scholarly journals Neuroprotective Effects of Insulin-Like Growth Factor-Binding Protein Ligand Inhibitors in Vitro and in Vivo

2003 ◽  
Vol 23 (10) ◽  
pp. 1160-1167 ◽  
Author(s):  
Kenneth B Mackay ◽  
Sarah A Loddick ◽  
Gregory S Naeve ◽  
Alicia M Vana ◽  
Gail M Verge ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Infarct Size ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Igf I

The role of brain insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in neuroprotection was further investigated using in vitro and in vivo models of cerebral ischemia by assessing the effects of IGF-I, IGF-II, and high affinity IGFBP ligand inhibitors (the peptide [Leu24, 59, 60, Ala31]hIGF-I (IGFBP-LI) and the small molecule NBI-31772 (1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6, 7-dihydroxyisoquinoline), which pharmacologically displace and elevate endogenous, bioactive IGFs from IGFBPs. Treatment with IGF-I, IGF-II, or IGFBP-LI (2 μg/mL) significantly ( P < 0.05) reduced CA1 damage in organotypic hippocampal cultures resulting from 35 minutes of oxygen and glucose deprivation by 71%, 60%, and 40%, respectively. In the subtemporal middle cerebral artery occlusion (MCAO) model of focal ischemia, intracerebroventricular (icv) administration of IGF-I and IGF-II at the time of artery occlusion reduced ischemic brain damage in a dose-dependent manner, with maximum reductions in total infarct size of 37% ( P < 0.01) and 38% ( P < 0.01), respectively. In this model of MCAO, icv administration of NBI-31772 at the time of ischemia onset also dose-dependently reduced infarct size, and the highest dose (100 μg) significantly reduced both total (by 40%, P < 0.01) and cortical (by 43%, P < 0.05) infarct volume. In the intraluminal suture MCAO model, administration of NBI-31772 (50 μg icv) at the time of artery occlusion reduced both cortical infarct volume (by 40%, P < 0.01) and brain swelling (by 24%, P < 0.05), and it was still effective when treatment was delayed up to 3 hours after the induction of ischemia. These results further define the neuroprotective properties of IGFs and IGFBP ligand inhibitors in experimental models of cerebral ischemia.

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 ROS-Dependent Neuroprotective Effects of NaHS in Ischemia Brain Injury Involves the PARP/AIF Pathway

2015 ◽  
Vol 36 (4) ◽  
pp. 1539-1551 ◽  
Author(s):  
Qian Yu ◽  
Zhihong Lu ◽  
Lei Tao ◽  
Lu Yang ◽  
Yu Guo ◽  
...  
Keyword(s):  
Brain Injury ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Ht22 Cells ◽  
In Vivo Models ◽  
The Brain

Background/Aims: Stroke is among the top causes of death worldwide. Neuroprotective agents are thus considered as potentially powerful treatment of stroke. Methods: Using both HT22 cells and male Sprague-Dawley rats as in vitro and in vivo models, we investigated the effect of NaHS, an exogenous donor of H2S, on the focal cerebral ischemia-reperfusion (I/R) induced brain injury. Results: Administration of NaHS significantly decreased the brain infarcted area as compared to the I/R group in a dose-dependent manner. Mechanistic studies demonstrated that NaHS-treated rats displayed significant reduction of malondialdehyde content, and strikingly increased activity of superoxide dismutases and glutathione peroxidase in the brain tissues compared with I/R group. The enhanced antioxidant capacity as well as restored mitochondrial function are NaHS-treatment correlated with decreased cellular reactive oxygen species level and compromised apoptosis in vitro or in vivo in the presence of NaHS compared with control. Further analysis revealed that the inhibition of PARP-1 cleavage and AIF translocation are involved in the neuroprotective effects of NaHS. Conclusion: Collectively, our results suggest that NaHS has potent protective effects against the brain injury induced by I/R. NaHS is possibly effective through inhibition of oxidative stress and apoptosis.

