1,8-cineole ameliorates ischaemic brain damage via TRPC6/CREB pathways in rats

2021 ◽  
Author(s):  
Chen Meng ◽  
Wenjing Zeng ◽  
Jing Lv ◽  
Yu Wang ◽  
Meiling Gao ◽  
...  
Keyword(s):  
Brain Damage ◽  
Transient Receptor Potential ◽  
Infarct Volume ◽  
Glucose Deprivation ◽  
Neurological Dysfunction ◽  
Male Rats ◽  
Neuroprotective Effects ◽  
Ischaemic Brain

Abstract Objectives A previous in vitro study reported that the monoterpene oxide 1,8-cineole (cineole) attenuates neuronal caused by oxygen–glucose deprivation/reoxygenation in culture. However, to date, there is no in vivo evidence showing neuroprotective effects of cineole against stroke. This study aimed to investigate whether cineole attenuates cerebral ischaemic damage in rats. Methods A rat model of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion was applied. Male rats were treated with oral cineole (100 mg/kg) for 7 consecutive days, then subjected to MCAO surgery. Infarct volume, neurologic deficits, apoptosis and expression levels of all-spectrin breakdown products of 145 kDa (SBDP145), transient receptor potential canonical (subtype) 6 (TRPC6) and phosphorylated CREB (p-CREB) were measured in ischaemic brain tissues. Key findings Cineole treatment significantly reduced infarct volume, neurological dysfunction, neuronal apoptosis, SBDP145 formation and TRPC6 degradation and enhanced p-CREB expression in MCAO rats compared with vehicle treatment. These neuroprotective effects were markedly suppressed by pharmacological inhibition of MEK or CaMKIV signalling. Conclusions Our study provides in vivo evidence demonstrating that cineole pretreatment attenuates ischaemic stroke-induced brain damage, mainly through blocking calpain-induced TRPC6 degradation and activating CREB via MEK/CREB and CaMKIV/CREB signalling pathways.

Abstract TP96: Neuroprotective Effects of IGF-1 in Middle-Aged Females Can Be Replicated by Antagomirs to microRNA (miR)-92b and miR-33a

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Shameena Bake ◽  
Homa Khosravian ◽  
Farida Sohrabji
Keyword(s):  
Infarct Volume ◽  
Cell Monolayer ◽  
Glucose Deprivation ◽  
Stroke Recovery ◽  
Female Rats ◽  
Middle Aged ◽  
Neuroprotective Effects ◽  
Lectin Staining

Background: Our previous studies show that intracerebroventricular (ICV) delivery of Insulin-like growth factor (IGF)-1 reduces MCAo-induced infarction in middle-aged female rats. Analysis of ischemic tissue at 4h showed that IGF1 treatment significantly reduced the expression of a group of miRNAs. To determine if inhibiting these miRNAs could replicate IGF-1-mediated neuroprotection, we examined the effects of antagomirs to miR-33a (A-mir33a) and miR-92b (A-mir92b) in in vivo and in vitro models of ischemia. Methods: Middle-aged (12 mo) acyclic female rats were subject to intraluminal MCAo for 90 min followed by reperfusion. Animals received a single tail vein injection of A-miR-33a, A-miR-92b, A-miR-33a+A-miR-92b or scrambled oligos (7ug/kg bwt) after 4h of reperfusion. We evaluated infarct volume (TTC staining) at 2d post stroke and behavioral recovery using neurological scores and adhesive removal test (ART). In parallel, human brain endothelial cell cultures were exposed to oxygen-glucose deprivation (OGD) in the presence of A-mir-33a, A-mir-92b or scrambled oligos. The integrity of the cell monolayer was assessed by tomato-lectin staining and cell death was assayed by LDH. Results: Single injection of A-mir92b during the acute stroke phase reduced infarct volume (p<0.04) and improved sensorimotor behavior (p<0.04) while A-mir33a treated animals were not different from scrambled control. However, the combination of A-mir-33a+A-mir-92b resulted in significantly smaller infarct volumes (p<0.04), less motor impairment (neurological score; p<0.02) and sensorimotor deficits (ART; p<0.05). In vitro studies showed that neither of the antagomirs reduced media LDH under OGD. As reported previously, OGD caused cell retraction and A-mir33a notably preserved the cell geometry (continuous lectin staining) to maintain the monolayer integrity and was similar to the normoxic control. Conclusions: IGF-1 regulated microRNAs appear to modulate specific aspects of stroke recovery. IV delivery of a combination of miRNA inhibitors may replicate the neuroprotective actions of IGF-1, thus providing a safer alternate to ICV delivery of IGF-1. Supported by R56 NS074895 and RF1 AG04218906

