scholarly journals Angiopoietin-1 Mimetic Peptide Promotes Neuroprotection after Stroke in Type 1 Diabetic Rats

2018 ◽  
Vol 27 (12) ◽  
pp. 1744-1752 ◽  
Author(s):  
Poornima Venkat ◽  
Tao Yan ◽  
Michael Chopp ◽  
Alex Zacharek ◽  
Ruizhuo Ning ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Neuroprotective Effects ◽  
Ischemic Brain ◽  
Mimetic Peptide ◽  
Tnf Α ◽  
Bbb Permeability ◽  
Angiopoietin 1

Angiopoietin-1 (Ang1) mediates vascular maturation and immune response. Diabetes decreases Ang1 expression and disrupts Ang1/Tie2 signaling activity. Vasculotide is an Ang1 mimetic peptide, and has anti-inflammatory effects. In this study, we test the hypothesis that vasculotide treatment induces neuroprotection and decreases inflammation after stroke in type 1 diabetic (T1DM) rats. T1DM rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with: 1) phosphate buffered saline (PBS); 2) vasculotide (3µg/kg, i.p. injection) administered half an hour prior to MCAo and at 8 and 24 hours after MCAo. Rats were sacrificed at 48 h after MCAo. Neurological function, infarct volume, hemorrhage, blood brain barrier (BBB) permeability and neuroinflammation were measured. Vasculotide treatment of T1DM-MCAo rats significantly improves functional outcome, decreases infarct volume and BBB permeability, but does not decrease brain hemorrhagic transformation compared with PBS-treated T1DM-MCAo rats. In the ischemic brain, Vasculotide treatment significantly decreases apoptosis, number of cleaved-caspase-3 positive cells, the expression of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF-α). Western blot analysis shows that vasculotide significantly decreases expression of receptor for advanced glycation end products (RAGE), MCP-1 and TNF-α in the ischemic brain compared with T1DM-MCAo rats. Vasculotide treatment in cultured primary cortical neurons (PCN) significantly decreases TLR4 expression compared with control. Decreased neuroinflammation and reduced BBB leakage may contribute, at least in part, to vasculotide-induced neuroprotective effects after stroke in T1DM rats.

scholarly journals Gingko biloba Extract (EGb 761) Prevents Ischemic Brain Injury by Activation of the Akt Signaling Pathway

2009 ◽  
Vol 37 (03) ◽  
pp. 547-555 ◽  
Author(s):  
Jae-Hyeon Cho ◽  
Jin-Hee Sung ◽  
Eun-Hae Cho ◽  
Chung-Kil Won ◽  
Hyo-Jong Lee ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Male Rats ◽  
Ischemic Brain Injury ◽  
Protective Effects ◽  
Egb 761 ◽  
Neuroprotective Effects ◽  
Ischemic Brain ◽  
Gingko Biloba

EGb 761 is a standardized extract of Gingko biloba that exerts protective effects against ischemic brain injury. This study investigated whether EGb 761 modulates the neuroprotective effects through Akt and its downstream targets, Bad and FKHR. Adult male rats were treated with EGb 761 (100 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO). Brains were collected 24 hours after MCAO and infarct volumes were analyzed. EGb 761 significantly reduced infarct volume. Potential activation was mearsured by phosphorylation of Akt at Ser473, Bad at Ser136, and FKHR at Ser256 using Western blot analysis. EGb 761 prevented the injury-induced decrease of pAkt and its down stream targets, pBad and pFKHR. Furthermore, EGb 761 prevented the injury-induced increase of cleaved caspase-3 levels. In conclusion, this study suggests that EGb 761 prevents cell death due to brain injury and that EGb 761 protection is affected by preventing the injury-induce decrease of Akt phosphorylation.

scholarly journals Pomalidomide Reduces Ischemic Brain Injury in Rodents

2019 ◽  
Vol 28 (4) ◽  
pp. 439-450 ◽  
Author(s):  
Yan-Rou Tsai ◽  
David Tweedie ◽  
Ignacio Navas-Enamorado ◽  
Michael T. Scerba ◽  
Cheng-Fu Chang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Damage ◽  
Infarct Volume ◽  
Serum Levels ◽  
Surfactant Protein ◽  
Artery Occlusion ◽  
Mitochondrial Activity ◽  
Pharmacokinetic Studies ◽  
Ischemic Brain ◽  
Tnf Α

