scholarly journals Nadph Oxidase Mediates Striatal Neuronal Injury after Transient Global Cerebral Ischemia

2010 ◽  
Vol 31 (3) ◽  
pp. 868-880 ◽  
Author(s):  
Hideyuki Yoshioka ◽  
Kuniyasu Niizuma ◽  
Masataka Katsu ◽  
Nobuya Okami ◽  
Hiroyuki Sakata ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nadph Oxidase ◽  
Late Phase ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Global Cerebral Ischemia ◽  
Striatal Neurons ◽  
Reactive Microglia ◽  
Transient Global Cerebral Ischemia

Medium spiny neurons (MSNs) constitute most of the striatal neurons and are known to be vulnerable to ischemia; however, the mechanisms of the vulnerability remain unclear. Activated forms of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (NOX), which require interaction between cytosolic and membrane-bound subunits, are among the major sources of superoxide in the central nervous system. Although increasing evidence suggests that NOX has important roles in neurodegenerative diseases, its roles in MSN injury after transient global cerebral ischemia (tGCI) have not been elucidated. To clarify this issue, C57BL/6 mice were subjected to tGCI by bilateral common carotid artery occlusion for 22 minutes. Western blot analysis revealed upregulation of NOX subunits and recruitment of cytosolic subunits to the cell membrane at early (3 to 6 hours) and late (72 hours) phases after tGCI. Taken together with immunofluorescent studies, this activation arose in MSNs and endothelial cells at the early phase, and in reactive microglia at the late phase. Pharmacological and genetic inhibition of NOX attenuated oxidative injury, microglial activation, and MSN death after tGCI. These findings suggest that NOX has pivotal roles in MSN injury after tGCI and could be a therapeutic target for brain ischemia.

scholarly journals Dynamics of pial vessels reactivity after brief cerebral ischemia

2015 ◽  
Vol 14 (1) ◽  
pp. 74-78 ◽  
Author(s):  
O. P. Gorshkova ◽  
M. V. Lensman ◽  
A. I. Artem'eva ◽  
D. P. Dvoretsky
Keyword(s):  
Cerebral Ischemia ◽  
Brain Perfusion ◽  
Artery Occlusion ◽  
Global Cerebral Ischemia ◽  
Pial Arteries ◽  
Pial Vessels ◽  
Transient Global Cerebral Ischemia ◽  
Pial Vessel ◽  
Arteries And Veins

Cerebral blood vessel reactivity is one of the main determinants of final outcome of brain ischemia. Most of studies on the vascular mechanisms of ischemic brain injury, however, focus on the acute changes within ischemic period or several hours after it. Dilatatory capacity of cerebral arterioles (perfusion reservoir) is considered as an important factor of brain perfusion elevation in critical situations.The aim of the present study was to examine the pial vessel reactivity in response to hypercapnia in rats, subjected to transient global cerebral ischemia, at 7, 14 and 21 days after ischemia. Materials and methods. Transient global cerebral ischemia was induced in anesthetized Wistar rats by bilateral common carotid artery occlusion for 12 min with simultaneous controlled hypotension to 45±3 mm Hg, followed by blood reinfusion and recovery from anesthesia. Three different groups of rats were re-anesthetized at 7, 14 or 21 days after ischemia and subjected to microvascular reactivity studies using in vivo video microscopy. Hypercapnia was caused by i.v. injection of acetazolamide. The changes in diameter of pial arteries and veins in response to hypercapnia were measured. Results and discussion. Global cerebral ischemia led to marked decrease in pial vessels (both arteries and veins) reactivity in response to hypercapnia, caused by i.v. injection of acetazolamide. In intact rats, i.v. injection of acetazolamide led to pial arteries dilation and pial veins constriction; in animals subjected to ischemia-reperfuion. the numbers of dilated large arteries and constricted small veins were much less, as well as the extent of arterial dilation. Reactivity changes were observed in all time points studied. Conclusions. Thus, transient global cerebral ischemia cause marked and long lasting (3 weeks) decrease in pial vessel reactivity in response to hypercapnia.

scholarly journals Neurovascular Coupling Varies with Level of Global Cerebral Ischemia in a Rat Model

2012 ◽  
Vol 33 (1) ◽  
pp. 97-105 ◽  
Author(s):  
Wesley B Baker ◽  
Zhenghui Sun ◽  
Teruyuki Hiraki ◽  
Mary E Putt ◽  
Turgut Durduran ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Carotid Artery ◽  
Electrical Response ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Laser Speckle ◽  
Global Cerebral Ischemia ◽  
Functional Responses ◽  
Bilateral Carotid