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.

scholarly journals Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke

2021 ◽  
Vol 118 (32) ◽  
pp. e2018850118
Author(s):  
Hiroo Takahashi ◽  
Ryo Asahina ◽  
Masayuki Fujioka ◽  
Takeshi K. Matsui ◽  
Shigeki Kato ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cortical Neurons ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Small Gtpase ◽  
Neuroprotective Effects ◽  
Necessary And Sufficient ◽  
Activity Dependent

Ischemic stroke, which results in loss of neurological function, initiates a complex cascade of pathological events in the brain, largely driven by excitotoxic Ca2+ influx in neurons. This leads to cortical spreading depolarization, which induces expression of genes involved in both neuronal death and survival; yet, the functions of these genes remain poorly understood. Here, we profiled gene expression changes that are common to ischemia (modeled by middle cerebral artery occlusion [MCAO]) and to experience-dependent activation (modeled by exposure to an enriched environment [EE]), which also induces Ca2+ transients that trigger transcriptional programs. We found that the activity-dependent transcription factor Npas4 was up-regulated under MCAO and EE conditions and that transient activation of cortical neurons in the healthy brain by the EE decreased cell death after stroke. Furthermore, both MCAO in vivo and oxygen-glucose deprivation in vitro revealed that Npas4 is necessary and sufficient for neuroprotection. We also found that this protection involves the inhibition of L-type voltage-gated Ca2+ channels (VGCCs). Next, our systematic search for Npas4-downstream genes identified Gem, which encodes a Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of L-type VGCCs to inhibit excess Ca2+ influx, thereby protecting neurons from excitotoxic death after in vitro and in vivo ischemia. Collectively, our findings indicate that Gem expression via Npas4 is necessary and sufficient to promote neuroprotection in the injured brain. Importantly, Gem is also induced in human cerebral organoids cultured under an ischemic condition, revealing Gem as a new target for drug discovery.

scholarly journals The Neuroprotective Effects of Insulin-Like Growth Factor 1 via the Hippo/YAP Signaling Pathway is Mediated by the PI3K/AKT Pathway Following Cerebral Ischemia-Reperfusion Injury

2021 ◽  
Author(s):  
Pian Gong ◽  
Yichun Zou ◽  
Wei Zhang ◽  
Qi Tian ◽  
Shoumeng Han ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Neuronal Death ◽  
Infarct Volume ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Neuroprotective Effects

Abstract Insulin-like growth factor 1 (IGF-1) exhibits neuroprotective properties, such as vasodilatory and anti-inflammatory effects following ischemic stroke. However, the specific molecular mechanisms of action of IGF-1 following ischemic stroke remain elusive. We wanted to explore whether IGF-1 regulates Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT signaling pathway to exert its neuroprotective effects following ischemic stroke. In the in vitro study, we used oxygen–glucose deprivation to injure cultured PC12 and SH-5YSY cells, and cortical primary neurons. Cell viability was measured using CCK-8 assay. For the in vivo analyses, Sprague–Dawley rats were subjected to middle cerebral artery occlusion; neurological function was assessed using the neurological deficit score; infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis was evaluated by TUNEL staining, H&E staining and Nissl staining. Western blot was used to measure the levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. We found that IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and decreased neurological deficits, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were reversed by an inhibitor of the PI3K/AKT signaling pathway, LY294002, which not only reduced expressions of PI3K and p-AKT, but also down-regulated expression of YAP/TAZ, leading to aggravation of neurological dysfunction. These findings indicate that neuroprotective effect of IGF-1 is partly realized by up-regulation of YAP/TAZ, which is mediated by activation of the PI3K/AKT signaling pathway following cerebral ischemic stroke.

scholarly journals Neuroprotective Effects of Ginsenosides against Cerebral Ischemia

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1102 ◽  
Author(s):  
Zhekang Cheng ◽  
Meng Zhang ◽  
Chengli Ling ◽  
Ying Zhu ◽  
Hongwei Ren ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Neurological Dysfunction ◽  
Control Group ◽  
Protective Effects ◽  
Ginsenoside Rb1 ◽  
Neuroprotective Effects