Stroke is a leading cause of death and severe disability worldwide. After cerebral ischemia, inflammation plays a central role in the development of permanent neurological damage. Reactive oxygen species (ROS) are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Prior cellular studies demonstrate that POM can mitigate oxidative stress and lower levels of pro-inflammatory cytokines, particularly TNF-α, which plays a prominent role in ischemic stroke-induced brain damage and functional deficits. To evaluate the potential value of POM in cerebral ischemia, POM was initially administered to transgenic mice chronically over-expressing TNF-α surfactant protein (SP)-C promoter (SP-C/TNF-α mice) to assess whether systemically administered drug could lower systemic TNF-α level. POM significantly lowered serum levels of TNF-α and IL-5. Pharmacokinetic studies were then undertaken in mice to evaluate brain POM levels following systemic drug administration. POM possessed a brain/plasma concentration ratio of 0.71. Finally, rats were subjected to transient middle cerebral artery occlusion (MCAo) for 60 min, and subsequently treated with POM 30 min thereafter to evaluate action on cerebral ischemia. POM reduced the cerebral infarct volume in MCAo-challenged rats and improved motor activity, as evaluated by the elevated body swing test. POM’s neuroprotective actions on ischemic injury represent a potential therapeutic approach for ischemic brain damage and related disorders, and warrant further evaluation.

Abstract TMP69: Endoglin Deficiency Exacerbates Ischemic Brain Injury

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Fanxia Shen ◽  
Vincent Degos ◽  
Zhenying Han ◽  
Eun-Jung Choi ◽  
William L. Young ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Paradoxical Embolism ◽  
Artery Occlusion ◽  
Vascular Density ◽  
Ischemic Brain Injury ◽  
Myocardial Repair ◽  
Ischemic Brain ◽  
Removal Time ◽  
Adhesive Removal

Background and Objective: Endoglin (Eng) deficiency causes hereditary hemorrhagic telangiectasia (HHT) and impairs myocardial repair. Pulmonary arteriovenous malformations in HHT patients are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that Eng deficiency exacerbates ischemic brain injury. Methods: Eng heterozygous ( Eng +/- ) mice and wild type (WT) mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Infarct volume and CD68 + cells were quantified 3 days and vascular density was determined 60 days after pMCAO. Behavior was assessed by corner test and adhesive removal test at 3, 15, 30 and 60 days after pMCAO. Matrix metalloproteinase 9 (Mmp9) and Notch1 expression in bone marrow (BM)-derived macrophages from Eng +/- and WT were analyzed using real-time RT-PCR. Results: Eng +/- mice had a larger Infarct volume than WT mice (22±6% of the affected hemisphere vs. 16±6%, p=0.04). Eng +/- mice had longer adhesive-removal time (p<0.05) and more frequent turning to the lesion side than WT mice at 15, 30 and 60 days (p<0.05) after pMCAO. Both groups had similar numbers of CD68 + cells in the peri-infarct area at 3 days after pMCAO (370±80 vs 338±44 cells/mm 2 , p=0.37), but Eng +/- mice had lower peri-infarct vessel density (417±69 vs 490±52 vessels/mm 2 , p=0.05) at 60 days after pMCAO. Up-regulation of Mmp9 and Notch1 expression in response to VEGF was attenuated in Eng +/- BM-derived macrophages. Conclusions: Endoglin deficiency exacerbated brain injury and behavior dysfunction in mice after pMCAO and was associated with reduced angiogenesis. Although macrophage homing was not affected, reduced expression of two angiogenic-related genes, Mmp9 and Notch1 , by Eng +/- BM-derived macrophages suggests a potential role of these cells in recovery from an ischemic injury.

