Peroxynitrite Formation in Focal Cerebral Ischemia—Reperfusion in Rats Occurs Predominantly in the Peri-Infarct Region

Fukuyama, Naoto; Takizawa, Shunya; Ishida, Hideyuki; Hoshiai, Kiyotaka; Shinohara, Yukito; Nakazawa, Hiroe

doi:10.1097/00004647-199802000-00001

Cited by 115 publications

(61 citation statements)

References 42 publications

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“…FR210575 reduced cortical infarct volume by 36% compared with vehicle treated control. The neuroprotective effect of FR210575 was more prominent in the cortex than in the striatum, consistent with previous reports concerning neuroprotectants in stroke models (Schmid-Elsaesser et al, 2000), and the observation that free radical formation in focal cerebral ischemia-reperfusion in rats occurs predominantly in the peri-infarct region (Fukuyama et al, 1998). Furthermore, our results could also be compatible with the observation that SOD activity Fig.…”

Section: Discussionsupporting

confidence: 93%

A Novel Potent Radical Scavenger, 8-(4-Fluorophenyl)-2-((2E)-3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine (FR210575), Prevents Neuronal Cell Death in Cultured Primary Neurons and Attenuates Brain Injury after Focal Ischemia in Rats

Iwashita¹,

Maemoto²,

Nakada³

et al. 2003

J Pharmacol Exp Ther

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Reactive oxygen species (ROS) play a vital role in brain damage after cerebral ischemia-reperfusion injury, and ROS scavengers have been shown to exert neuroprotective effects against ischemic brain injury. We have recently identified 8-(4-fluorophenyl)-2-((2E)-3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (FR210575) as a novel, powerful freeradical scavenger. In the present study, the neuroprotective efficacy of FR210575 was evaluated in two neuronal death models in vitro as well as rat focal cerebral ischemia models in vivo. In the first model, primary cortical cultures were exposed to a high oxygen atmosphere (50% O 2 ) for 48 h to induce cell death with apoptotic features. Treatment with FR210575 (10 Ϫ7 -10 Ϫ5 M) significantly inhibited neuronal death. The second model used a growth-factor withdrawal paradigm. Withdrawal of TIP (transferrin, insulin, putrescine and progesterone)-supplemented medium induced apoptotic cell death after 2 days, but treatment with FR210575 exhibited dramatic protection against neuronal death. In two models of cerebral ischemia [photothrombotic occlusion of middle cerebral artery (MCA) for transient model and by permanent MCA occlusion for permanent model], rats received 3-h intravenous infusion (1-10 mg/kg/3 h) of FR210575, with brain damage determined 24 h later. FR210575 (3.2 mg/kg/3 h) significantly reduced the volume of focal damage in the cortex by 36% in the transient model and also reduced the size of ischemic brain damage in the permanent model. These findings indicate that the powerful radical scavenger FR210575 has potent neuroprotective activity and that FR210575 could be an attractive candidate for the treatment of stroke or other neurodegenerative disorders.Oxidative stress is important in neuronal degeneration, including in cerebrovascular injuries such as stroke, neuropathology such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, as well as in a normal aging (Facchinetti et al., 1998). Reactive oxygen species (ROS) are critical factors for inducing neuronal damage in vitro and in vivo. For example, deprivation of survival factors results in an increase in the cellular levels of ROS (Lieberthal et al., 1998) and subsequent cellular apoptosis, both of which can be blocked by antioxidants or ROS scavengers (Atabay et al., 1996). It has been shown that normal mammalian cells are dependent upon the presence of specific growth factors for maintenance of viability. In the absence of those survival factors, these cells die by apoptosis (Raff, 1992). High-oxygen-induced neuronal death of embryonic neurons is a useful in vitro model of apoptosis (Enokido and Hatanaka, 1993;Ratan et al., 1994). Increases in ROS levels occur in this model, and specific nitric oxide radical scavengers block apoptosis (Satoh et al., 1998;Ishikawa et al., 1999). The brain is particularly susceptible to radical-mediated neuronal damage because of high levels of oxygen consumption unsaturated fatty acids and iron stores, combined with...