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

Abstract 44: Hdac3i Alleviated Ischemic Stroke Injury Through Modulating Aim2 Inflammasome and Microglia Polarization

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Meijuan Zhang ◽  
Mingxu Xia ◽  
Qiuchen Zhao ◽  
Yun Xu
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Glucose Deprivation ◽  
Vehicle Group ◽  
Triphenyltetrazolium Chloride ◽  
Bv2 Cells ◽  
Severity Scores ◽  
Microglia Polarization

Background: Inflammasome in microglia are critical to elicit inflammatory cascades in ischemic stroke. Histone deacetylases 3 (HDAC3) regulate acetylation states of histone and non-histone proteins and could be a powerful regulator of inflammatory process in stroke. Methods: Primary microglia, BV2 cells subjected to oxygen glucose deprivation (OGD) or LPS stimulation were applied to mimic inflammatory response in vitro . Middle cerebral artery occlusion (MCAO) model were applied to mimic acute stroke in vivo . Ischemic infarct volume and neurological functions were evaluated through 2,3,5-triphenyltetrazolium chloride (TTC) staining and Neurological Severity Scores (NSS) respectively. Expression of HDAC3, AIM2 inflammasome were detected by western blotting, PCR. Immunofluorescence was used to detect M1/M2 polarization. Luciferase activity of absent in melanoma 2 (AIM2) reporter promoter constructs was measured by fluorospectrophotometer. AIM2 knockdown and over-expression leti-virus were constructed to decrease or increase AIM2 expression. HDAC3 inhibitor RGFP966 was used to inhibit acetylation activity of HDAC3. Results: HDAC3 is widely distributed in cerebral cortex, lateral ventricular , hippocampus, cerebellar cortex ; HDAC3 and AIM2 expression were enhanced in LPS stimulated-microglia and MCAO model. A marked stimulatory effect of RGFP966 on H3K9Ac was observed in nuclear extracts form BV2 cells at the dosage of 15 uM. Treatment of RGFP966 increased both IL-4-stimulated expression of Ym-1 and CD206 at 4 h, 10 h, 24 h, 48 h. AIM2, NLRP-1 and NLRP3 significantly increased in MCAO+Vehicle group compared to sham group, but decreased in MCAO+RGFP966 group. RGFP966 inhibited the elevation of circulatory IL-18 and IL-1β induced by stroke. RGFP966 decreased infracted size and alleviated neurological deficit. Conclusions: HDAC3i alleviated ischemic stroke injury through modulating AIM2 inflammasome and microglia polarization. Selective HDAC3 inhibitor-RGFP966 could be a potential medication for combating ischemic brain injury.

scholarly journals A Probable Dual Mode of Action for Both L- and D-Lactate Neuroprotection in Cerebral Ischemia

2015 ◽  
Vol 35 (10) ◽  
pp. 1561-1569 ◽  
Author(s):  
Ximena Castillo ◽  
Katia Rosafio ◽  
Matthias T Wyss ◽  
Konstantin Drandarov ◽  
Alfred Buck ◽  
...  
Keyword(s):  
Alternative Energy ◽  
Receptor Agonist ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Receptor Expression ◽  
Neuroprotective Effects ◽  
Energy Substrate ◽  
Deprivation Model

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

scholarly journals Protective Effects of Aqueous Extract ofLuehea divaricataagainst Behavioral and Oxidative Changes Induced by 3-Nitropropionic Acid in Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Aline Alves Courtes ◽  
Letícia Priscila Arantes ◽  
Rômulo Pillon Barcelos ◽  
Ingrid Kich da Silva ◽  
Aline Augusti Boligon ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Aqueous Extract ◽  
Antioxidant Properties ◽  
Male Rats ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Nitropropionic Acid ◽  
3 Nitropropionic Acid