In this study, cerebral blood flow, oxygenation, metabolic, and electrical functional responses to forepaw stimulation were monitored in rats at different levels of global cerebral ischemia from mild to severe. Laser speckle contrast imaging and optical imaging of intrinsic signals were used to measure changes in blood flow and oxygenation, respectively, along with a compartmental model to calculate changes in oxygen metabolism from these measured changes. To characterize the electrical response to functional stimulation, we measured somatosensory evoked potentials (SEPs). Global graded ischemia was induced through unilateral carotid artery occlusion, bilateral carotid artery occlusion, bilateral carotid and right subclavian artery (SCA) occlusion, or carotid and SCA occlusion with negative lower body pressure. We found that the amplitude of the functional metabolic response remained tightly coupled to the amplitude of the SEP at all levels of ischemia observed. However, as the level of ischemia became more severe, the flow response was more strongly attenuated than the electrical response, suggesting that global ischemia was associated with an uncoupling between the functional flow and electrical responses.

scholarly journals iNOS-Derived NO and Nox2-Derived Superoxide Confer Tolerance to Excitotoxic Brain Injury through Peroxynitrite

2007 ◽  
Vol 27 (8) ◽  
pp. 1453-1462 ◽  
Author(s):  
Takayuki Kawano ◽  
Alexander Kunz ◽  
Takato Abe ◽  
Hélène Girouard ◽  
Josef Anrather ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Brain Injury ◽  
Nadph Oxidase ◽  
Cortical Neurons ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
No Donor ◽  
Inos Inhibitor ◽  
Common Carotid Artery Occlusion

Sublethal injurious stimuli induce tolerance to subsequent lethal insults, a phenomenon termed preconditioning. Inducible nitric oxide synthase (iNOS) is essential for the preconditioning induced by transient bilateral common carotid artery occlusion (BCCAO) or by systemic administration of the endotoxin lipopolysaccharide (LPS). We used a model of brain injury produced by neocortical injection of N-methyl-d-aspartate (NMDA) to investigate the mechanisms by which iNOS-derived nitric oxide (NO) contributes to tolerance induced by LPS or BCCAO. We found that the tolerance is blocked by the iNOS inhibitor aminoguanidine, is not observed in iNOS-null mice, and is rescued by the NO donor DTPA NONOate. Lipopolysaccharide failed to induce preconditioning in mice lacking the nox2 subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, suggesting that superoxide derived from NADPH oxidase is needed for the induction of the tolerance. Because superoxide reacts with NO to form peroxynitrite, we investigated the role of peroxynitrite. We found that LPS induces the peroxynitrite marker 3-nitrotyrosine in cortical neurons and that the peroxynitrite decomposition catalyst FeTPPS abolishes LPS-induced preconditioning. These results suggest that the protective effect of iNOS-derived NO is mediated by peroxynitrite formed by the reaction of NO with NADPH oxidase-derived superoxide. Thus, peroxynitrite, in addition to its well-established deleterious role in ischemic brain injury and neurodegeneration, can also be beneficial by inducing tolerance to excitotoxicity.

scholarly journals Study ofαB-Crystallin Expression in Gerbil BCAO Model of Transient Global Cerebral Ischemia

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Ting Li ◽  
Xiaoye Mo ◽  
Zheng Jiang ◽  
Wenfang He ◽  
Wei Lu ◽  
...  
Keyword(s):  
Small Heat Shock Protein ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Global Cerebral Ischemia ◽  
Slow Recovery ◽  
Glia Cells ◽  
Transient Global Cerebral Ischemia ◽  
Bilateral Carotid ◽  
Bilateral Carotid Artery Occlusion ◽  
Bilateral Carotid Artery

αB-crystallin (α-BC), the fifth member of mammalian small heat shock protein family (HspB5), is known to be expressed in many tissues and has a distinctive interaction with cytoskeleton components. In this study, we investigated thatα-BC and microtubule-associated protein-2 (MAP-2), a neuron-specific cytoskeleton protein, were coexpressed in neurons of Gerbil cortex, while in subcortex Gerbil brains, we found that several MAP-2-negative glia cells also expressα-BC. When subjected to 10-minute bilateral carotid artery occlusion (BCAO), an increment was observed inα-BC-positive cells after 6-hour reperfusion and peaked at around 7 days after. In the same circumstances, the number and the staining concentration of MAP-2 positive neurons significantly decreased immediately after 6-hour reperfusion, followed by a slow recovery, which is consistent with the increase ofα-BC. Our results suggested thatα-BC plays an important role in brain ischemia, providing the early protection of neurons by giving intracellular supports through the maintenance of cytoskeleton and extracellular supports through the protection of glia cells.

scholarly journals Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Haixia Wen ◽  
Luxi Li ◽  
Lixuan Zhan ◽  
Yunyan Zuo ◽  
Kongping Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Mitochondrial Membrane ◽  
Neuronal Damage ◽  
Late Phase ◽  
Global Cerebral Ischemia ◽  
Heat Shock Protein 60 ◽  
Inner Mitochondrial Membrane ◽  
Adult Rats ◽  
Transient Global Cerebral Ischemia ◽  
Hypoxic Postconditioning

AbstractMitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.

scholarly journals Capillary Flow and Diameter Changes during Reperfusion after Global Cerebral Ischemia Studied by Intravital Video Microscopy

