scholarly journals Netrin-1 Overexpression Promotes White Matter Repairing and Remodeling after Focal Cerebral Ischemia in Mice

2013 ◽  
Vol 33 (12) ◽  
pp. 1921-1927 ◽  
Author(s):  
Xiaosong He ◽  
Yaning Li ◽  
Haiyan Lu ◽  
Zhijun Zhang ◽  
Yongting Wang ◽  
...  
Keyword(s):  
White Matter ◽  
Gene Transfer ◽  
Negative Impact ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Neural Function ◽  
Oligodendrocyte Progenitor Cells ◽  
Neurobehavioral Outcomes ◽  
Deleted In Colorectal Carcinoma ◽  
Cerebral Artery Occlusion

Damage of oligodendrocytes after ischemia has negative impact on white matter integrity and neuronal function. In this work, we explore whether Netrin-1 (NT-1) overexpression facilitates white matter repairing and remodeling. Adult CD-1 mice received stereotactic injection of adeno-associated virus carrying NT-1 gene ( AAV-NT-1). One week after gene transfer, mice underwent 60 minutes of middle cerebral artery occlusion. The effect of NT-1 on neural function was evaluated by neurobehavioral tests. Proliferated oligodendrocyte progenitor cells (OPCs), newly matured oligodendrocytes, and remyelination were semi-quantified by immunohistochemistry. The role of NT-1 in oligodendrogenesis was further explored by examining specific NT-1 receptors and their function. Netrin-1 overexpression was detected in neurons and astrocytes 2 weeks after AAV-NT-1 gene transfer and significantly improved the neurobehavioral outcomes compared with the control ( P<0.05). In comparison with the control, proliferated OPCs, newly matured oligodendrocytes, and remyelination were greatly increased in the ipsilateral hemisphere of AAV-NT-1-transduced mice. Furthermore, both NT-1 receptors deleted in colorectal carcinoma and UNC5H2 were expressed on OPCs whereas only UNC5H2 was expressed in myelinated axons. Our study indicated that NT-1 promoted OPC proliferation, differentiation, and increased remyelination, suggesting that NT-1 is a promising factor for white matter repairing and remodeling after ischemia.

Abstract WP115: Netrin-1 Promotes Oligodendrogenesis After Experimental Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Xiaosong He ◽  
Yongting Wang ◽  
Yaning Li ◽  
Yifang Lv ◽  
Yaohui Tang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
White Matter ◽  
Gene Transfer ◽  
Neural Development ◽  
Treated Group ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
Neurobehavioral Outcomes

Introduction: oligodendrocyte injury after ischemic stroke influences the integrity of white matter, which ultimately leads to neurological deficits. Netrin-1 (NT-1) plays a crucial role in axon guidance during neural development. Also, it promotes oligodendrocyte progenitor cell proliferation. Our previous study demonstrates that netrin-1 overexpression improves neurobehavioral outcomes after ischemia by promoting focal angiogenesis. In this study, we investigate whether netrin-1 facilitates white matter recovery during focal ischemia and further to explore which specific receptor involves in the white matter reconstruction. Methods: sixty adult male ICR mice underwent adeno-associated virus (AAV) mediated AAV-Netrin-1 or AAV-GFPgene transfer. These mice received one hour transient middle artery occlusion (MCAO) and 7, 14, 28 days reperfusion at one week after the gene transfer. Western blot and immunohischemistry were used to determine the location and quantification of exogenous NT-1 expression. Neuronalbehavior test were performed to eveluate the neuralbehavioral outcomes. Oligodendrocyte progenietor cell proliferation, maturation and myelination were examined by immunohischemistry. Results: NT-1 was highly expressed in the mouse brain after two weeks of AAV-NT-1 gene transfer, which mainly expressed in neurons and astrocytes. Neurobehavioral outcomes were greatly improved at 7, 14 and 28 days after reperfusion in AAV-NT-1 treated mice compared to the GFP control mice ( p <0.05), The number of proliferated oligodendrocyte progenietor cells, mature oligodendrocytes and MBP positive neurofilaments in the corpus callosum and the striatum in the ipsilateral hemisphere at 7, 14 and 28 days after reperfusion were increased in the NT-1 treated group compared to GFP control mice ( p <0.01). NT-1 receptor DCC and Unc5H2 are involved in the proliferation of oligodendrocyte progenitor cells,But only Unc5h2 was involved in the re-myelination process. Conclusion: NT-1 overexpression improves neurobehavioral outcomes and promotes oligodendrocyte progenietor cell proliferation and maturation. Oue results suggest that netrin-1 not only promotes angiogenesis but also enchances remyelination.

