scholarly journals The Positive Effect of MiR1 Antagomir on Ischemic Neurological Disorders Via Changing the Expression of Bcl-w and Bad Genes

2020 ◽  
Vol 11 (6) ◽  
pp. 811-820
Author(s):  
Anis Talebi ◽  
Keyword(s):  
Treatment Group ◽  
Normal Saline ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Positive Control ◽  
Artery Occlusion ◽  
Sham Control ◽  
Non Coding Rnas ◽  
Cerebral Artery Occlusion ◽  
Positive Effect

Introduction: MicroRNAs (miRNAs or miRs) are non-coding RNAs. Studies have shown that miRNAs are expressed aberrantly in stroke. The miR1 enhances ischemic damage, and a previous study has demonstrated that reduction of miR1 level has a neuroprotective effect on the Middle Cerebral Artery Occlusion (MCAO). Since apoptosis is one of the important processes in neural protection, the possible effect of miR1 on this pathway has been tested in this study. Post-ischemic administration of miR1 antagomir reduces infarct volume via bcl-w and bad expression. Methods: Rats were divided into four experimental groups: sham, control, positive control, and antagomir treatment group. One hour after MCAO surgery, the rats were received intravenously (Tail vein) 0.1 mL Normal Saline (NS), 0.1 mL rapamycin, and 300 pmol/g miR1 antagomir (soluble in 0.1 mL normal saline) in control, positive control, and treatment group, respectively. Twenty-four hours after reperfusion infarct volume was measured. The expression of miR1, bcl-w, and bad were analyzed using real-time PCR in sham, control, and treated groups. Results: Our results indicate that administration of miR1 antagomir reduces infarct volume significantly, it also decreases miR1 and bad expression while increases bcl-w expression. Conclusion: Understanding the precise neuroprotective mechanism of miR1 antagomir can make it a proper treatment and an innovative approach for stroke therapy.

Neuroprotective effects of erythropoietin pretreatment in a rodent model of transient middle cerebral artery occlusion

2014 ◽  
Vol 121 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Bernardo Oliveira Ratilal ◽  
Mariana Moreira Coutinho Arroja ◽  
Joao Pedro Fidalgo Rocha ◽  
Adelaide Maria Afonso Fernandes ◽  
Andreia Pereira Barateiro ◽  
...  
Keyword(s):  
Treatment Group ◽  
Middle Cerebral Artery ◽  
Brain Edema ◽  
Cerebral Artery ◽  
Plasma Levels ◽  
Infarct Volume ◽  
Neuron Specific Enolase ◽  
Artery Occlusion ◽  
Mca Occlusion ◽  
Cerebral Artery Occlusion

Object There is an unmet clinical need to develop neuroprotective agents for neurosurgical and endovascular procedures that require transient cerebral artery occlusion. The aim in this study was to explore the effects of a single dose of recombinant human erythropoietin (rhEPO) before middle cerebral artery (MCA) occlusion in a focal cerebral ischemia/reperfusion model. Methods Twenty-eight adult male Wistar rats were subjected to right MCA occlusion via the intraluminal thread technique for 60 minutes under continuous cortical perfusion monitoring by laser Doppler flowmetry. Rats were divided into 2 groups: control and treatment. In the treated group, rhEPO (1000 IU/kg intravenously) was administered 10 minutes before the onset of the MCA ischemia. At 24-hour reperfusion, animals were examined for neurological deficits, blood samples were collected, and animals were killed. The following parameters were evaluated: brain infarct volume, ipsilateral hemispheric edema, neuron-specific enolase plasma levels, parenchyma histological features (H & E staining), Fluoro-Jade–positive neurons, p-Akt and total Akt expression by Western blot analysis, and p-Akt–positive nuclei by immunohistochemical investigation. Results Infarct volume and Fluoro-Jade staining of degenerating neurons in the infarct area did not vary between groups. The severity of neurological deficit (p < 0.001), amount of brain edema (78% reduction in treatment group, p < 0.001), and neuron-specific enolase plasma levels (p < 0.001) were reduced in the treatment group. Perivascular edema was histologically less marked in the treatment group. No variations in the expression or localization of p-Akt were seen. Conclusions Administration of rhEPO before the onset of 60-minute transient MCA ischemia protected the brain from this insult. It is unlikely that rhEPO pretreatment leads to direct neuronal antiapoptotic effects, as supported by the lack of Akt activation, and its benefits are most probably related to an indirect effect on brain edema as a consequence of blood-brain barrier preservation. Although research on EPO derivatives is increasing, rhEPO acts through distinct neuroprotective pathways and its clinical safety profile is well known. Clinically available rhEPO is a potential therapy for prevention of neuronal injury induced by transitory artery occlusion during neurovascular procedures.

