scholarly journals Lack of Neuroprotective Effects of High-Density Lipoprotein Therapy in Stroke under Acute Hyperglycemic Conditions

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6365
Author(s):  
David Couret ◽  
Cynthia Planesse ◽  
Jessica Patche ◽  
Nicolas Diotel ◽  
Brice Nativel ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Neuroprotective Effect ◽  
Hemorrhagic Transformation ◽  
High Density ◽  
Cerebral Infarct ◽  
High Density Lipoproteins ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Acute Hyperglycemia

Introduction: The pleiotropic protective effects of high-density lipoproteins (HDLs) on cerebral ischemia have never been tested under acute hyperglycemic conditions. The aim of this study is to evaluate the potential neuroprotective effect of HDL intracarotid injection in a mouse model of middle cerebral artery occlusion (MCAO) under hyperglycemic conditions. Methods: Forty-two mice were randomized to receive either an intracarotid injection of HDLs or saline. Acute hyperglycemia was induced by an intraperitoneal injection of glucose (2.2 g/kg) 20 min before MCAO. Infarct size (2,3,5-triphenyltetrazolium chloride (TTC)-staining), blood–brain barrier leakage (IgG infiltration), and hemorrhagic changes (hemoglobin assay by ELISA and hemorrhagic transformation score) were analyzed 24 h post-stroke. Brain tissue inflammation (IL-6 by ELISA, neutrophil infiltration and myeloperoxidase by immunohisto-fluorescence) and apoptosis (caspase 3 activation) were also assessed. Results: Intraperitoneal D-glucose injection allowed HDL- and saline-treated groups to reach a blood glucose level of 300 mg/dl in the acute phase of cerebral ischemia. HDL injection did not significantly reduce mortality (19% versus 29% in the saline-injected group) or cerebral infarct size (p = 0.25). Hemorrhagic transformations and inflammation parameters were not different between the two groups. In addition, HDL did not inhibit apoptosis under acute hyperglycemic conditions. Conclusion: We observed a nonsignificant decrease in cerebral infarct size in the HDL group. The deleterious consequences of reperfusion such as hemorrhagic transformation or inflammation were not improved by HDL infusion. In acute hyperglycemia, HDLs are not potent enough to counteract the adverse effects of hyperglycemia. The addition of antioxidants to therapeutic HDLs could improve their neuroprotective capacity.

scholarly journals High-Density Lipoprotein Therapy in Stroke: Evaluation of Endothelial SR-BI-Dependent Neuroprotective Effects

2020 ◽  
Vol 22 (1) ◽  
pp. 106
Author(s):  
Alexy Tran-Dinh ◽  
Angélique Levoye ◽  
David Couret ◽  
Lauriane Galle-Treger ◽  
Martine Moreau ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Infarct Volume ◽  
High Density ◽  
High Density Lipoproteins ◽  
Protective Effects ◽  
Neuroprotective Effects

High-density lipoproteins (HDLs) display endothelial protective effects. We tested the role of SR-BI, an HDL receptor expressed by endothelial cells, in the neuroprotective effects of HDLs using an experimental model of acute ischemic stroke. After transient intraluminal middle cerebral artery occlusion (tMCAO), control and endothelial SR-BI deficient mice were intravenously injected by HDLs or saline. Infarct volume and blood-brain barrier (BBB) breakdown were assessed 24 h post tMCAO. The potential of HDLs and the role of SR-BI to maintain the BBB integrity was assessed by using a human cellular model of BBB (hCMEC/D3 cell line) subjected to oxygen-glucose deprivation (OGD). HDL therapy limited the infarct volume and the BBB leakage in control mice relative to saline injection. Interestingly, these neuroprotective effects were thwarted by the deletion of SR-BI in endothelial cells and preserved in mice deficient for SR-BI in myeloid cells. In vitro studies revealed that HDLs can preserve the integrity of the BBB in OGD conditions, and that this effect was reduced by the SR-BI inhibitor, BLT-1. The protection of BBB integrity plays a pivotal role in HDL therapy of acute ischemic stroke. Our results show that this effect is partially mediated by the HDL receptor, SR-BI expressed by endothelial cells.

scholarly journals Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1860 ◽  
Author(s):  
Mark B. Plotnikov ◽  
Galina A. Chernysheva ◽  
Vera I. Smolyakova ◽  
Oleg I. Aliev ◽  
Eugene S. Trofimova ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Rat Model ◽  
Focal Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Specific Inhibitor ◽  
Fold Increase ◽  
Neuroprotective Activity ◽  
Prophylactic Regimen ◽  
Neuroprotective Effects