Rapid Alteration of Tau in Oligodendrocytes After Focal Ischemic Injury in the Rat: Involvement of Free Radicals

1997 ◽  
Vol 17 (6) ◽  
pp. 612-622 ◽  
Author(s):  
Elaine A. Irving ◽  
Kazutaka Yatsushiro ◽  
James McCulloch ◽  
Deborah Dewar
Keyword(s):  
White Matter ◽  
Spin Trap ◽  
Focal Cerebral Ischemia ◽  
Subcortical White Matter ◽  
Artery Occlusion ◽  
Time Dependent ◽  
Mk 801 ◽  
Protein Tau ◽  
Glutamate Receptor Antagonists ◽  
Cerebral Artery Occlusion

Glial inclusions containing the microtubule-associated protein tau are present in a variety of chronic neurodegenerative conditions. We now report a rapid and time-dependent increase of tau immunoreactivity within oligodendrocytes after focal cerebral ischemia in the rat. The number of tau positive oligodendrocytes in the ipsilateral subcortical white matter increased six- to eightfold by 40 minutes after permanent middle cerebral artery occlusion (MCAO). Tau was detected using antibodies that label both the N- and C-terminal of the protein, suggesting accumulation of full-length protein within these cells. Pretreatment with the spin trap agent α-phenyl-tert-butyl-nitrone (PBN)(100mg/kg) reduced the number of tau-positive oligodendrocytes by 55% in the subcortical white matter of the ischemic hemisphere compared with untreated animals at 40 minutes after MCAO. In contrast, pretreatment with glutamate receptor antagonists MK-801 (0.5 mg/kg) or 2,3-dihydroxy-6-nitro-7-sulpfamoylbenzo(f)quinoxaline (NBQX) (2 × 30 mg/kg), failed to reduce the number of tau-positive oligodendrocytes after 40 minutes of ischemia. The results indicate that oligodendrocytes respond rapidly to an ischemic challenge and that free radical-mediated mechanisms are involved in the cascade leading to increased tau immunoreactivity.

scholarly journals Increased serum QUIN/KYNA is a reliable biomarker of post-stroke cognitive decline

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Adrien Cogo ◽  
Gabrielle Mangin ◽  
Benjamin Maïer ◽  
Jacques Callebert ◽  
Mikael Mazighi ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Artery ◽  
Quinolinic Acid ◽  
Neuronal Death ◽  
Artery Occlusion ◽  
Serum Biomarkers ◽  
Diabetic Mice ◽  
Stroke Patients ◽  
Cerebral Artery Occlusion

Abstract Background Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments. As patients survive longer, post-stroke cognitive impairment (PSCI) has become a major health public issue. Diabetes has been identified as an independent predictive factor for PSCI. Here, we characterized a clinically relevant mouse model of PSCI, induced by permanent cerebral artery occlusion in diabetic mice, and investigated whether a reliable biomarker of PSCI may emerge from the kynurenine pathway which has been linked to inflammatory processes. Methods Cortical infarct was induced by permanent middle cerebral artery occlusion in male diabetic mice (streptozotocin IP). Six weeks later, cognitive assessment was performed using the Barnes maze, hippocampi long-term potentiation using microelectrodes array recordings, and neuronal death, white matter rarefaction and microglia/macrophages density assessed in both hemispheres using imunohistochemistry. Brain and serum metabolites of the kynurenin pathway were measured using HPLC and mass fragmentography. At last, these same metabolites were measured in the patient’s serum, at the acute phase of stroke, to determine if they could predict PSCI 3 months later. Results We found long-term spatial memory was impaired in diabetic mice 6 weeks after stroke induction. Synaptic plasticity was completely suppressed in both hippocampi along with increased neuronal death, white matter rarefaction in both striatum, and increased microglial/macrophage density in the ipsilateral hemisphere. Brain and serum quinolinic acid concentrations and quinolinic acid over kynurenic acid ratios were significantly increased compared to control, diabetic and non-diabetic ischemic mice, where PSCI was absent. These putative serum biomarkers were strongly correlated with degradation of long-term memory, neuronal death, microglia/macrophage infiltration and white matter rarefaction. Moreover, we identified these same serum biomarkers as potential predictors of PSCI in a pilot study of stroke patients. Conclusions we have established and characterized a new model of PSCI, functionally and structurally, and we have shown that the QUIN/KYNA ratio could be used as a surrogate biomarker of PSCI, which may now be tested in large prospective studies of stroke patients.