Abstract WMP45: Targeted Inhibition of the Alternative Complement Pathway Enhances Rehabilitation-Induced Cognitive and Motor Recovery in a Murine Model of Chronic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Ali Alawieh ◽  
Meredith Andersen ◽  
DeAnna L Adkins ◽  
Stephen Tomlinson
Keyword(s):  
Cognitive Performance ◽  
Infarct Volume ◽  
Alternative Pathway ◽  
Artery Occlusion ◽  
Motor Recovery ◽  
Acute Injury ◽  
Neuroprotective Effects ◽  
Recovery Processes ◽  
Targeted Inhibition ◽  
A Site

Introduction: Activation of inflammatory cascades after stroke exacerbate acute injury and limit response to rehabilitation (rehab). The complement (C) system is a prominent component of inflammatory injury after stroke, but can also contribute to neuroprotective recovery processes. We investigated the neuroprotective effects of CR2fH, a site-targeted C inhibitor that specifically inhibits the alternative pathway and prevents amplification of the C cascade. We assessed how CR2fH affects chronic outcomes, and how acute C inhibition impacts the response to rehab therapy. Methods: Mice were subjected to 1hr middle cerebral artery occlusion and 15 days of reperfusion. Mice were treated with CR2fH or vehicle and then randomized to normal housing or an enriched environment (EE) to model cognitive and motor rehab. Animals were assessed for infarct volume using MRI at days 4 and 14 after injury, and for their performance on several motor and cognitive tasks. Expression of inflammatory markers in the brain was assessed using high throughput Nanostring analysis and immunostaining. Results: Compared to vehicle or EE only, treatment with CR2fH 90 mins after cerebral ischemia significantly reduced infarct volume and improved motor and cognitive performance up to 15 days, as assessed with mNSS scores, corner task, locomotor activity, pasta handling, and passive avoidance tasks (p’s<0.01). Less prominent, although still significant improvement was also achieved when CR2fH was administered 6 or 12 hrs. after ischemia (p’s<0.05). EE alone did not significantly reduce infarct volume or improve performance on motor tasks, but resulted in a significant improvement in cognitive performance compared to vehicle (p’s<0.05). A combination of EE and CR2fH therapy resulted in a significant potentiation of cognitive and motor recovery compared to either single intervention (p’s<0.05). CR2fH related behavioral improvements correlated with reduction in C deposition and inflammatory microglial activation during recovery. Conclusions: Since a humanized version of CR2fH, TT30, was shown to be safe, tolerated and nonimmunogenic in humans, targeted inhibition of alternative C pathway is a candidate therapy to promote recovery and potentiate response to rehab after stroke.

scholarly journals Ceftriaxone therapy attenuates brain trauma in rats by affecting glutamate transporters and neuroinflammation and not by its antibacterial effects

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Sher-Wei Lim ◽  
Hui-Chen Su ◽  
Tee-Tau Eric Nyam ◽  
Chung-Ching Chio ◽  
Jinn-Rung Kuo ◽  
...  
Keyword(s):  
Neuronal Apoptosis ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Body Weight Loss ◽  
Motor Dysfunction ◽  
Vehicle Group ◽  
Sprague Dawley ◽  
Antibacterial Effects ◽  
Neuroprotective Effects ◽  
Tnf Α

Abstract Background Ceftriaxone is a β-lactam antibiotic used to treat central nervous system infections. Whether the neuroprotective effects of ceftriaxone after TBI are mediated by attenuating neuroinflammation but not its antibacterial actions is not well established. Methods Anesthetized male Sprague–Dawley rats were divided into sham-operated, TBI + vehicle, and TBI + ceftriaxone groups. Ceftriaxone was intraperitoneally injected at 0, 24, and 48 h with 50 or 250 mg/kg/day after TBI. During the first 120 min after TBI, we continuously measured heart rate, arterial pressure, intracranial pressure (ICP), and cerebral perfusion pressure. The infarct volume was measured by TTC staining. Motor function was measured using the inclined plane. Glutamate transporter 1 (GLT-1), neuronal apoptosis and TNF-α expression in the perilesioned cortex were investigated using an immunofluorescence assay. Bacterial evaluation was performed by Brown and Brenn’s Gram staining. These parameters above were measured at 72 h after TBI. Results Compared with the TBI + vehicle group, the TBI + ceftriaxone 250 mg/kg group showed significantly lower ICP, improved motor dysfunction, reduced body weight loss, decreased infarct volume and neuronal apoptosis, decreased TBI-induced microglial activation and TNF-α expression in microglia, and increased GLT-1 expression in neurons and microglia. However, the grades of histopathological changes of antibacterial effects are zero. Conclusions The intraperitoneal injection of ceftriaxone with 250 mg/kg/day for three days may attenuate TBI by increasing GLT-1 expression and reducing neuroinflammation and neuronal apoptosis, thereby resulting in an improvement in functional outcomes, and this neuroprotective effect is not related to its antibacterial effects.

