Combination effects of normobaric hyperoxia and edaravone on focal cerebral ischemia-induced neuronal damage in mice

doi:10.1016/j.neulet.2008.06.033

Neuroscience Letters

Volume 441, Issue 2, 22 August 2008, Pages 224-228

https://doi.org/10.1016/j.neulet.2008.06.033 Get rights and content

Abstract

We evaluated the potential neuroprotective effects of combination treatment with normobaric hyperoxia (NBO) and edaravone, a potent scavenger of hydroxyl radicals, on acute brain injuries after stroke. Mice subjected to 2-h filamental middle cerebral artery occlusion were treated with NBO (95% O₂, during the ischemia) alone, with edaravone (1.5 mg/kg, intravenously after the ischemia) alone, with both of these treatments (combination), or with vehicle. The histological and neurological score were assessed at 22-h after reperfusion. Infarct volume was significantly reduced in the combination group [36.3 ± 6.7 mm³ (n = 10) vs. vehicle: 65.5 ± 5.9 mm³ (n = 14) P < 0.05], but not in the two monotherapy-groups [NBO: 50.5 ± 5.8 mm³ (n = 14) and edaravone: 56.7 ± 5.8 mm³ (n = 10)]. The combination therapy reduced TUNEL-positive cells in the ischemic boundary zone both in cortex [6.0 ± 1.4 × 10²/mm² (n = 5) vs. vehicle: 18.9 ± 2.4 × 10²/mm² (n = 5), P < 0.01] and subcortex [11.6 ± 1.5 × 10²/mm² (n = 5) vs. vehicle: 22.5 ± 2.1 × 10²/mm² (n = 5), P < 0.01]. NBO and combination groups exhibited significantly reduced neurological deficit scores at 22-h after reperfusion (vs. vehicle, P < 0.05). Combination therapy with NBO plus edaravone prevented the neuronal damage after focal cerebral ischemia and reperfusion in mice, compared with monotherapy of NBO or edaravone.

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Cited by (28)