A novel specific inhibitor of c-Jun N-terminal kinase, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI.

scholarly journals Neuroprotective Effects of Danshen Chuanxiongqin Injection Against Ischemic Stroke: Metabolomic Insights by UHPLC-Q-Orbitrap HRMS Analysis

2021 ◽  
Vol 8 ◽  
Author(s):  
Peipei Zhou ◽  
Lin Zhou ◽  
Yingying Shi ◽  
Zhuolun Li ◽  
Liwei Liu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Brain Tissue ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Cerebral Infarct ◽  
Sphingolipid Metabolism ◽  
Neuroprotective Effects ◽  
Behavioral Abnormality

The incidence of cerebral ischemic stroke characterized by high mortality is increasing every year. Danshen Chuanxiongqin Injection (DSCXQ), a traditional Chinese medicine (TCM) preparation, is often applied to treat cerebral apoplexy and its related sequelae. However, there is a lack of systematic research on how DSCXQ mediates its protective effects against cerebral ischemia stroke. Metabolomic analysis based on UHPLC-Q-Orbitrap HRMS was employed to explore the potential mechanisms of DSCXQ on ischemic stroke induced by transient middle cerebral artery occlusion (MCAO). Pattern analysis and metabolomic profiling, combined by multivariate analysis disclosed that 55 differential metabolites were identified between Sham group and Model group, involving sphingolipid metabolism, glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, primary bile acid biosynthesis, pantothenate and CoA synthesis and valine, leucine and isoleucine biosynthesis pathways. DSCXQ could reverse brain metabolic deviations in stroke by significantly upregulating the levels of L-tryptophan, Lyso (18:0/0:0), LPC (18:2), Indole-3-methyl acetate, and downregulating the levels of sphinganine 1-phosphate, L-threonic acid, glutaconic acid and N6,N6,N6-Trimethyl-L-lysine. In our study, we focused on the neuroprotective effects of DSCXQ against neuroinflammatory responses and neuronal apoptosis on a stroke model based on sphingolipid metabolism. The expressions of Sphk1, S1PR1, CD62P, Bcl-2, Bax, and cleaved Caspase-3 in brain tissue were evaluated. The neurological deficit, cerebral infarct size and behavioral abnormality were estimated. Results showed that DSCXQ intervention significantly reduced cerebral infarct size, ameliorated behavioral abnormality, inhibited the expression of Sphk1, S1PR1, CD62P, Bax, Cleaved Caspase-3, while increased the level of Bcl-2, and prevented neuronal apoptosis. The limitations are that our study mainly focused on the verification of sphingolipid metabolism pathway in stroke, and while other metabolic pathways left unverified. Our study indicates that SphK1-SIP axis may potentiate neuroinflammatory responses and mediate brain damage through neuronal apoptosis, and DSCXQ could suppress the activity of SphK1-SIP axis to protect brain tissue in cerebral ischemia. In conclusion, this study facilitates our understanding of metabolic changes in ischemia stroke and the underlying mechanisms related to the clinical application of DSCXQ.

Neuroprotective Effects of Alisol A 24-acetate on Cerebral Ischemia-reperfusion Injury by Regulating PI3K/AKT Pathway

2021 ◽  
Author(s):  
Taotao Lu ◽  
Huihong Li ◽  
Yangjie Zhou ◽  
Wei Wei ◽  
Linlin Ding ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Brain Regions ◽  
Global Cerebral Ischemia ◽  
Akt Pathway ◽  
Object Recognition Test ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion

Abstract BackgroundNeuroinflammation and apoptosis are involved in the pathogenesis of ischemic stroke. Alisol A 24-acetate (24A) has a strong inhibitory effect on inflammation and cell apoptosis. The neuroprotective effect of 24A in the global cerebral ischemia/ reperfusion (GCI/R) is still unclear. Methods GCI/R mice was used to investigated the neuroprotective effect of 24A. Modified neurological deficit scores, Morris Water Maze and object recognition test were used to evaluate behaviors. The metabolism in brain regions was detected by MRS. The changes of microglia, astrocytes and neurons was detected. The inflammation and apoptosis were measured.Results The results showed that 24A improved behavioral dysfunction and brain metabolism, alleviate neuroinflammation and apoptosis, inhibited microglia and astrocytes activation, which is associated with the activation of PI3K/AKT pathway. ConclusionsTaken together, our study demonstrated that 24A could alleviate GCI/R injury through anti-neuroinflammation and anti-apoptosis via regulating the PI3K/AKT pathway.

