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PubMed2003

Free radical scavenger protects against inner hair cell loss after cochlear ischemia.

We investigated the protective effects of edaravone, a free radical scavenger, against ischemic damage of inner hair cells (IHCs) in gerbils. Cochlear ischemia was induced in the animals by occluding the vertebral arteries bilaterally for 15 min. Edaravone (1 mg/kg, i.v.) or saline was administered 1 h after ischemia. Hearing was assessed by auditory brain response (ABR). In animals treated with saline, the ABR threshold shift was 24.1 dB and there was a 26.5% decrease in the number of IHCs. By contrast, in animals treated with edaravone, the threshold shift was 7.5 dB and only 8.8% of IHCs was lost. These results suggest that edaravone protects against damage to the inner ear following transient ischemia.

Analysis of Variance↗

PubMed2005

Correction of defective interdomain interaction within ryanodine receptor by antioxidant is a new therapeutic strategy against heart failure.

BACKGROUND: Defective interdomain interaction within the ryanodine receptor (RyR2) seems to play a key role in the pathogenesis of heart failure, as shown in recent studies. In the present study we investigated the effect of oxidative stress on the interdomain interaction, its outcome in the cardiac function in heart failure, and the possibility of preventing the problem with antioxidants. METHODS AND RESULTS: Sarcoplasmic reticulum (SR) vesicles were isolated from dog left ventricular (LV) muscle (normal or rapid ventricular pacing for 4 weeks with or without the antioxidant edaravone). In the edaravone-treated paced dogs (EV+), but not in the untreated paced dogs (EV-), normal cardiac function was restored almost completely. In the SR vesicles isolated from the EV-, oxidative stress of the RyR2 (reduction in the number of free thiols) was severe, but it was negligible in EV+. The oxidative stress of the RyR2 destabilized interdomain interactions within the RyR2 (EV-), but its effect was reversed in EV+. Abnormal Ca2+ leak through the RyR2 was found in EV- but not in EV+. The amount of the RyR2-bound FKBP12.6 was less in EV- than in normal dogs, whereas it was restored almost to a normal amount in EV+. The NO donor 3-morpholinosydnonimine (SIN-1) reproduced, in normal SR, several abnormal features seen in failing SR, such as defective interdomain interaction and abnormal Ca2+ leak. Both cell shortening and Ca2+ transients were impaired by SIN-1 in isolated normal myocytes, mimicking the pathophysiological conditions in failing myocytes. Incubation of failing myocytes with edaravone restored the normal properties. CONCLUSIONS: During the development of heart failure, edaravone ameliorated the defective interdomain interaction of the RyR2. This prevented Ca2+ leak and LV remodeling, leading to an improvement of cardiac function and an attenuation of LV remodeling.

Animals↗

PubMed2006

Susceptibility of brain microvascular endothelial cells to advanced glycation end products-induced tissue factor upregulation is associated with intracellular reactive oxygen species.

There is accumulating evidence that advanced glycation end products (AGEs) are relevant to the formation of vascular complications in diabetes mellitus. The aim of this study was to investigate whether AGEs have a significant effect on tissue factor (TF) expression in brain microvascular endothelial cells compared with that in other arterial endothelial cells. Cultured bovine brain microvascular endothelial cells (BBMECs) and aortic endothelial cells (BAECs) were incubated in medium containing glyceraldehyde-derived AGE (glycer-AGE). TF mRNA expression, protein expression, and activity were measured at multiple time points after glycer-AGE incubation. Participation of reactive oxygen species (ROS) in the effect of glycer-AGE on TF expression was investigated by treatment with a free radical scavenger, edaravone, and intracellular ROS measurements with dihydroethidium (DHE). Basic TF mRNA expression was greater in BBMECs than in BAECs. Glycer-AGE significantly upregulated TF mRNA expression in both cells, and the upregulation was more prominent in BBMECs than in BAECs. TF protein expression and activity were also upregulated with a pattern of being greater in BBMECs than in BAECs. Edaravone significantly attenuated the AGE-induced upregulation of TF mRNA expression, protein expression, and activity. Intracellular ROS levels measured with DHE-stained fluorescent intensity were significantly upregulated by glycer-AGE with a pattern of being greater in BBMECs than in BAECs. AGE-induced ROS upregulation was attenuated by edaravone like AGE-induced TF upregulation. These results suggest that brain microvascular endothelial cells are more susceptible to AGE-induced TF upregulation than aortic endothelial cells, and that this susceptibility is associated with levels of intracellular ROS.