2004 ◽  
Vol 24 (4) ◽  
pp. 383-391 ◽  
Author(s):  
Erik F. Hauck ◽  
Sebastian Apostel ◽  
Julie F. Hoffmann ◽  
Axel Heimann ◽  
Oliver Kempski
Keyword(s):  
Cerebral Ischemia ◽  
Capillary Flow ◽  
Fluorescein Isothiocyanate ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Global Cerebral Ischemia ◽  
Sham Operation ◽  
Cranial Window ◽  
Bilateral Carotid ◽  
Flow Velocities

The reaction of cerebral capillaries to ischemia is unclear. Based on Hossmann's observation of postischemic “delayed hypoperfusion,” we hypothesized that capillary flow is decreased during reperfusion because of increased precapillary flow resistance. To test this hypothesis, we measured cerebral capillary erythrocyte velocity and diameter changes by intravital microscopy in gerbils. A cranial window was prepared over the frontoparietal cortex in 26 gerbils anesthetized with halothane. The animals underwent either a sham operation or fifteen minutes of bilateral carotid artery occlusion causing global cerebral ischemia. Capillary flow velocities were measured by frame-to-frame tracking of fluorescein isothiocyanate labeled erythrocytes in 1800 capillaries after 1-hour reperfusion. Capillary flow velocities were decreased compared to control (0.25 ± 0.27mm/s vs. 0.76 ± 0.45 mm/s; P < 0.001). Precapillary arteriole diameters in reperfused animals were reduced to 76.3 ± 6.9% compared to baseline ( P < 0.05). Capillary diameters in reperfused animals (2.87 ± 0.97 μm) were reduced ( P < 0.001) compared to control (4.08 ± 1.19 μm). Similar reductions of precapillary (24%) and capillary vessel diameters (30%) and absolute capillary flow heterogeneity indicate that delayed (capillary) hypoperfusion occurs as a consequence of increased precapillary arteriole tone during reperfusion.

Changes in Smad1/5/9 expression and phosphorylation in astrocytes of the rat hippocampus after transient global cerebral ischemia

2021 ◽  
Vol 113 ◽  
pp. 101941
Author(s):  
Takayuki Nakajima ◽  
Yuji Kunieda ◽  
Yusuke Takahashi ◽  
Yuki Tanaka ◽  
Tomohiro Kondo ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Rat Hippocampus ◽  
Global Cerebral Ischemia ◽  
Transient Global Cerebral Ischemia

scholarly journals Inhibition of MLKL-dependent necroptosis via downregulating interleukin-1R1 contributes to neuroprotection of hypoxic preconditioning in transient global cerebral ischemic rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lixuan Zhan ◽  
Xiaomei Lu ◽  
Wensheng Xu ◽  
Weiwen Sun ◽  
En Xu
Keyword(s):  
Plasma Membrane ◽  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Interleukin 1 ◽  
Hypoxic Preconditioning ◽  
Global Cerebral Ischemia ◽  
Free Calcium ◽  
Membrane Translocation ◽  
Vessel Occlusion ◽  
Transient Global Cerebral Ischemia

Abstract Background Our previous study indicated that hypoxic preconditioning reduced receptor interacting protein (RIP) 3-mediated necroptotic neuronal death in hippocampal CA1 of adult rats after transient global cerebral ischemia (tGCI). Although mixed lineage kinase domain-like (MLKL) has emerged as a crucial molecule for necroptosis induction downstream of RIP3, how MLKL executes necroptosis is not yet well understood. In this study, we aim to elucidate the molecular mechanism underlying hypoxic preconditioning that inactivates MLKL-dependent neuronal necroptosis after tGCI. Methods Transient global cerebral ischemia was induced by the four-vessel occlusion method. Twenty-four hours before ischemia, rats were exposed to systemic hypoxia with 8% O2 for 30 min. Western blotting was used to detect the expression of MLKL and interleukin-1 type 1 receptor (IL-1R1) in CA1. Immunoprecipitation was used to assess the interactions among IL-1R1, RIP3, and phosphorylated MLKL (p-MLKL). The concentration of intracellular free calcium ion (Ca2+) was measured using Fluo-4 AM. Silencing and overexpression studies were used to study the role of p-MLKL in tGCI-induced neuronal death. Results Hypoxic preconditioning decreased the phosphorylation of MLKL both in neurons and microglia of CA1 after tGCI. The knockdown of MLKL with siRNA decreased the expression of p-MLKL and exerted neuroprotective effects after tGCI, whereas treatment with lentiviral delivery of MLKL showed opposite results. Mechanistically, hypoxic preconditioning or MLKL siRNA attenuated the RIP3-p-MLKL interaction, reduced the plasma membrane translocation of p-MLKL, and blocked Ca2+ influx after tGCI. Furthermore, hypoxic preconditioning downregulated the expression of IL-1R1 in CA1 after tGCI. Additionally, neutralizing IL-1R1 with its antagonist disrupted the interaction between IL-1R1 and the necrosome, attenuated the expression and the plasma membrane translocation of p-MLKL, thus alleviating neuronal death after tGCI. Conclusions These data support that the inhibition of MLKL-dependent neuronal necroptosis through downregulating IL-1R1 contributes to neuroprotection of hypoxic preconditioning against tGCI.

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