia inducible factor (HIF) was reduced by 48% in Sirt1neu-/- (Figure 1D, n=3). Conclusions: We generated and utilized an inducible, neuronal-specific knockout mouse to demonstrate that neuronal Sirt1 specifically is required for RPC-induced ischemic tolerance. Additionally, Sirt1 regulates glycolysis in the brain, possibly through its interaction with HIF.

Abstract 91: Remodeling After Stroke: The Recovering Brain Is Vulnerable To Lipoxygenase-dependent Semaphorin Signaling

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Anton Pekcec ◽  
Kazim Yigitkanli ◽  
Joo Eun Jung ◽  
Hulya Karatas ◽  
Eng H Lo ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Cortical Neurons ◽  
Second Messengers ◽  
Artery Occlusion ◽  
Tube Formation ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Axon Extension ◽  
Cultured Cortical Neurons ◽  
Cerebral Artery Occlusion

Background and Purpose— Recovery from stroke is limited in part by an inhibitory environment in the post-ischemic brain, but factors preventing successful remodeling are not well known. We sought to investigate if signaling from the axon guidance molecule semaphorin 3A (Sema3A) via eicosanoid second messengers can contribute to this inhibitory environment, and if blocking the Sema3A pathway can provide a benefit following experimental stroke. Methods— Cultured cortical neurons from mice were treated with recombinant Sema3A, or with the eicosanoids 12-HETE and 12-HPETE. Neurons from ALOX15 knockout mice, and a human brain endothelial cell line, were treated similarly. The filament model of MCAO was used to induce experimental stroke in mice, in some of which Sema3A was injected stereotactically into the striatum. The 12/15-LOX inhibitor LOXBlock-1 was injected intraperitoneally one week after MCAO. Results— Expression levels of 12/15-lipoxygenase (12/15-LOX) were increased within two hours after exposure of primary neurons to 90nM recombinant Sema3A. Either Sema3A, or the 12/15-lipoxygenase (12/15-LOX) metabolites 12-HETE and 12-HPETE at 300nM, blocked axon extension in neurons compared to solvent controls, and decreased tube formation in endothelial cells. The Sema3A effect was reversed by inhibiting 12/15-LOX, and neurons derived from 12/15-LOX knockout mice were insensitive to Sema3A. Following middle cerebral artery occlusion to induce stroke in mice, immunohistochemistry showed both Sema3A and 12/15-LOX are increased in the cortex up to two weeks. To determine if a Sema3A-dependent damage pathway is activated following ischemia, we injected recombinant Sema3A into the striatum. Sema3A alone did not cause injury in normal brains. But when injected into post-ischemic brains, Sema3A increased cortical damage by 79%, and again this effect was reversed by 12/15-LOX inhibition. Administration of the 12/15-LOX inhibitor LOXBlock-1 7 days after transient MCAO increased vascularization in the infarcted and peri-infarct area one week later. Conclusions— Our findings suggest that blocking the semaphorin pathway may provide a novel therapeutic strategy to improve stroke recovery.

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