Abstract WP152: Novel Therapy With Pdgf-b Nanoparticles for Cerebral Infarction

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Soh Takagishi ◽  
Koichi Arimura ◽  
Katsuma Iwaki ◽  
Ataru Nishimura ◽  
Masaharu Murata ◽  
...  
Keyword(s):  
Cerebral Infarction ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Reperfusion Therapy ◽  
Artery Occlusion ◽  
Neurological Function ◽  
Novel Therapy ◽  
Infarct Area ◽  
Neurotrophin 3 ◽  
Cerebral Artery Occlusion

Background and Purpose: Treatment for cerebral infarction beyond the indication of reperfusion therapy has not yet been established, and novel approaches are needed. It has been reported that platelet-derived growth factor (PDGF)-B played a neuroprotective role by enhancing cell survival and tissue repair for a long period after cerebral infarction in experimental animal models. However, PDGF-B is difficult to administer at effective concentrations in infarct area. In general, nanoparticles are very small and stable, making them prone to accumulation without being metabolized in infarct area. Therefore, we converted PDGF-B into nanoparticles and examined its therapeutic effect for cerebral infarction. Methods: PDGF-B nanoparticles (PDGF-B NP) and wild-type nanoparticles (wNP) were injected one day after transient middle cerebral artery occlusion (tMCAO) using the CB-17 mouse model. We analyzed temporal histological changes and neurological function recovery. Fucntional recovery was assess using Cylinder test at 3 and 7 days after the tMCAO. As for the mechanism of neuroprotective effect, phosphorylation of Akt, neurotrophin-3 (NT-3), and expression of angiogenesis were also examined in the infarct area and compared them with wNP control at 7 days after tMCAO. Result: We found that PDGF-B NP was distributed specifically in the infarct area. As compared with wNP group, PDGF-B NP group significantly suppressed cerebral infarct volume and improved neurological function at 3 and 7 days after cerebral infarction compared with wNP group. Akt was strongly phosphorylated in the infarction area with PDGF-B NP administration compared with wNP. Moreover, PDGF-B NP significantly induced angiogenesis, NT-3 expression, and reduced cell apoptosis after cerebral infarction compared with wNP. Conclusion: PDGF-B NP activated PDGF-B-Akt signaling in infarct area and played various important roles leading to neuroprotection after cerebral infarction. Our results suggested that treatment with PDGF-B NP may be useful for cerebral infarction beyond reperfusion therapy.

scholarly journals Neuroprotective Effect of a Formula, Moschus Combined with Borneolum Synthcticum, from Traditional Chinese Medicine on Ischemia Stroke in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Xin-hua Xia ◽  
Qiang Li ◽  
Mei Liu
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Caspase 3 ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
Caspase 9 ◽  
Related Proteins ◽  
Cerebral Artery Occlusion

Moschus compatible with borneolum synthcticum is a well-known herb pair in Traditional Chinese Medicine and the present study aims to assess the neuroprotective effect of a formula composed of this herb pair on ischemia stroke in rats. The middle cerebral artery occlusion model of focal cerebral ischemia in rat was performed by using intraluminal suture method. The behavioral scores, infarct volume, and neuron ultrastructure of model and formula-treated rats were investigated after the 2 h of ischemia and 24 h of reperfusion. Meanwhile the expression levels of caspase-3, caspase-9, Bcl-2, and Bax were measured by western blot analysis. The formula treatment showed obvious neuroprotective effect according to significant decrease of the neurological scores(P<0.01)and the infarct volumes(P<0.05)when compared to the MCAO group. We also observed that this formula had antiapoptosis activity on neuron cell under electron microscope. Furthermore, our result supported the idea that pro- and postadministration of this formula had an antiapoptosis effect by decreasing remarkably the expression of caspase-3 and caspase-9(P<0.05)as well as increasing significantly the ratio of Bcl-2 to Bax(P<0.01). All evidences demonstrated the neuroprotective effect of this formula on ischemia stroke due to decrease of brain infract volume and modulation of the expression of apoptosis-related proteins.