scholarly journals Relation of Apparent Diffusion Coefficient Changes and Metabolic Disturbances after 1 Hour of Focal Cerebral Ischemia and at Different Reperfusion Phases in Rats

2001 ◽  
Vol 21 (4) ◽  
pp. 430-439 ◽  
Author(s):  
Laszlo Olah ◽  
Stefan Wecker ◽  
Mathias Hoehn
Keyword(s):  
Energy Metabolism ◽  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Atp Depletion ◽  
Apparent Diffusion ◽  
Tissue Acidosis ◽  
Cerebral Artery Occlusion ◽  
Energy Failure

Changes in apparent diffusion coefficients (ADC) were compared with alterations of adenosine triphosphate (ATP) concentration and pH in different phases of transient focal cerebral ischemia to study the ADC threshold for breakdown of energy metabolism and tissue acidosis during ischemia and reperfusion. Male Wistar rats underwent 1 hour of middle cerebral artery occlusion without recirculation (n = 3) or with 1 hour (n = 4) or 10 hours of reperfusion (n = 5) inside the magnet, using a remotely controlled thread occlusion model. ADC maps were calculated from diffusion-weighted images and normalized to the preischemic value to obtain relative ADC maps. Hemispheric lesion volume (HLV) was determined on the last relative ADC maps at different relative ADC thresholds and was compared to the HLV measured by ATP depletion and by tissue acidosis. The HLVs, defined by ATP depletion and tissue acidosis, were 26.0% ± 10.6% and 38.1% ± 6.5% at the end of ischemia, 3.3% ± 2.4% and 4.8% ± 3.5% after 1 hour of reperfusion, and 11.2% ± 4.7% and 10.9% ± 5.2% after 10 hours of recirculation, respectively. The relative ADC thresholds for energy failure were consistently approximately 77% of the control value in the three different groups. The threshold for tissue acidosis was higher at the end of ischemia (86% of control) but was similar to the results obtained for ATP depletion after 1 hour (78% of control) and 10 hours (76% of control) of recirculation. These results indicate that the described relative ADC threshold of approximately 77% of control provides a good estimate for the breakdown of energy metabolism not only during middle cerebral artery occlusion but also at the early phase of reperfusion, when recovery of energy metabolism is expected to occur, or some hours later, when development of secondary energy failure was described.

scholarly journals Leukocyte-Endothelium Interactions during Permanent Focal Cerebral Ischemia in Mice

2004 ◽  
Vol 24 (6) ◽  
pp. 668-676 ◽  
Author(s):  
Hiroharu Kataoka ◽  
Seong-Woong Kim ◽  
Nikolaus Plesnila
Keyword(s):  
Cerebral Ischemia ◽  
Brain Damage ◽  
Molecular Mechanisms ◽  
Focal Cerebral Ischemia ◽  
Fluorescent Microscopy ◽  
Capillary Density ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
Adherent Leukocytes

The contribution of leukocyte infiltration to brain damage after permanent focal cerebral ischemia and the underlying molecular mechanisms are still unclear. Therefore, the aim of this study was to establish a mouse model for the visualization of leukocytes in the cerebral microcirculation in vivo and to investigate leukocyte-endothelial interaction (LEI) after permanent middle cerebral artery occlusion (MCAO). Sham-operated 129/Sv mice showed physiologic LEI in pial venules as observed by intravital fluorescent microscopy. Permanent focal cerebral ischemia induced a significant increase of LEI predominantly in pial venules. The number of rolling and adherent leukocytes reached 36.5 ± 13.2/100 μm × min and 22.5 ± 7.9/100 μm × min, respectively at 120 minutes after MCAO ( P = 0.016 vs. control). Of note, rolling and adherent leukocytes were also observed in arterioles of ischemic animals (7.3 ± 3.0/100 μm × min rolling and 3.0 ± 3.6/100 μm × min adherent). Capillary density was not different between groups. These results demonstrate that leukocytes accumulate in the brain not only after transient but also after permanent focal cerebral ischemia and may therefore contribute to brain damage after stroke without reperfusion.