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Section: Discussionsupporting

confidence: 93%

A Novel Potent Radical Scavenger, 8-(4-Fluorophenyl)-2-((2E)-3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine (FR210575), Prevents Neuronal Cell Death in Cultured Primary Neurons and Attenuates Brain Injury after Focal Ischemia in Rats

Iwashita¹,

Maemoto²,

Nakada³

et al. 2003

J Pharmacol Exp Ther

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“…Alone, hyperglycemia increases both superoxide (O 2 Ϫ ) and NO levels, driving the production of the cytotoxic radical ONOO Ϫ while reducing NO bioavailability within the vasculature ; however, ONOO Ϫ is also generated during ischemia/reperfusion (Fukuyama et al, 1998;Gursoy-Ozdemir et al, 2004). Peroxynitrite is capable of thiol oxidation and tyrosine nitration, both of which can alter the function of enzymes and other cellular components (Fukuyama et al, 1998;Turko and Murad, 2002).…”

Section: Cerebrovascular Reactivity and Oxidative Stress In Diabetes 411mentioning

confidence: 99%

Cerebral Myogenic Reactivity and Blood Flow in Type 2 Diabetic Rats: Role of Peroxynitrite in Hypoxia-Mediated Loss of Myogenic Tone

Kelly-Cobbs¹,

Prakash²,

Coucha³

et al. 2012

J Pharmacol Exp Ther

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Dysregulation of cerebral vascular function and, ultimately, cerebral blood flow (CBF) may contribute to complications such as stroke and cognitive decline in diabetes. We hypothesized that 1) diabetes-mediated neurovascular and myogenic dysfunction impairs CBF and 2) under hypoxic conditions, cerebral vessels from diabetic rats lose myogenic properties because of peroxynitrite (ONOO Ϫ )-mediated nitration of vascular smooth muscle (VSM) actin. Functional hyperemia, the ability of blood vessels to dilate upon neuronal stimulation, and myogenic tone of isolated middle cerebral arteries (MCAs) were assessed as indices of neurovascular and myogenic function, respectively, in 10-to 12-week control and type 2 diabetic Goto-Kakizaki rats. In addition, myogenic behavior of MCAs, nitrotyrosine (NY) levels, and VSM actin content were measured under normoxic and hypoxic [oxygen glucose deprivation (OGD)] conditions with and without the ONOO Ϫ decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl) prophyrinato iron (III), chloride (FeTPPs). The percentage of myogenic tone was higher in diabetes, and forced dilation occurred at higher pressures. Functional hyperemia was impaired. Consistent with these findings, baseline CBF was lower in diabetes. OGD reduced the percentage of myogenic tone in both groups, and FeTPPs restored it only in diabetes. OGD increased VSM NY in both groups, and although FeTPPs restored basal levels, it did not correct the reduced filamentous/globular (F/G) actin ratio. Acute alterations in VSM ONOO Ϫ levels may contribute to hypoxic myogenic dysfunction, but this cannot be solely explained by the decreased F/G actin ratio due to actin nitration, and mechanisms may differ between control and diabetic animals. Our findings also demonstrate that diabetes alters the ability of cerebral vessels to regulate CBF under basal and hypoxic conditions.

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“…After ischemiareperfusion, superoxide anion and OH radicals and hydrogen peroxide are produced by infiltrating phagocytes and vascular and glial cells. 38,39 Furthermore, peroxynitrite is generated by the interaction between the superoxide anion and nitric oxide, promoting lipid peroxidation, mitochondrial membrane and DNA damage, activation or inhibition of multiple signaling pathways, and BBB disruption. 38,40,41 We assumed that RNP Figure 6.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 Furthermore, peroxynitrite is generated by the interaction between the superoxide anion and nitric oxide, promoting lipid peroxidation, mitochondrial membrane and DNA damage, activation or inhibition of multiple signaling pathways, and BBB disruption. 38,40,41 We assumed that RNP Figure 6. Radical-containing nanoparticle (RNP) improved multiple reactive oxygen species (ROS) scavenging capacities in the ischemic brain.…”