scholarly journals Modulator of apoptosis-1 is a potential therapeutic target in acute ischemic injury

2018 ◽  
Vol 39 (12) ◽  
pp. 2406-2418 ◽  
Author(s):  
Su Jing Chan ◽  
Hui Zhao ◽  
Kazuhide Hayakawa ◽  
Chou Chai ◽  
Chong Teik Tan ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Infarct Volume ◽  
Neuronal Loss ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
In Vivo Models ◽  
The Brain

Modulator of apoptosis 1 (MOAP-1) is a Bax-associating protein highly enriched in the brain. In this study, we examined the role of MOAP-1 in promoting ischemic injuries following a stroke by investigating the consequences of MOAP-1 overexpression or deficiency in in vitro and in vivo models of ischemic stroke. MOAP-1 overexpressing SH-SY5Y cells showed significantly lower cell viability following oxygen and glucose deprivation (OGD) treatment when compared to control cells. Consistently, MOAP-1−/− primary cortical neurons were observed to be more resistant against OGD treatment than the MOAP-1+/+ primary neurons. In the mouse transient middle cerebral artery occlusion (tMCAO) model, ischemia triggered MOAP-1/Bax association, suggested activation of the MOAP-1-dependent apoptotic cascade. MOAP-1−/− mice were found to exhibit reduced neuronal loss and smaller infarct volume 24 h after tMCAO when compared to MOAP-1+/+ mice. Correspondingly, MOAP-1−/− mice also showed better integrity of neurological functions as demonstrated by their performance in the rotarod test. Therefore, both in vitro and in vivo data presented strongly support the conclusion that MOAP-1 is an important apoptotic modulator in ischemic injury. These results may suggest that a reduction of MOAP-1 function in the brain could be a potential therapeutic approach in the treatment of acute stroke.

Neuroprotective effects of nicardipine in a rat model of ischemia and reperfusion

1997 ◽  
Vol 2 (6) ◽  
pp. E4 ◽  
Author(s):  
Mamoru Kittaka ◽  
Steven L. Giannotta ◽  
Vladimir Zelman ◽  
Jorge D. Correale ◽  
Christopher M. DeGiorgio ◽  
...  
Keyword(s):  
Brain Temperature ◽  
Neuron Specific Enolase ◽  
Neuronal Injury ◽  
Artery Occlusion ◽  
Specific Marker ◽  
Neuroprotective Effects ◽  
Doppler Flowmetry ◽  
Ischemic Brain ◽  
Edema Volume ◽  
Cerebral Artery Occlusion

A reversible middle cerebral artery occlusion was performed in rats to determine whether nicardipine, a dihydropyridine voltage-sensitive Ca++ channel (VSCC) antagonist, exerts neuroprotective effects when administered 10 minutes following an ischemic insult, and if it does, whether this is due to its vasodilatory action and effect on cerebral blood flow (CBF) or to direct blockade of Ca++ entry into ischemic brain cells. An increase in the intracellular calcium, [Ca++]i, plays a major role in neuronal injury during cerebral ischemia. Although a large amount of Ca++ enters neurons through the VSCC during ischemia, inconsistent neuroprotective effects have been reported with the antagonists of the VSCC. An intraperitoneal injection of nicardipine (1.2 mg/kg) was administered to rats at 10 minutes after the onset of ischemia, and 8, 16, and 24 hours after occlusion. Cortical CBF was determined by laser-Doppler flowmetry. Neurological and neuropathological examinations were performed after 72 hours. Neuron-specific enolase, a specific marker for the incidence of neuronal injury, was measured in plasma. The CBF in the ischemic core and periphery, as well as brain temperature and physiological parameters, were not affected by nicardipine during occlusion or reperfusion. However, nicardipine treatment significantly improved motor neurological outcome by 32%, and the infarction and edema volume in the pallium as well as the edema volume in the striatum were significantly reduced by 28%, 37%, and 53%, respectively. Nicardipine also significantly reduced the neuron-specific enolase plasma levels by 50%, 42%, and 59% at 24, 48, and 72 hours after the occlusion, respectively. It is concluded that nicardipine may attenuate focal ischemic brain injury by exerting direct neuroprotective and antiedematous effects that do not depend on CBF.