Animals↗

PubMed2005

ONO-1078 reduces NMDA-induced brain injury and vascular cell adhesion molecule-1 expression in rats.

AIM: To determine whether ONO-1078 (pranlukast), a potent cysteinyl leukotriene receptor 1 (CysLT1) antagonist, has an effect on N-methyl-D-aspartate (NMDA)-induced brain injury and vascular cell adhesion molecule-1 (VCAM-1) expression in rats. METHODS: Brain injury was induced by direct microinjection of NMDA (0.3 mumol in 1 muL of sterile 0.1 mol/L PBS, pH 7.4) into the cerebral cortex. The lesion volume (area), brain edema and neuron density were assessed by an image analyzer and the expression of VCAM-1 in the cortex was detected by Western blot 24 h after NMDA injection. ONO-1078 (0.03, 0.1, or 0.3 mg/kg) and edaravone (MCI-186, 10 mg/kg), a neuroprotective agent, were ip injected 30 min before and after NMDA injection. RESULTS: NMDA microinjection produced well-defined focal lesions dose- and time-dependently. ONO-1078 (0.1, 0.3 mg/kg) and edaravone (10 mg/kg) decreased the total lesion volume, lesion area and brain edema induced by NMDA. Furthermore, ONO-1078 (0.1, 0.3 mg/kg) significantly inhibited the enhanced expression of VCAM-1 in the injured cortices, but edaravone did not have this effect. CONCLUSION: CysLT1 receptor antagonist ONO-1078 attenuates NMDA-induced brain damage in rats, and this might relate to the attenuation of NMDA receptor-dependent neurotoxicity and the inhibition of the upregulation of VCAM-1 expression.

Animals↗

PubMed2005

Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers.

There is substantial experimental evidence that free radicals are produced in the brain during ischemia, during reperfusion and during intracranial hemorrhage. Removal of pathologically produced free radicals is therefore a viable approach to neuroprotection. Four compounds with free radical scavenging activity (tirilazad, ebselen, edaravone) or free radical trapping properties (NXY-059) have been examined in experimental models of stroke and evaluated clinically as neuroprotective agents. Both experimental and clinical results are reviewed in this article. Ebselen was a modestly effective neuroprotectant in a rat transient middle cerebral artery occlusion (MCAO) model when given before the start of ischemia, but not when the insult was severe. Data from the permanent MCAO model and an embolic stroke model suggested a bell shaped dose-response curve. The weak preclinical profile may explain the lack of success in clinical trials. Preclinical data on tirilazad in animal models of acute ischemic stroke are neither comprehensive nor consistent. There was little evidence of efficacy in permanent MCAO or when the drug was given several hours post-occlusion. This may explain the negative clinical trials as these did not target patients likely to reperfuse and treatment started several hours after stroke onset. While preclinical data on subarachnoid hemorrhage demonstrated an attenuation of vasospasm the clinical data were inconsistent. There is very limited published preclinical data on edaravone but it has been approved in Japan as a neuroprotectant for the treatment of stroke. Evidence is based on a single placebo controlled trial in a relatively small number of patients. The status of possible development of edaravone outside of Japan is not known. NXY-059 has been found to be a very effective agent in transient and permanent MCAO and thromboembolic models of acute ischemic stroke. Its preclinical development has been governed by adherence with the recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR) group and is now being investigated in Phase III clinical trials using a therapeutic time window and plasma concentrations that are effective in rat and primate models of stroke.