Normobaric hyperoxia therapy in acute ischemic stroke: A literature review
2024, Heliyon
Ischemic stroke is one of the most severe cerebrovascular diseases that leads to disability and death and seriously endangers health and quality of life. Insufficient oxygen supply is a critical factor leading to ischemic brain injury. However, effective therapies for ischemic stroke are lacking. Oxygen therapy has been shown to increase oxygen supply to ischemic tissues and improve prognosis after cerebral ischemia/reperfusion. Normobaric hyperoxia (NBHO) has been shown to have neuroprotective effects during ischemic stroke and is considered an appropriate neuroprotective therapy for ischemic stroke. Evidence indicates that NBHO plays a neuroprotective role through different mechanisms in acute ischemic stroke. Recent studies have also reported that combinations with other drug therapies can enhance the efficacy of NBHO in ischemic stroke. Here, we aimed to provide a summary of the potential mechanisms underlying the use of NBHO in ischemic stroke and an overview of the benefits of NBHO in ischemic stroke.
We screened 83 articles on PubMed and other websites. A quick review was conducted, including clinical trials, animal trials, and reviews of studies in the field of NBHO treatment published before July 1, 2023. The results were described and synthesized, and the bias risk and evidence quality of all included studies were assessed.
The results were divided into four categories: the mechanism of NBHO, animal and clinical trials of NBHO, the clinical application and prospects of NBHO, and adverse reactions of NBHO.
NBHO is a simple, non-invasive therapy that may be delivered early after stroke onset, with promising potential for the treatment of acute ischemic stroke. However, the optimal therapeutic regimen remains uncertain. Further studies are needed to confirm its efficacy and safety.
A novel free radical scavenger, NSP-116, ameliorated the brain injury in both ischemic and hemorrhagic stroke models
2019, Journal of Pharmacological Sciences
Citation Excerpt :
Therefore, modulation of excess free radicals may ameliorate ischemic reperfusion injury. Previous reports showed that edaravone had protective effects on cerebral ischemia by protecting peri-vascular cells which modulate vascular contraction/dilation.28,29 In this study, NSP-116 also attenuated neurological deficits in both t-MCAO models (Fig. 3B).
Reperfusion injury is a serious problem in ischemic stroke therapy, which leads to neuronal damage and intracranial hemorrhage (ICH). A novel free radical scavenger, NSP-116, has anti-oxidative effect and may ameliorate reperfusion injury. The purpose of this study was to investigate the effects of NSP-116 on both ischemic and hemorrhagic stroke models.
First, we assessed whether NSP-116 has protective effects in vitro. Pre-treatment of NSP-116 decreased neuronal cell damage induced by H₂O₂ or LPS. Moreover, NSP-116 also suppressed mitochondria damage and apoptosis in H₂O₂-induced neuronal injury model. Based on these results, we used a middle cerebral artery occlusion (MCAO)-induced ischemic stroke model or a collagenase-induced ICH model. Using the MCAO model, we evaluated the cerebral blood flow (CBF), neurological deficit, and infarct volume. Hematoma volume was assessed at 3 days after ICH. In the MCAO model, oral administration of NSP-116 at 30 mg/kg attenuated the reduction of CBF, neurological deficits, and infarct formation. Interestingly, NSP-116 also ameliorated hematoma expansion and neurological deficits in the ICH model. Additionally, pre-treatment of NSP-116 suppressed the brain microvascular endothelial cell death induced by collagenase treatment.
Collectively, our findings indicated that oral administration of NSP-116 attenuates both ischemic and hemorrhagic brain injuries after stroke.
Protective effects of the astaxanthin derivative, adonixanthin, on brain hemorrhagic injury
2018, Brain Research
Citation Excerpt :
Collectivity, these results indicate that neuroprotection by adonixanthin in the ICH mouse model is mediated by direct antioxidant effects. A wide range of antioxidant drugs, including carotenoids, have been used in previous studies, for example, edaravone as a free radical scavenger (Inokuchi et al., 2009; Lee et al., 2010; Nonaka et al., 2008) and sulforaphane as a nuclear factor erythroid 2-related factor 2 (Nrf2) inducer, which protected against neuronal damage during hemorrhagic stroke (Zhao et al., 2016). Adonixanthin may use the same mechanisms of action as those reported previously.
Astaxanthin is beneficial for human health and is used as a dietary supplement. The present study was performed in order to examine the protective effects of the astaxanthin derivative, adonixanthin, against cell death caused by hemoglobin, collagenase, lipopolysaccharide, and hydrogen peroxide, which are associated with hemorrhagic brain injury.
In an in vitro study, adonixanthin exerted cytoprotective effects against each type of damage, and its effects were stronger than those of astaxanthin. The increased production of reactive oxygen species in human brain endothelial cells in the hemoglobin treatment group was inhibited by adonixanthin. Moreover, adonixanthin suppressed cell death in SH-SY5Y cells. In an in vivo study, the oral administration of adonixanthin improved blood-brain barrier hyper-permeability in an autologous blood ICH model. We herein demonstrated for the first time that adonixanthin exerted protective effects against hemorrhagic brain damage by activating antioxidant defenses, and has potential as a protectant against intracerebral hemorrhage.
Edaravone is a free radical scavenger that protects against laser-induced choroidal neovascularization in mice and common marmosets
2016, Experimental Eye Research
Citation Excerpt :
