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

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000087091.01171.ae ◽

2003 ◽

Vol 23 (10) ◽

pp. 1160-1167 ◽

Cited By ~ 39

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.

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

Human Cell ◽

10.1007/s13577-021-00527-x ◽

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18794839 ◽

2018 ◽

Vol 39 (12) ◽

pp. 2406-2418 ◽

Cited By ~ 3

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600585 ◽

2007 ◽

Vol 28 (4) ◽

pp. 812-823 ◽

Cited By ~ 54

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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In Vitro and In Vivo Models of Cerebral Ischemia Show Discrepancy in Therapeutic Effects of M2 Macrophages

PLoS ONE ◽

10.1371/journal.pone.0067063 ◽

2013 ◽

Vol 8 (6) ◽

pp. e67063 ◽

Cited By ~ 31

Author(s):

Virginie Desestret ◽

Adrien Riou ◽

Fabien Chauveau ◽

Tae-Hee Cho ◽

Emilie Devillard ◽

...

Keyword(s):

Cerebral Ischemia ◽

Therapeutic Effects ◽

M2 Macrophages ◽

In Vivo Models

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A Novel and Potent Poly(ADP-Ribose) Polymerase-1 Inhibitor, FR247304 (5-Chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.104.066944 ◽

2004 ◽

Vol 310 (2) ◽

pp. 425-436 ◽

Cited By ~ 63

Author(s):

Akinori Iwashita ◽

Nobuteru Tojo ◽

Shigeru Matsuura ◽

Syunji Yamazaki ◽

Kazunori Kamijo ◽

...

Keyword(s):

Cerebral Ischemia ◽

Neuronal Damage ◽

In Vivo Models

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

Brain Research ◽

10.1016/s0006-8993(02)04058-1 ◽

2003 ◽

Vol 963 (1-2) ◽

pp. 214-223 ◽

Cited By ~ 10

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

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The Absorption, Distribution, and Excretion of 18 Elements of Tibetan Medicine Qishiwei Zhenzhu Pills in Rats with Cerebral Ischemia

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/4508533 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Yinglian Song ◽

Ke Fu ◽

Dewei Zhang ◽

Min Xu ◽

Ruixia Wu ◽

...

Keyword(s):

Cerebral Ischemia ◽

Inductively Coupled Plasma ◽

Microwave Digestion ◽

Venous Blood ◽

Artery Occlusion ◽

Tibetan Medicine ◽

Inductively Coupled ◽

Icp Ms

The aim of this study is to determine 18 elements in Tibetan medicine Qishiwei Zhenzhu pills (QSW) and their absorption, distribution, and excretion in rats with cerebral ischemia. Microwave digestion and inductively coupled plasma mass spectrometry (ICP-MS) were used to determine 18 elements of QSW in simulated gastrointestinal (GI) juice. Rats were given QSW (66.68 mg/kg) followed by middle cerebral artery occlusion (MCAO). Sham rats received saline and were not subjected to MCAO. ICP-MS was applied to determine the content of 18 elements in hepatic venous blood, abdominal aortic blood, brain, liver, kidney, hair, urine, and feces 24 h after MCAO. In vitro results showed that the extraction rate of Mn, Cu, Sr, Pb, Au, and Hg of QSW in gastric juice (1 h) was higher than that in water, and the contents of Cu, Au, Sr, and As were higher in intestinal juice (4 h) than in water. In vivo results showed that the contents of elements in the blood were quite low, and QSW increased Ni, Cr, Sr, Co, and V in artery blood and decreased V in venous blood. Elements in the tissues were also low, and QSW increased brain Li but decreased Cr and Cd; QSW increased kidney Ag and Cs and liver Mn but decreased liver Ni. QSW increased urinary excretion of Li, Sr, Hg, Cs, and V; QSW increased Hg content in hair but decreased Ni. Stool is the main excretion pathway of the elements in QSW, with Ba, Mn, Sr, Cd, V, Cu, Cs, Li, Pb, Ag, Hg, Cr, As, and Co the highest. In summary, this study examined the distribution of 18 elements in QSW-treated MCAO rats. The accumulation of these elements in blood and tissues was extremely low, and the majority was excreted in feces within 24 h, highlighting the importance of the gut-microbiota-brain axis in QSW-mediated brain protection.

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