Protective effects of free radical inhibitors in intracerebral hemorrhage in rat

Peeling, James; Yan, Hui-Jin; Chen, Shang-Gong; Campbell, Mark; Bigio, Marc R. Del

doi:10.1016/s0006-8993(98)00253-4

Cited by 79 publications

(48 citation statements)

References 34 publications

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“…80,140,143,145 Once released from RBCs, hemoglobin is degraded into heme and iron, causing injury to surrounding cells. 95,133,139,157 Cytotoxicity Thrombin has been shown to induce various components of the complement system, an enzymatic cascade of blood and cell surface proteins. Thrombin primarily activates complement C3d and C9.…”

Section: Red Blood Cell Lysismentioning

confidence: 99%

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

Babu¹,

Bagley²,

Di³

et al. 2012

FOC

165

138

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Intracerebral hemorrhage (ICH) is a subtype of stoke that may cause significant morbidity and mortality. Brain injury due to ICH initially occurs within the first few hours as a result of mass effect due to hematoma formation. However, there is increasing interest in the mechanisms of secondary brain injury as many patients continue to deteriorate clinically despite no signs of rehemorrhage or hematoma expansion. This continued insult after primary hemorrhage is believed to be mediated by the cytotoxic, excitotoxic, oxidative, and inflammatory effects of intraparenchymal blood. The main factors responsible for this injury are thrombin and erythrocyte contents such as hemoglobin. Therapies including thrombin inhibitors, N-methyl-D-aspartate antagonists, chelators to bind free iron, and antiinflammatory drugs are currently under investigation for reducing this secondary brain injury. This review will discuss the molecular mechanisms of brain injury as a result of intraparenchymal blood, potential targets for therapeutic intervention, and treatment strategies currently in development.

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Section: Red Blood Cell Lysismentioning

confidence: 99%

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

Babu¹,

Bagley²,

Di³

et al. 2012

FOC

165

138

View full text Add to dashboard Cite

show abstract

“…Peeling et al 6 found some improvement in neurologic deficits when dimethylurea or ␣-phenyl-N-tert-butylnitrone was given 2 hours after ICH in a rat (collagenase) model, but there was no effect on edema. Peeling et al 6 also found that NXY-059, a free radical-trapping agent, improved neurologic deficits and reduced inflammation in the rat collagenase ICH model.…”

Section: Effect Of Edaravone On Ich-induced Brain Injurymentioning

confidence: 99%

“…5 There is some limited evidence that free radicals may be a target for reducing ICH-induced brain injury. 6,7 The purpose of the current study was to examine whether systemic edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free-radical scavenger (particularly of hydroxyl radicals), could reduce iron-, thrombin-, and ICH-induced brain edema and behavioral deficits in a rat model. Edavarone (Mitsubishi Pharma Corp) has been used in patients with acute cerebral infarction in Japan.…”

mentioning

confidence: 99%

Edaravone Attenuates Brain Edema and Neurologic Deficits in a Rat Model of Acute Intracerebral Hemorrhage

Nakamura

Kuroda

Yamashita

et al. 2008

Stroke

130

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Background and Purpose-Our previous studies have demonstrated that oxidative DNA injury occurs in the brain after intracerebral hemorrhage (ICH). We therefore examined whether edaravone, a free-radical scavenger, could reduce ICH-induced brain injury. Methods-These experiments used pentobarbital-anesthetized, male Sprague-Dawley rats that received an infusion of either 100 L autologous whole blood (ICH), FeCl 2 , or thrombin into the right basal ganglia. The rats were humanely killed 24 hours later. There were 4 sets of experiments. In the first, the dose-dependent effects of edaravone on ICH-induced brain injury were examined by measuring brain edema and neurologic deficits. In the second set, apurinic/apyrimidinic abasic sites and 8-hydroxyl-2Ј-deoxyguanosine, which are hallmarks of DNA oxidation, were investigated after treatment for ICH. In the third, the effect of delayed treatment with edaravone on ICH-induced injury was determined, whereas the fourth examined the effects of edaravone on iron-and thrombin-induced brain injury. Results-Systemic administration of edaravone immediately or 2 hours after ICH reduced brain water content 24 hours after ICH compared with vehicle (PϽ0.05). Edaravone treatment immediately or 2 hours after ICH also ameliorated neurologic deficits (PϽ0.05). Edaravone also attenuated ICH-induced changes in apurinic/apyrimidinic abasic sites and 8-hydroxyl-2Ј-deoxyguanosine and reduced iron-and thrombin-induced brain injury. Conclusions-Edaravone attenuates ICH-induced brain edema, neurologic deficits, and oxidative injury. It also reduces iron-and thrombin-induced brain injury. These results suggest that edaravone is a potential therapeutic agent for ICH.

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“…TS-011, at doses of 0.001, 0.01, and 0.1 mg/kg i.v., or vehicle (10% hydroxypropyl-␤ cyclodextrin) was administered immediately after collagenase injection. Twenty-four hours later, circling behavior, beam walking, and forelimb extension tests were performed to access the degree of motor dysfunction according to the method of Peeling et al (1998). Higher neurologic deficit score denotes more severely impaired function.…”

Section: Effects Of Pretreatment Of Rats With Ts-011 On the Acute Falmentioning

confidence: 99%

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Miyata

Seki²,

Tanaka³

et al. 2005

J Pharmacol Exp Ther

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The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-NЈ-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC 50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC 50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 M. TS-011 (0.01-1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.Each year, 750,000 strokes occur in the United States. Approximately 80% of the strokes are ischemic, and 20% are hemorrhagic. Hemorrhagic stroke commonly occurs after rupture of aneurysms or head trauma. There is an initial period of cerebral ischemia lasting several hours due to a rise in cerebral spinal fluid (CSF) pressure and acute cerebral vasospasm. One-half of the patients that survive later develop delayed vasospasm. The mortality in the 1st month hovers around 50%. The majority of deaths (Ͼ60%) occur during the first 2 days and is associated with ischemic brain injury (Broderick et al., 1994). The factors that contribute to the acute fall in cerebral blood flow following subarachnoid hemorrhage (SAH) remain uncertain.Ischemic strokes are caused by blockage of cerebral arteries. In the ischemic neuronal tissue, there is depletion of

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Protective effects of free radical inhibitors in intracerebral hemorrhage in rat

Cited by 79 publications

References 34 publications

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

Edaravone Attenuates Brain Edema and Neurologic Deficits in a Rat Model of Acute Intracerebral Hemorrhage

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

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