Section: Discussionmentioning

confidence: 99%

Neurovascular Unit Protection From Cerebral Ischemia–Reperfusion Injury by Radical-Containing Nanoparticles in Mice

Hosoo

Marushima

Nagasaki

et al. 2017

Stroke

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C erebral large vessel occlusion is a life-threatening disease and causes neurological disorders. In addition to early recanalization with intravenous tissue plasminogen alteplase injection, multiple randomized control trials have recently demonstrated the efficacy and safety of mechanical thrombectomy using a stent retriever.1-6 However, reactive oxygen species (ROS) generation increases during reperfusion, which impairs survival and aggravates neurological function because of secondary brain injury, including hemorrhage in the ischemic area and brain edema. The functional disability rate was 30% to 70% after mechanical thrombectomy, and symptomatic hemorrhagic complication rate was up to 10%. [1][2][3][4][5][6] Oxidative stress suppression after reperfusion is a potential therapeutic strategy and can improve survival and the functional prognosis. Nitroxide (NO) radicals are free radical scavengers with known neuroprotective functions against cerebral ischemia in rodent models.7-9 The 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) is a stable Background and Purpose-Reperfusion therapy by mechanical thrombectomy is used to treat acute ischemic stroke.However, reactive oxygen species generation after reperfusion therapy causes cerebral ischemia-reperfusion injury, which aggravates cerebral infarction. There is limited evidence for clinical efficacy in stroke for antioxidants. Here, we developed a novel core-shell type nanoparticle containing 4-amino-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (nitroxide radical-containing nanoparticles [RNPs]) and investigated its ability to scavenge reactive oxygen species and confer neuroprotection. Methods-C57BL/6J mice underwent transient middle cerebral artery occlusion and then received RNPs (9 mg/kg) through the common carotid artery. Infarction size, neurological scale, and blood-brain barrier damage were visualized by Evans blue extravasation 24 hours after reperfusion. RNP distribution was detected by rhodamine labeling. Blood-brain barrier damage, neuronal apoptosis, and oxidative neuronal cell damage were evaluated in ischemic brains. Multiple free radicalscavenging capacities were analyzed by an electron paramagnetic resonance-based method. Results-RNPs were detected in endothelial cells and around neuronal cells in the ischemic lesion. Infarction size, neurological scale, and Evans blue extravasation were significantly lower after RNP treatment. RNP treatment preserved the endothelium and endothelial tight junctions in the ischemic brain; neuronal apoptosis, O 2 − production, and gene oxidation were significantly suppressed. Reactive oxygen species scavenging capacities against OH, ROO, and O 2 − improved by RNP treatment. Conclusions-An intra-arterial RNP injection after cerebral ischemia-reperfusion injury reduced blood-brain barrier damage and infarction volume by improving multiple reactive oxygen species scavenging capacities. Therefore, RNPs can provide neurovascular unit protection. Visual Overview-An online visual overview is available for this a...

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Peroxynitrite Formation in Focal Cerebral Ischemia—Reperfusion in Rats Occurs Predominantly in the Peri-Infarct Region

Cited by 115 publications

References 42 publications

A Novel Potent Radical Scavenger, 8-(4-Fluorophenyl)-2-((2E)-3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine (FR210575), Prevents Neuronal Cell Death in Cultured Primary Neurons and Attenuates Brain Injury after Focal Ischemia in Rats

A Novel Potent Radical Scavenger, 8-(4-Fluorophenyl)-2-((2E)-3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine (FR210575), Prevents Neuronal Cell Death in Cultured Primary Neurons and Attenuates Brain Injury after Focal Ischemia in Rats

Cerebral Myogenic Reactivity and Blood Flow in Type 2 Diabetic Rats: Role of Peroxynitrite in Hypoxia-Mediated Loss of Myogenic Tone

Neurovascular Unit Protection From Cerebral Ischemia–Reperfusion Injury by Radical-Containing Nanoparticles in Mice

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