Neuroprotective effects of a new synthetic peptide, CMX-9236, in in vitro and in vivo models of cerebral ischemia

2003 ◽  
Vol 963 (1-2) ◽  
pp. 214-223 ◽  
Author(s):  
Victor E Shashoua ◽  
David S Adams ◽  
Anne Boyer-Boiteau ◽  
Ann Cornell-Bell ◽  
Fuhai Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Synthetic Peptide ◽  
Neuroprotective Effects ◽  
In Vivo Models

scholarly journals Cellular Origin and Regulation of D-and L-Serine in in Vitro and in Vivo Models of Cerebral Ischemia

2014 ◽  
Vol 34 (12) ◽  
pp. 1928-1935 ◽  
Author(s):  
Takato Abe ◽  
Masataka Suzuki ◽  
Jumpei Sasabe ◽  
Shinichi Takahashi ◽  
Miyuki Unekawa ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nmda Receptor ◽  
Cultured Cells ◽  
Long Term Potentiation ◽  
Artery Occlusion ◽  
In Vitro Experiments ◽  
In Vivo Models ◽  
Cellular Origin

D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-Serine from L-Serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-Serine remain elusive. The D-/L-Serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-Serine is derived from neurons, while L-Serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3-PGDH), which synthesizes L-Serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-Serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH.

scholarly journals Neuronal Estrogen Receptor-α Mediates Neuroprotection by 17β-Estradiol

2009 ◽  
Vol 30 (5) ◽  
pp. 935-942 ◽  
Author(s):  
Joachim G Elzer ◽  
Sajjad Muhammad ◽  
Tim M Wintermantel ◽  
Anne Regnier-Vigouroux ◽  
Jochen Ludwig ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Infarct Volume ◽  
Estrogen Receptor Α ◽  
Mutant Mice ◽  
In Vivo Model ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
17Β Estradiol

17β-Estradiol (E2) was shown to exert neuroprotective effects both in in vitro and in vivo models of stroke. Although these effects of E2 are known to require estrogen receptor-α (ERα), the cellular target of estrogen-mediated neuroprotection remains unknown. Using cell type-specific ER mutant mice in an in vivo model of stroke, we specifically investigated the role of ERα in neuronal cells versus its role in the microglia in the mediation of neuroprotection by estrogens. We generated and analyzed two different tissue-specific knockout mouse lines lacking ERα either in cells of myeloid lineage, including microglia, or in the neurons of the forebrain. Both E2-treated and E2-untreated mutant and control mice were subjected to a permanent middle cerebral artery occlusion for 48 h, and the infarct volume was quantified. Although the infarct volume of E2-treated female myeloid-specific ERα knockout mice was similar to that of E2-treated control mice, both male and female neuron-specific ERα mutant mice had larger infarcts than did control mice after E2 treatment. We conclude that neuronal ERα in female and male mice mediates neuroprotective estrogen effects in an in vivo mouse model of stroke, whereas microglial ERα is dispensable.

scholarly journals Neuroprotective effect of Danshensu derivatives as anti-ischaemia agents on SH-SY5Y cells and rat brain

2013 ◽  
Vol 33 (4) ◽  
Author(s):  
Sunisa Seetapun ◽  
Jia Yaoling ◽  
Yang Wang ◽  
Yi Zhun Zhu
Keyword(s):  
Rat Brain ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
In Vitro Study ◽  
Artery Occlusion ◽  
Neuroprotective Effects ◽  
Inhibit Lipid Peroxidation ◽  
Cysteine Derivative

Novel Danshensu derivatives (3–8) were designed and synthesized to improve bioactivity based on the strategy of ‘medicinal chemical hybridization’. Our previous studies indicated that these compounds exhibited noticeable cardioprotective activities. Here, we investigate whether these novel Danshensu derivatives exert neuroprotective activities. An in vitro study revealed that these compounds could increase cell viability and reduce LDH (lactate dehydrogenase) leakage. Moreover, Danshensu-cysteine derivative compounds 6 and 8 could significantly inhibit lipid peroxidation of cell membrane and regulate the expression of apoptosis-related protein (Bcl-2, Bax and caspase 3). An in vivo study demonstrated that treatment with compound 6 at 30 mg/kg markedly decreased the infarct volume of MCAO (middle cerebral artery occlusion) insulted rat brain. Furthermore, treatment with compound 6 showed the antioxidant capacity by increasing the activity of SOD (superoxide dismutase) and GPx (glutathione peroxidase) and decreasing the level of MDA (malondialdehyde) and the ROS (reactive oxygen species) production significantly. These results suggested that these novel conjugates exert significant neuroprotective effects as anti-ischaemia agents and those with high potential merit further investigation.