N-Myc Downstream-Regulated Gene 2 (Ndrg2): A Critical Mediator of Estrogen-Induced Neuroprotection Against Cerebral Ischemic Injury

2021 ◽  
Author(s):  
Lixia Zhang ◽  
Yulong Ma ◽  
Min Liu ◽  
Miao Sun ◽  
Jin Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Male Mice ◽  
Neuroprotective Effects ◽  
Female Mice ◽  
Ndrg2 Expression ◽  
Cerebral Ischemic Injury ◽  
Cerebral Ischemic

Abstract Growing evidence indicates that estrogen plays a pivotal role in neuroprotection against cerebral ischemia, but the molecular mechanism of this protection is still elusive. N-myc downstream‐regulated gene 2 (Ndrg2), an estrogen-targeted gene, has been shown to exert neuroprotective effects against cerebral ischemia in male mice. However, the role of Ndrg2 in the neuroprotective effect of estrogen remains unknown. In this study, we first detected NDRG2 expression levels in the cortex and striatum in both female and male mice with western blot analyses. We then detected cerebral ischemic injury by constructing middle cerebral artery occlusion and reperfusion (MCAO-R) models in Ndrg2 knockout or conditional knockdown female mice. We further implemented estrogen, ERα or ERβ agonist replacement in the ovariectomized (OVX) Ndrg2 knockouts or conditional knockdowns female mice, then tested for NDRG2 expression, glial fibrillary acidic protein (GFAP) expression, and extent of cerebral ischemic injury. We found that NDRG2 expression was significantly higher in female than in male mice in both the cortex and striatum. Ndrg2 knockouts and conditional knockdowns showed significantly aggravated cerebral ischemic injury in female mice. Estrogen and ERβ replacement treatment (DPN) led to NDRG2 upregulation in both the cortex and striatum of OVX mice. Estrogen and DPN also led to GFAP upregulation in OVX mice. However, the effect of estrogen and DPN in activating astrocytes was lost in Ndrg2 knockouts OVX mice and primary cultured astrocytes, but partially retained in conditional knockdowns OVX mice. Most importantly, we found that the neuroprotective effects of E2 and DPN against cerebral ischemic injury were lost in Ndrg2 knockouts OVX mice but partially retained in conditional knockdowns OVX mice. These findings demonstrate that estrogen alleviated cerebral ischemic injury via ERβ upregulation of Ndrg2, which could activate astrocytes, indicating that Ndrg2 is a critical mediator of E2-induced neuroprotection against cerebral ischemic injury.

Abstract 173: The Neuroprotective Effect Of JZL184 is Comparable With Therapeutic Hypothermia in a Rat Model of Cardiac Arrest

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Jing Xu ◽  
Guanghui Zheng ◽  
Juntao Hu ◽  
Weiwei Ge ◽  
Jennifer Bradley ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Therapeutic Hypothermia ◽  
Rat Model ◽  
Neuroprotective Effect ◽  
Experimental Studies ◽  
Flow Index ◽  
Protective Effects ◽  
Cerebral Microcirculation ◽  
Sprague Dawley ◽  
Neuroprotective Effects

Introduction: JZL184 is a synthetic monoacylglycerol lipase inhibitor that reduces brain edema, infarct size and alleviates inflammation following cerebral ischemia in experimental studies. In this study, we compared its cerebral protective effects with therapeutic hypothermia following cardiopulmonary resuscitation (CPR) in a rat model. Hypothesis: JZL184 will have similar neuroprotective effects to therapeutic hypothermia after cardiac arrest (CA) by reducing brain and blood brain barrier (BBB) injury and preserving cerebral microcirculation following CPR. Methods: Thirty six male Sprague-Dawley rats weighing between 450-550 g were randomized: 1) control 2) hypothermia 3) JZL184. Ventricular fibrillation was induced and untreated for 6 min for all rats. Resuscitation was attempted with a 4 Joule defibrillation after 8 min of CPR. Immediately following resuscitation, either hypothermia (33+0.5 o C) or JZL184 (16 mg/k, IP) was administered. Cerebral microcirculation, S-100β, NSE and Evan’s Blue (EB) concentrations were analyzed at 6hrs after resuscitation. Results: NSE and S-100β levels were higher in control compared to hypothermia and JZL18 at 6hr post ROSC (p < 0.001) (Fig. 1). Compared with control, there was a significant decrease in brain permeability to EB in Hypothermia and JZL184 after 6hr post ROSC (p<0.001) (Fig. 2). Microvascular flow index (MFI) was reduced in control compared with hypothermia and JZL184 6hr post ROSC (p <0.01). Conclusions: JZL184 administered following resuscitation reduced brain and BBB injury and preserved cerebral microcirculation at 6 hr post arrest to the same extent as hypothermia in a rat model of cardiac arrest.