Abstract W MP91: Supply-demand Mismatch Transients Trigger Peri-infarct Depolarizations In Ischemic Penumbra

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Daniel von Bornstädt ◽  
Jessica Seidel ◽  
Mathias Bernard Houben ◽  
Ergin Dilekoz ◽  
Tao Qin ◽  
...  
Keyword(s):  
Tactile Stimulation ◽  
Focal Cerebral Ischemia ◽  
Sensory Stimulation ◽  
Artery Occlusion ◽  
Cortical Activation ◽  
Normobaric Hyperoxia ◽  
Critical Range ◽  
O2 Supply ◽  
Cerebral Artery Occlusion ◽  
Distal Middle Cerebral Artery

Background: Peri-infarct depolarizations (PIDs) worsen the outcome of ischemic stroke. Unlike their impact on metabolism and perfusion, triggering factors are virtually unknown. We hypothesized that transient worsening of O2 supply-demand mismatch precipitates a PID in critically hypoperfused penumbra. Methods: We optically imaged cortical blood flow and oxygenation during distal middle cerebral artery occlusion in mice under full systemic physiological monitoring, and tested whether a transient (5 min) drop in O2 supply (hypotension or hypoxia) or increase in O2 demand (somatosensory cortical activation) can trigger PIDs during acute focal cerebral ischemia. Results: Transient hypotension (<70 mmHg) or hypoxia (<90 mmHg) triggered a PID 90% of the time (p<0.01). Increasing the O2 demand by functional activation (tactile stimulation) of moderately ischemic cortex (contralesional forepaw or shoulder S1) increased the 5-min incidence of PIDs by approximately five-fold (p=0.001). Cortical oxyhemoglobin levels dropped by 35-40% in the activated S1 immediately before a PID (p=0.004) confirming increased O2 demand. Cortical foci from which PIDs originated during tactile stimulation had 27-32% residual CBF, indicating the presence of a critical range of ischemia vulnerable to PID initiation upon increased demand. Consistently, activation of non-ischemic cortex (hindpaw S1) or severely ischemic cortex (whisker S1) did not significantly increase the PID rate. Both tetrodotoxin (1 μM topical) and normobaric hyperoxia prevented somatosensory triggering of PIDs. Conclusion: PIDs are triggered upon O2 supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. We propose that minimizing sensory stimulation and hypoxic or hypotensive transients in the early stages of stroke and brain injury would reduce PID incidence and their adverse impact on outcome.

Blocking A1 astrocyte conversion with semaglutide attenuates blood-brain barrier disruption in mice after middle cerebral artery occlusion

2021 ◽  
Author(s):  
Qi Zhang ◽  
Chang Liu ◽  
Rubing Shi ◽  
Huimin Shan ◽  
Lidong Deng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Signaling Pathways ◽  
Middle Cerebral Artery Occlusion ◽  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Rna Seq ◽  
Neurobehavioral Outcomes ◽  
Cerebral Artery Occlusion

Abstract Background Astrocytes play an essential role in the modulation of blood-brain barrier function. Neurological diseases induce astrocytes to transform into a neurotoxic A1 phenotype, thus exacerbating brain injury. However, the effect of A1 astrocyte on the function of BBB after stroke is unknown. Method: Adult male ICR mice (n = 78) were subjected to 90-minute transient middle cerebral artery occlusion. Immunohistochemical staining of A1 (C3d) and A2 (S100A10) was performed to characterize phenotypic changes of astrocytes overtime after stroke. Glucagon-like peptide-1 receptor agonist semaglutide was intraperitoneally injected into the mice to inhibit A1 astrocyte. Infarct volume, atrophy volume, neurobehavioral outcomes, and BBB permeability were examined. RNA-seq was adopted to explore the potential targets and signaling pathways of A1 astrocytes induced BBB dysfunction. Results Astrocytes assumed the A2 phenotype at the early stage of ischemic stroke but gradually transformed to the A1 phenotype. Semaglutide treatment reduced M1 microglia polarization and A1 astrocytes conversion after ischemic stroke (p < 0.05). Ischemia induced brain infarct volume, atrophy volume and neuroinflammation were reduced in the semaglutide treated mice. Neurobehavioral outcomes were improved compared to the control mice (p < 0.05). Further study demonstrated that semaglutide treatment reduced the gap formation of tight junction proteins ZO-1, claudin-5 and occludin, as well as IgG leakage following three days of ischemic stroke (p < 0.05). In vitro experiments revealed that A1 astrocyte-conditioned medium disrupted BBB integrity. RNA-seq further showed that A1 astrocytes were enriched in inflammatory factors and chemokines, as well as significantly modulating TNF and chemokine signaling pathways, which are closely related to barrier damage. Conclusion We concluded that astrocytes undergo a conversion from A2 phenotype to A1 phenotype overtime after ischemic stroke. A1 astrocytes aggravated BBB disruption, suggesting that block of A1 astrocytes conversion provides a novel strategy for the treatment of ischemic stroke.