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease. Accordingly, 3-nitropropionic acid (3-NP) has been found to effectively produce HD-like symptoms.Luehea divaricata(L. divaricata), popularly known in Brazil as “açoita-cavalo,” may act as a neuroprotective agentin vitroandin vivo. We evaluated the hypothesis that the aqueous extract ofL. divaricatacould prevent behavioral and oxidative alterations induced by 3-NP in rats. 25 adult Wistar male rats were divided into 5 groups: (1) control, (2)L. divaricata(1000 mg/kg), (3) 3-NP, (4)L. divaricata(500 mg/kg) + 3-NP, and (5)L. divaricata(1000 mg/kg) + 3-NP. Groups 2, 4, and 5 receivedL. divaricatavia intragastric gavage daily for 10 days. Animals in groups 3, 4, and 5 received 20 mg/kg 3-NP daily from days 8–10. At day 10, parameters of locomotor activity and biochemical evaluations were performed. Indeed, rats treated with 3-NP showed decreased locomotor activity compared to controls. Additionally, 3-NP increased levels of reactive oxygen species and lipid peroxidation and decreased ratio of GSH/GSSG and acetylcholinesterase activity in cortex and/or striatum. Our results suggest that rats pretreated withL. divaricataprior to 3-NP treatment showed neuroprotective effects when compared to 3-NP treated controls, which may be due to its antioxidant properties.

scholarly journals Inhibition of microRNA-181 Reduces Forebrain Ischemia-Induced Neuronal Loss

2013 ◽  
Vol 33 (12) ◽  
pp. 1976-1982 ◽  
Author(s):  
Jeong-mi Moon ◽  
Lijun Xu ◽  
Rona G Giffard
Keyword(s):  
Cell Death ◽  
Neuronal Survival ◽  
Infarct Volume ◽  
Glutamate Transporter ◽  
Neuronal Loss ◽  
Male Rats ◽  
Global Cerebral Ischemia ◽  
Forebrain Ischemia

MicroRNA (miRNA), miR-181a, is enriched in the brain, and inhibition of miR-181a reduced astrocyte death in vitro and infarct volume after stroke in vivo. This study investigated the role of miR-181a in neuronal injury in vitro and hippocampal neuronal loss in vivo after forebrain ischemia. miR-181a levels were altered by transfection with mimic or antagomir. N2a cells subjected to serum deprivation and oxidative stress showed less cell death when miR-181a was reduced and increased death when miR-181a increased; protection was associated with increased Bcl-2 protein. In contrast, transfected primary neurons did not show altered levels of cell death when miR-181a levels changed. Naive male rats and rats stereotactically infused with miR-181a antagomir or control were subjected to forebrain ischemia and cornus ammonis (CA)1 neuronal survival and protein levels were assessed. Forebrain ischemia increased miR-181a expression and decreased Bcl-2 protein in the hippocampal CA1 region. miR-181a antagomir reduced miR-181a levels, reduced CA1 neuronal loss, increased Bcl-2 protein, and significantly prevented the decrease of glutamate transporter 1. Thus, miR-181a antagomir reduced evidence of astrocyte dysfunction and increased CA1 neuronal survival. miR-181a inhibition is thus a potential target in the setting of forebrain or global cerebral ischemia as well as focal ischemia.

scholarly journals Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy

2021 ◽  
Vol 22 (13) ◽  
pp. 6898
Author(s):  
Karol Chojnowski ◽  
Mikolaj Opielka ◽  
Wojciech Nazar ◽  
Przemyslaw Kowianski ◽  
Ryszard T. Smolenski
Keyword(s):  
Ischemic Stroke ◽  
Brain Ischemia ◽  
Excitatory Amino Acid ◽  
Infarct Volume ◽  
In Vivo Studies ◽  
Amino Acid Transporters ◽  
Tissue Slices ◽  
Neuroprotective Effects

Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue slices or cell lines subjected to ischemic conditions demonstrated that Guo counteracts destructive events that occur during ischemic conditions, e.g., glutaminergic excitotoxicity, reactive oxygen and nitrogen species production. Moreover, Guo mitigates neuroinflammation and regulates post-translational processing. Guo asserts its neuroprotective effects via interplay with adenosine receptors, potassium channels, and excitatory amino acid transporters. Subsequently, guanosine activates several prosurvival molecular pathways including PI3K/Akt (PI3K) and MEK/ERK. Due to systemic degradation, the half-life of exogenous Guo is relatively low, thus creating difficulty regarding adequate exogenous Guo distribution. Nevertheless, in vivo studies performed on ischemic stroke rodent models provide promising results presenting a sustained decrease in infarct volume, improved neurological outcome, decrease in proinflammatory events, and stimulation of neuroregeneration through the release of neurotrophic factors. In this comprehensive review, we discuss molecular signaling related to Guo protection against brain ischemia. We present recent advances, limitations, and prospects in exogenous guanosine therapy in the context of ischemic stroke.

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