RTN1-C mediates cerebral ischemia/reperfusion injury via modulating autophagy

2020 ◽  
Author(s):  
Jun Ling ◽  
Haijian Cai ◽  
Muya Lin ◽  
Shunli Qi ◽  
Jian Du ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Cerebral Ischemia Reperfusion

Abstract It has been widely accepted that autophagic cell death exacerbates the progression of cerebral ischemia/reperfusion (I/R). Our previous study revealed that overexpression of reticulon protein 1-C (RTN1-C) is involved in cerebral I/R injury. However, the underlying mechanisms have not been studied intensively. This study was designed to evaluate the effect of RTN1-C on autophagy under cerebral I/R. Using an in vitro oxygen-glucose deprivation followed by reoxygenation and a transient middle cerebral artery occlusion model in rats, we found that the expression of RTN1-C protein was significantly upregulated. We also revealed that RTN1-C knockdown suppressed overactivated autophagy both in vivo and in vitro, as indicated by decreased expressions of autophagic proteins. The number of Beclin-1/propidium iodide-positive cells was significantly less in the LV-shRTN1-C group than in the LV-shNC group. In addition, rapamycin, an activator of autophagy, aggravated cerebral I/R injury. RTN1-C knockdown reduced brain infarct volume, improved neurological deficits, and attenuated cell vulnerability to cerebral I/R injury after rapamycin treatment. Taken together, our findings demonstrated that the modulation of autophagy from RTN1-C may play vital roles in cerebral I/R injury, providing a potential therapeutic treatment for ischemic brain injury.

Neuroprotective effects of a novel water-soluble poly(ADP-ribose) polymerase-1 inhibitor, MP-124, in in vitro and in vivo models of cerebral ischemia

2011 ◽  
Vol 1389 ◽  
pp. 169-176 ◽  
Author(s):  
Yasuhiro Egi ◽  
Shigeru Matsuura ◽  
Tomoyuki Maruyama ◽  
Masakazu Fujio ◽  
Satoshi Yuki ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Water Soluble ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Soluble Poly

scholarly journals LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3

Human Cell ◽  
2021 ◽  
Author(s):  
Jiaying Zhu ◽  
Zhu Zhu ◽  
Yipin Ren ◽  
Yukang Dong ◽  
Yaqi Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Mice Model ◽  
Down Regulation

AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

scholarly journals The Rapid Decrease in Astrocyte-Associated Dystroglycan Expression by Focal Cerebral Ischemia is Protease-Dependent

2007 ◽  
Vol 28 (4) ◽  
pp. 812-823 ◽  
Author(s):  
Richard Milner ◽  
Stephanie Hung ◽  
Xiaoyun Wang ◽  
Maria Spatz ◽  
Gregory J del Zoppo
Keyword(s):  
Cerebral Ischemia ◽  
Basal Lamina ◽  
Focal Cerebral Ischemia ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Receptor Expression ◽  
Cerebral Microvessels ◽  
The Impact

During focal cerebral ischemia, the detachment of astrocytes from the microvascular basal lamina is not completely explained by known integrin receptor expression changes. Here, the impact of experimental ischemia (oxygen—glucose deprivation (OGD)) on dystroglycan expression by murine endothelial cells and astrocytes grown on vascular matrix laminin, perlecan, or collagen and the impact of middle cerebral artery occlusion on αβ-dystroglycan within cerebral microvessels of the nonhuman primate were examined. Dystroglycan was expressed on all cerebral microvessels in cortical gray and white matter, and the striatum. Astrocyte adhesion to basal lamina proteins was managed in part by α-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro. Furthermore, dystroglycan and integrin α6β4 expressions on astrocyte end-feet decreased in parallel both in vivo and in vitro. The rapid loss of astrocyte dystroglycan during OGD appears protease-dependent, involving an matrix metalloproteinase-like activity. This may explain the rapid detachment of astrocytes from the microvascular basal lamina during ischemic injury, which could contribute to significant changes in microvascular integrity.

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