scholarly journals Impact of Age and Sex on α-Syn (α-Synuclein) Knockdown-Mediated Poststroke Recovery

Stroke ◽  
2020 ◽  
Vol 51 (10) ◽  
pp. 3138-3141
Author(s):  
Bharath Chelluboina ◽  
Taehee Kim ◽  
Suresh L. Mehta ◽  
Joo-Yong Kim ◽  
Saivenkateshkomal Bathula ◽  
...  
Keyword(s):  
Brain Damage ◽  
Infarct Volume ◽  
Critical Role ◽  
Artery Occlusion ◽  
Motor Deficits ◽  
Ischemic Brain ◽  
Therapeutic Opportunity ◽  
Interfering Rna ◽  
Cerebral Artery Occlusion ◽  
Age And Sex

Background and Purpose: Increased expression of α-Syn (α-Synuclein) is known to mediate secondary brain damage after stroke. We presently studied if α-Syn knockdown can protect ischemic brain irrespective of sex and age. Methods: Adult and aged male and female mice were subjected to transient middle cerebral artery occlusion. α-Syn small interfering RNA (siRNA) was administered intravenous at 30 minutes or 3 hour reperfusion. Poststroke motor deficits were evaluated between day 1 and 7 and infarct volume was measured at day 7 of reperfusion. Results: α-Syn knockdown significantly decreased poststroke brain damage and improved poststroke motor function recovery in adult and aged mice of both sexes. However, the window of therapeutic opportunity for α-Syn siRNA is very limited. Conclusions: α-Syn plays a critical role in ischemic brain damage and preventing α-Syn protein expression early after stroke minimizes poststroke brain damage leading to better functional outcomes irrespective of age and sex.

scholarly journals Reduction of Infarct Volume by Magnesium after Middle Cerebral Artery Occlusion in Rats

1991 ◽  
Vol 11 (6) ◽  
pp. 1025-1030 ◽  
Author(s):  
Yoshio Izumi ◽  
Simon Roussel ◽  
Elisabeth Pinard ◽  
Jacques Seylaz
Keyword(s):  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Brain ◽  
Mca Occlusion ◽  
Cerebral Artery Occlusion ◽  
Hyperglycemic Effect

The effects of magnesium, an endogenous inhibitor of calcium entry into neurons, upon ischemic brain damage were investigated using a well-characterized model of focal cerebral ischemia in rats. Infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride transcardiac perfusion 48 h after middle cerebral artery (MCA) occlusion. The area of ischemic damage was quantified by image analysis in coronal sections taken every 0.5 mm. MgCl2 (1 mmol/kg) was injected intraperitoneally just after MCA occlusion and again 1 h later. Posttreatment with MgCl2 (16 control and 16 treated rats) significantly reduced the cortical infarct volume. Compensation for the hyperglycemic effect of MgCl2 with insulin (17 rats) further reduced the infarct volume in the neocortex. No systemic effects of either treatment could account for the observed neuroprotection.

scholarly journals Intraventricular Brain-Derived Neurotrophic Factor Reduces Infarct Size after Focal Cerebral Ischemia in Rats

1997 ◽  
Vol 17 (5) ◽  
pp. 500-506 ◽  
Author(s):  
Wolf-R. Schäbitz ◽  
Stefan Schwab ◽  
Matthias Spranger ◽  
Werner Hacke
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Neurotrophic Factor ◽  
Cortical Neurons ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion

Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 μg/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls ( P < 0.05; analysis of variance and Scheffe's test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 ± 27.1 mm3 in BDNF-treated animals and 139.2 ± 56.4 mm3 in controls (mean ± SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 ± 7.1 mm3 in BDNF-treated animals and 37.9 ± 19.8 mm3 in controls (mean ± SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal cerebral ischemia in rats and support the hypothesis of a neuroprotective role for BDNF in stoke.

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