scholarly journals Hypothermia revisited: Impact of ischaemic duration and between experiment variability

2017 ◽  
Vol 37 (10) ◽  
pp. 3380-3390 ◽  
Author(s):  
Sarah SJ Rewell ◽  
Amy L Jeffreys ◽  
Steven A Sastra ◽  
Susan F Cox ◽  
John A Fernandez ◽  
...  
Keyword(s):  
Animal Models ◽  
Ischaemic Stroke ◽  
Infarct Volume ◽  
Meta Analysis ◽  
Positive Control ◽  
Artery Occlusion ◽  
Novel Therapies ◽  
Target Temperature ◽  
Focal Ischaemia ◽  
Cerebral Artery Occlusion

To assess the true effect of novel therapies for ischaemic stroke, a positive control that can validate the experimental model and design is vital. Hypothermia may be a good candidate for such a positive control, given the convincing body of evidence from animal models of ischaemic stroke. Taking conditions under which substantial efficacy had been seen in a meta-analysis of hypothermia for focal ischaemia in animal models, we undertook three randomised and blinded studies examining the effect of hypothermia induced immediately following the onset of middle cerebral artery occlusion on infarct volume in rats (n = 15, 23, 264). Hypothermia to a depth of 33℃ and maintained for 130 min significantly reduced infarct volume compared to normothermia treatment (by 27–63%) and depended on ischaemic duration (F(3,244) = 21.242, p < 0.05). However, the protective effect varied across experiments with differences in both the size of the infarct observed in normothermic controls and the time to reach target temperature. Our results highlight the need for sample size and power calculations to take into account variations between individual experiments requiring induction of focal ischaemia.

scholarly journals ATP Induces Mild Hypothermia in Rats but has a Strikingly Detrimental Impact on Focal Cerebral Ischemia

2012 ◽  
Vol 33 (1) ◽  
pp. e1-e10 ◽  
Author(s):  
Meijuan Zhang ◽  
Wenjin Li ◽  
Guangming Niu ◽  
Rehana K Leak ◽  
Jun Chen ◽  
...  
Keyword(s):  
Mild Hypothermia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Core Body Temperature ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Dependent Manner ◽  
Systemic Side Effects ◽  
Cerebral Artery Occlusion

Ischemic stroke is a devastating condition lacking effective therapies. A promising approach to attenuate ischemic injury is mild hypothermia. Recent studies show that adenosine nucleotides can induce hypothermia in mice. The purpose of the present study was to test the hypothesis that adenosine 5′-triphosphate (ATP) induces mild hypothermia in rats and reduces ischemic brain injury. We found that intraperitoneal injections of ATP decreased core body temperature in a dose-dependent manner; the dose appropriate for mild hypothermia was 2 g/kg. When ATP-induced hypothermia was applied to stroke induced by middle cerebral artery occlusion, however, a neuroprotective effect was not observed. Instead, the infarct volume grew even larger in ATP-treated rats. This was accompanied by an increased rate of seizure events, hemorrhagic transformation, and higher mortality. Continuous monitoring of physiologic parameters revealed that ATP reduced heartbeat rate and blood pressure. ATP also increased blood glucose, accompanied by severe acidosis and hypocalcemia. Western blotting showed that ATP decreased levels of both phospho-Akt and total-Akt in the cortex. Our results reveal that, despite inducing hypothermia, ATP is not appropriate for protecting the brain against stroke. Instead, we show for the first time that ATP treatment is associated with exaggerated ischemic outcomes and dangerous systemic side effects.

scholarly journals CELSR1 Promotes Neuroprotection in Cerebral Ischemic Injury Mainly through the Wnt/PKC Signaling Pathway

2020 ◽  
Vol 21 (4) ◽  
pp. 1267 ◽  
Author(s):  
Li-Hong Wang ◽  
Geng-Lin Zhang ◽  
Xing-Yu Liu ◽  
Ai Peng ◽  
Hai-Yuan Ren ◽  
...  
Keyword(s):  
Motor Function ◽  
Cell Apoptosis ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic ◽  
Cerebral Artery Occlusion

Cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1) is a member of a special subgroup of adhesion G protein-coupled receptors. Although Celsr1 has been reported to be a sensitive gene for stroke, the effect of CELSR1 in ischemic stroke is still not known. Here, we investigated the effect of CELSR1 on neuroprotection, neurogenesis and angiogenesis in middle cerebral artery occlusion (MCAO) rats. The mRNA expression of Celsr1 was upregulated in the subventricular zone (SVZ), hippocampus and ischemic penumbra after cerebral ischemic injury. Knocking down the expression of Celsr1 in the SVZ with a lentivirus significantly reduced the proliferation of neuroblasts, the number of CD31-positive cells, motor function and rat survival and increased cell apoptosis and the infarct volume in MCAO rats. In addition, the expression of p-PKC in the SVZ and peri-infarct tissue was downregulated after ischemia/ reperfusion. Meanwhile, in the dentate gyrus of the hippocampus, knocking down the expression of Celsr1 significantly reduced the proliferation of neuroblasts; however, it had no influence on motor function, cell apoptosis or angiogenesis. These data indicate that CELSR1 has a neuroprotective effect on cerebral ischemia injury by reducing cell apoptosis in the peri-infarct cerebral cortex and promoting neurogenesis and angiogenesis, mainly through the Wnt/PKC pathway.

scholarly journals Postischemic Administration of AK275, a Calpain Inhibitor, Provides Substantial Protection against Focal Ischemic Brain Damage

1994 ◽  
Vol 14 (4) ◽  
pp. 537-544 ◽  
Author(s):  
Raymond T. Bartus ◽  
Keith L. Baker ◽  
Angie D. Heiser ◽  
Sean D. Sawyer ◽  
Reginald L. Dean ◽  
...  
Keyword(s):  
Brain Damage ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Focal Ischemia ◽  
Artery Occlusion ◽  
Calpain Inhibitor ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Diastereomeric Mixture ◽  
Cerebral Artery Occlusion

Experiments were conducted to determine whether a potent, reversible calpain inhibitor could reduce the cortical ischemic brain damage associated with focal ischemia in the rat. AK275 (Z-Leu–Abu–CONH–CH2CH3), the active isomer of the diastereomeric mixture, CX275, was employed in conjunction with a novel method of perfusing drug directly onto the infarcted cortical surface. This protocol reduced or eliminated numerous, nonspecific pharmacokinetic, hemodynamic, and other potentially confounding variables that might complicate interpretation of any drug effect. Focal ischemia was induced using a variation of the middle cerebral artery occlusion method. These studies demonstrated a reliable and robust neuroprotective effect of AK275 over the concentration range of 10 to 200 μ M (perfused supracortically at 4 μl/h for 21 h). Moreover, a 75% reduction in infarct volume was observed when initiation of drug treatment was delayed for 3 h postocclusion. Our data further support an important role of calpain in ischemia-induced neuropathology and suggest that calpain inhibitors may provide a unique and potentially powerful means of treating stroke and other ischemic brain incidents.

scholarly journals Neuroprotection in Diet-Induced Ketotic Rat Brain after Focal Ischemia

2008 ◽  
Vol 28 (12) ◽  
pp. 1907-1916 ◽  
Author(s):  
Michelle A Puchowicz ◽  
Jennifer L Zechel ◽  
Jose Valerio ◽  
Douglas S Emancipator ◽  
Kui Xu ◽  
...  
Keyword(s):  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Hypoxia Inducible Factor ◽  
Focal Ischemia ◽  
Artery Occlusion ◽  
Potential Mechanism ◽  
Apoptotic Protein ◽  
Cerebral Artery Occlusion ◽  
Intraventricular Infusion ◽  
The Brain

Neuroprotective properties of ketosis may be related to the upregulation of hypoxia inducible factor (HIF)-1α, a primary constituent associated with hypoxic angiogenesis and a regulator of neuroprotective responses. The rationale that the utilization of ketones by the brain results in elevation of intracellular succinate, a known inhibitor of prolyl hydroxylase (the enzyme responsible for the degradation of HIF-1α) was deemed as a potential mechanism of ketosis on the upregulation of HIF-1α. The neuroprotective effect of diet-induced ketosis (3 weeks of feeding a ketogenic diet), as pretreatment, on infarct volume, after reversible middle cerebral artery occlusion (MCAO), and the upregulation of HIF-1α were investigated. The effect of β-hydroxybutyrate (BHB), as a pretreatment, via intraventricular infusion (4 days of infusion before stroke) was also investigated following MCAO. Levels of HIF-1α and Bcl-2 (anti-apoptotic protein) proteins and succinate content were measured. A 55% or 70% reduction in infarct volume was observed with BHB infusion or diet-induced ketosis, respectively. The levels of HIF-1α and Bcl-2 proteins increased threefold with diet-induced ketosis; BHB infusions also resulted in increases in these proteins. As hypothesized, succinate content increased by 55% with diet-induced ketosis and fourfold with BHB infusion. In conclusion, the biochemical link between ketosis and the stabilization of HIF-1α is through the elevation of succinate, and both HIF-1α stabilization and Bcl-2 upregulation play a role in ketone-induced neuroprotection in the brain.