scholarly journals Adenovirus-Mediated Gene Transfer of Glial Cell Line-Derived Neurotrophic Factor Prevents Ischemic Brain Injury after Transient Middle Cerebral Artery Occlusion in Rats

1999 ◽  
Vol 19 (12) ◽  
pp. 1336-1344 ◽  
Author(s):  
Hisashi Kitagawa ◽  
Chihoko Sasaki ◽  
Kenichi Sakai ◽  
Atsushi Mori ◽  
Yasuhide Mitsumoto ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Brain Injury ◽  
Gene Transfer ◽  
Neurotrophic Factor ◽  
Treated Group ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Gdnf Gene ◽  
Cerebral Artery Occlusion

To examine a possible protective effect of exogenous glial cell line-derived neurotrophic factor (GDNF) gene expression against ischemic brain injury, a replication-defective adenoviral vector containing GDNF gene (Ad-GDNF) was directly injected into the cerebral cortex at 1 day before 90 minutes of transient middle cerebral artery occlusion (MCAO) in rats. 2,3,5-Triphenyltetrazolium chloride staining showed that infarct volume of the Ad-GDNF-injected group at 24 hours after the transient MCAO was significantly smaller than that of vehicle- or Ad-LacZ-treated group. Enzyme-linked immunosorbent assay (ELISA) for immunoreactive GDNF demonstrated that GDNF gene products in the Ad-GDNF-injected group were higher than those of vehicle-treated group at 24 hours after transient MCAO. Immunoreactive GDNF staining was obviously detected in the cortex around the needle track just before or 24 hours after MCAO in the Ad-GDNF group, whereas no or slight GDNF staining was detected in the vehicle group. The numbers of TUNEL, immunoreactive caspase-3, and cytochrome c-positive neurons induced in the ipsilateral cerebral cortex at 24 hours after transient MCAO were markedly reduced by the Ad-GDNF group. These results suggest that the successful exogenous GDNF gene transfer ameliorates ischemic brain injury after transient MCAO in association with the reduction of apoptotic signals.

scholarly journals Cortical Spreading Depression Protects against Subsequent Focal Cerebral Ischemia in Rats

1996 ◽  
Vol 16 (2) ◽  
pp. 221-226 ◽  
Author(s):  
Kazushi Matsushima ◽  
Matthew J. Hogan ◽  
Antoine M. Hakim
Keyword(s):  
Cerebral Ischemia ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Occipital Cortex ◽  
Artery Occlusion ◽  
Microdialysis Probe ◽  
Cerebral Artery Occlusion ◽  
Subcortical Infarct

The possibility that cortical spreading depression (CSD) may have neuroprotective action during subsequent focal cerebral ischemia was examined in rats. Three days before the imposition of focal cerebral ischemia CSDs were elicited by applying potassium chloride (KCl) for 2 h through a microdialysis probe implanted in the occipital cortex. Control animals were handled identically except that saline was infused instead of KCl. Focal ischemia was produced by the intraluminal suture method and cortical and subcortical infarct volumes were measured 7 days later. Neocortical infarct volume was reduced from 124.8 ± 49.5 mm3 in the controls to 62.9 ± 59.5 mm3 in the animals preconditioned with CSD (p = 0.012). There was no difference between the two groups in the subcortical infarct volume or in CBF, measured by the hydrogen clearance method, during or immediately after the ischemic interval. Our data indicate that preconditioning CSD applied 3 days before middle cerebral artery occlusion may increase the brain's resistance to focal ischemic damage and may be used as a model to explore the neuroprotective molecular responses of neuronal and glial cells.

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