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, Radicut) is a radical scavenger has been used to treat acute ischemic stroke in Japan. Edaravone exerts neuroprotective effects against cerebrovascular injury and focal cerebral ischemia-induced neuronal damage (Kikuchi et al., 2013; Nonaka et al., 2008), reduces lesion size of lacunar infarctions (Nakase et al., 2011), and protects against endotoxin-induced liver injury (Zong et al., 2014). An ophthalmic study showed that edaravone also attenuates retinal ischemia/reperfusion (Song et al., 2008), improves the retinal cell physiology associated with branch retinal vein occlusion (Maeno et al., 2009), ameliorates photoreceptor cell death in retinal detachment (Roh et al., 2011), and protects against retinal damage in streptozotocin-induced diabetic mice (Yuan et al., 2014).
Choroidal neovascularization (CNV) is a main characteristic in exudative type of age-related macular degeneration (AMD). Our study aimed to evaluate the effects of edaravone, a free radical scavenger on laser-induced CNV. CNV was induced by laser photocoagulation to the subretinal choroidal area of mice and common marmosets. Edaravone was administered either intraperitoneally twice a day for 2 weeks or intravenously just once after laser photocoagulation. The effects of edaravone on laser-induced CNV were evaluated by fundus fluorescein angiography, CNV area measurements, and the expression of 4-hydroxy-2-nonenal (4-HNE) modified proteins, a marker of oxidative stress. Furthermore, the effects of edaravone on the production of H₂O₂-induced reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF)-induced cell proliferation were evaluated using human retinal pigment epithelium cells (ARPE-19) and human retinal microvascular endothelial cells, respectively. CNV areas in the edaravone-treated group were significantly smaller in mice and common marmosets. The expression of 4-HNE modified proteins was upregulated 3 h after laser photocoagulation, and intravenously administered edaravone decreased it. In in vitro studies, edaravone inhibited H₂O₂-induced ROS production and VEGF-induced cell proliferation. These findings suggest that edaravone may protect against laser-induced CNV by inhibiting oxidative stress and endothelial cell proliferation.
Non-pharmaceutical therapies for stroke: Mechanisms and clinical implications
2014, Progress in Neurobiology
Citation Excerpt :
Further studies are needed to ensure the safety of NBO and investigate the optimal usage of NBO, including therapeutic time window, duration, flow rates, the combination of thrombolysis and the subtype of the ischemic stroke. Other associated therapies including the combination of minocycline, cilostazol and edaravone also require more clinical evidence (Nonaka et al., 2008, 2009; Jin et al., 2013). Lastly, prospective studies using modern neuroimaging methods are needed to assess the degree and durability of clinical benefits, especially the long-term benefits, from this treatment.
Stroke is deemed a worldwide leading cause of neurological disability and death, however, there is currently no promising pharmacotherapy for acute ischemic stroke aside from intravenous or intra-arterial thrombolysis. Yet because of the narrow therapeutic time window involved, thrombolytic application is very restricted in clinical settings. Accumulating data suggest that non-pharmaceutical therapies for stroke might provide new opportunities for stroke treatment. Here we review recent research progress in the mechanisms and clinical implications of non-pharmaceutical therapies, mainly including neuroprotective approaches such as hypothermia, ischemic/hypoxic conditioning, acupuncture, medical gases and transcranial laser therapy. In addition, we briefly summarize mechanical endovascular recanalization devices and recovery devices for the treatment of the chronic phase of stroke and discuss the relative merits of these devices.
Protective effect of penehvclidine hvdrochloride on ischemia-reperfusion injury in rats
2014, Asian Pacific Journal of Tropical Medicine
To investigate the protective effect of penehvclidine hvdrochloride on ischemia-reperfusion injury in rats.
The model of ischemia-reperfusion injury was established in rats through clamping rental pedicles for 50 min followed by reperfusion. A total of 60 Wistar rats were randomly divided into 4 groups including fake surgery group, model group, low PHC dosage group and high dosage penehvclidine hvdrochloride (PHC) group. Seven days before the experiment, rats in fake surgery group and model group were given 10 mL/kg normal saline, while rats in low PHC dosage group and high dosage PHC group were given 200 and 50 mg/kg PHC, respectively. The urine volume, diet volume, Cre, PU, BUN, IL-6, IL-8, TNF-α, NO MDA concentration, SOD and GSH-Px were determined.
Compared with rats in model group, decreased urine volume, diet volume, Cre, PU, BUN, IL-6, IL-8, TNF-α, NO MDA concentration and increased SOD and GSH-Px activity could be seen in low PHC dosage group and high dosage PHC group (P<0.05).
Administration of PHC before ischemia-reperfusion injury can help protect ischemia-reperfusion injury.

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Combination effects of normobaric hyperoxia and edaravone on focal cerebral ischemia-induced neuronal damage in mice

Abstract

Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger

Stroke

A pilot study of hyperbaric oxygen in the treatment of human stroke

Stroke

Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage

Proc. Natl. Acad. Sci. U.S.A.

Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion

J. Cereb. Blood Flow Metab.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a novel free radical scavenger, for treatment of cardiovascular diseases

Recent Patents Cardiovasc. Drug Discov.

Hyperbaric oxygen combined with intravenous edaravone for treatment of acute embolic stroke: a pilot clinical trial

Neurol. Med. Chir. (Tokyo)

Effects of a novel free radical scavenger, MCl-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model

J. Pharmacol. Exp. Ther.

Normobaric hyperoxia extends the reperfusion window in focal cerebral ischemia

Ann. Neurol.