scholarly journals Increase in Endogenous Brain Superoxide Dismutase as a Potential Mechanism of Lipopolysaccharide-Induced Brain Ischemic Tolerance

2000 ◽  
Vol 20 (8) ◽  
pp. 1190-1196 ◽  
Author(s):  
Régis Bordet ◽  
Dominique Deplanque ◽  
Patrice Maboudou ◽  
François Puisieux ◽  
Qian Pu ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Protein Synthesis ◽  
Infarct Volume ◽  
Brain Activity ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Low Doses ◽  
Cerebral Artery Occlusion ◽  
Delayed Neuroprotection

A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours before 60-minute middle cerebral artery occlusion, induced a delayed neuroprotection proven by the significant decrease (–35%) of brain infarct volume in comparison with control, whereas infarct volumes remained unchanged in rats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotective effect of LPS was induced only with low doses (0.25 to 1 mg/kg), whereas this effect disappeared with a higher dose (2 mg/kg). The delayed neuroprotection of LPS was induced in the cortical part of the infarcted zone, not in the subcortical part. The beneficial effect of LPS on consequences of middle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) and indomethacin (3 mg/kg) administered 1 hour before LPS, whereas both drugs had no direct effect on infarct volume by themselves, suggesting that activation of inflammatory pathway is involved in the development of LPS-induced brain ischemic tolerance. Preadministration of cycloheximide, an inhibitor of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechanism. Superoxide dismutase (SOD) could be one of the synthesized proteins because lipopolysaccharide increased SOD brain activity 72 hours, but not 12 hours, after its administration, which paralleled the development of brain ischemic tolerance. In contrast, catalase brain activity remained unchanged after LPS administration. The LPS-induced delayed increase in SOD brain content was suppressed by a previous administration of indomethacin. These data suggest that the delayed neuroprotective effect of low doses of LPS is mediated by an increased synthesis of brain SOD that could be triggered by activation of inflammatory pathway.

scholarly journals Adenosine A1 Receptor Antagonist and Mitochondrial ATP-Sensitive Potassium Channel Blocker Attenuate the Tolerance to Focal Cerebral Ischemia in Rats

2004 ◽  
Vol 24 (7) ◽  
pp. 771-779 ◽  
Author(s):  
Mitsuyoshi Yoshida ◽  
Kazuhiko Nakakimura ◽  
Ying Jun Cui ◽  
Mishiya Matsumoto ◽  
Takefumi Sakabe
Keyword(s):  
Cerebral Ischemia ◽  
Receptor Antagonist ◽  
Channel Blocker ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Artery Occlusion ◽  
A1 Receptor ◽  
Cerebral Artery Occlusion ◽  
Development Of Tolerance

Involvement of adenosine and adenosine triphosphate-sensitive potassium (KATP) channels in the development of ischemic tolerance has been suggested in global ischemia, but has not been studied extensively in focal cerebral ischemia. This study evaluated modulating effects of adenosine A1 receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) and mitochondrial KATP channel blocker 5HD (5-hydroxydecanoate) on the development of tolerance to focal cerebral ischemia in rats. Preconditioning with 30-minute middle cerebral artery occlusion (MCAO) reduced cortical and subcortical infarct volume following 120-minute MCAO (test ischemia) given 72 hours later. The neuroprotective effect of preconditioning was attenuated by 0.1 mg/kg DPCPX given before conditioning ischemia (30-minute MCAO), but no influence was provoked when it was administered before test ischemia. DPCPX had no effect on infarct volume after conditioning or test ischemia when given alone. The preconditioning-induced neuroprotection disappeared when 30 mg/kg 5HD was administered before test ischemia. These results suggest a possible involvement of adenosine A1 receptors during conditioning ischemia and of mitochondrial KATP channels during subsequent severe ischemia in the development of tolerance to focal cerebral ischemia.

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