scholarly journals Sustained Blockade of Brain AT1 Receptors before and after Focal Cerebral Ischemia Alleviates Neurologic Deficits and Reduces Neuronal Injury, Apoptosis, and Inflammatory Responses in the Rat

2004 ◽  
Vol 24 (5) ◽  
pp. 536-547 ◽  
Author(s):  
Min Lou ◽  
Annegret Blume ◽  
Yi Zhao ◽  
Peter Gohlke ◽  
Günther Deuschl ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
At1 Receptor ◽  
Neuroprotective Effects ◽  
Reactive Microglia ◽  
At1 Receptors ◽  
Before And After

In the present study, we investigate whether a long-term blockade of brain AT1 receptors in male Wistar rats before and after ischemic injury exerts neuroprotective effects and modulates apoptosis and inflammatory responses, which are associated with the post-ischemic progression of brain damage. The AT1 receptor antagonist irbesartan was continuously infused intracerebroventricularly using osmotic minipumps over a 5-day period before and for 3 or 7 days after middle cerebral artery occlusion (MCAO) for 90 minutes. Neurologic status was evaluated daily, starting 24 hours after MCAO. After MCAO (3 and 7 days), brains were removed for the measurement of infarct size and immunohistochemical evaluation of apoptosis and accumulation of reactive microglia and macrophages. Treatment with irbesartan before ischemia improved motor functions, whereas post-ischemic treatment improved sensory functions. Blockade of brain AT1 receptors reduced the infarct size on days 3 and 7 after MCAO. In the peri-infarct cortex, irbesartan treatment decreased the number of apoptotic cells on day 3 and attenuated the invasion of activated microglia and macrophages on days 3 and 7 after ischemia. Long-term blockade of brain AT1 receptors improves the recovery from cerebral ischemia. Antiapoptotic mechanisms and inhibition of post-ischemic inflammation are involved in the AT1 receptor blockade-induced neuroprotective effects in ischemic brain tissue.

scholarly journals Neuroprotective effects of adenosine deaminase in the striatum

2016 ◽  
Vol 36 (4) ◽  
pp. 709-720 ◽  
Author(s):  
Risa Tamura ◽  
Hiroyuki Ohta ◽  
Yasushi Satoh ◽  
Shigeaki Nonoyama ◽  
Yasuhiro Nishida ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Adenosine Deaminase ◽  
Neuronal Damage ◽  
Brain Slices ◽  
Field Potential ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Negative Effect

Adenosine deaminase (ADA) is a ubiquitous enzyme that catabolizes adenosine and deoxyadenosine. During cerebral ischemia, extracellular adenosine levels increase acutely and adenosine deaminase catabolizes the increased levels of adenosine. Since adenosine is a known neuroprotective agent, adenosine deaminase was thought to have a negative effect during ischemia. In this study, however, we demonstrate that adenosine deaminase has substantial neuroprotective effects in the striatum, which is especially vulnerable during cerebral ischemia. We used temporary oxygen/glucose deprivation (OGD) to simulate ischemia in rat corticostriatal brain slices. We used field potentials as the primary measure of neuronal damage. For stable and efficient electrophysiological assessment, we used transgenic rats expressing channelrhodopsin-2, which depolarizes neurons in response to blue light. Time courses of electrically evoked striatal field potential (eFP) and optogenetically evoked striatal field potential (optFP) were recorded during and after oxygen/glucose deprivation. The levels of both eFP and optFP decreased after 10 min of oxygen/glucose deprivation. Bath-application of 10 µg/ml adenosine deaminase during oxygen/glucose deprivation significantly attenuated the oxygen/glucose deprivation-induced reduction in levels of eFP and optFP. The number of injured cells decreased significantly, and western blot analysis indicated a significant decrease of autophagic signaling in the adenosine deaminase-treated oxygen/glucose deprivation slices. These results indicate that adenosine deaminase has protective effects in the striatum.

Sign in / Sign up

Export Citation Format

Share Document