Animals↗

PubMed2006

Wide therapeutic time window for fasudil neuroprotection against ischemia-induced delayed neuronal death in gerbils.

The neuroprotective potential and therapeutic time window for fasudil, a Rho-kinase inhibitor (RKI), were evaluated for delayed neuronal death in gerbils. A preliminary screening was done on fasudil, ozagrel, and edaravone using a single administration in a delayed neuronal death study. Intraperitoneal (i.p.) administration of edaravone, a free radical scavenger (3, 10 mg/kg) immediately after re-circulation did not reduce neuronal degeneration. We previously reported that ozagrel, a thromboxane A(2) synthetase inhibitor (30 mg/kg) also did not reduce neuronal degeneration, while fasudil (3, 30 mg/kg) significantly protected against the ischemia-induced neuronal loss. To clarify the therapeutic time window of fasudil, which showed a positive effect in a preliminary screening, animals received their first i.p. administration of fasudil (10 mg/kg) 24 or 48 h after ischemia. Administration of fasudil twice daily was continued until day 6. Fasudil significantly protected against the ischemia-induced delayed neuronal death when the treatment was started 24 h after ischemia. In gerbils, hydroxyfasudil, an active metabolite of fasudil, was found following an i.p. administration of fasudil (10 mg/kg), and the value of the area under the plasma level curve of hydroxyfasudil was 7 times higher than that of fasudil. Hydroxyfasudil may contribute to the potency of fasudil. The present findings indicate that the RKI fasudil reduces ischemic neuronal damage with a wide therapeutic time window in gerbil, and may be useful in the treatment of acute ischemic stroke in humans.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2006

Cysteinyl leukotriene receptor 1 is involved in N-methyl-D-aspartate-mediated neuronal injury in mice.

AIM: To determine whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in N-methyl-D-aspartate (NMDA)-induced excitotoxic injury in the mouse brain. METHODS: Brain injury was induced by NMDA microinjection (50-150 nmol in 0.5 microL) into the cerebral cortex. The changes in CysLT1 receptor expression 24 h after NMDA injection and the effects of a CysLT1 receptor antagonist, pranlukast (0.01 and 0.1 mg/kg), an NMDA receptor antagonist, ketamine (30 mg/kg), and an antioxidant, edaravone (9 mg/kg) were observed. RESULTS: In the NMDA-injured brain, the CysLT1 receptor mRNA, and protein expression were upregulated, and the receptor was mainly localized in the neurons and not in the astrocytes. Pranlukast, ketamine and edaravone decreased NMDA-induced injury; pranlukast (0.1 mg/kg) and ketamine inhibited the upregulated expression of the CysLT1 receptor. CONCLUSION: CysLT1 receptor expression in neurons is upregulated after NMDA injection, and NMDA-induced responses are inhibited by CysLT1 receptor antagonists, indicating that the increased CysLT1 receptor is involved in NMDA excitotoxicity.

Animals↗

PubMed2004

Montelukast, a cysteinyl leukotriene receptor-1 antagonist, dose- and time-dependently protects against focal cerebral ischemia in mice.

Our previous studies showed that cysteinyl leukotriene receptor-1 (CysLT1) antagonist pranlukast has a neuroprotective effect on cerebral ischemia in rats and mice. However, whether the neuroprotective effect of pranlukast is its special action or a common action of CysLT1 receptor antagonists remains to be clarified. This study was performed to determine whether montelukast, another CysLT1 receptor antagonist, has the neuroprotective effect on focal cerebral ischemia in mice, and to observe its dose- and time-dependent properties. Permanent focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Montelukast was injected intraperitoneally either as multiple doses (once a day for 3 days and 30 min before MCAO) or as a single dose (at 30 min before, 30 min after, or 1 h after MCAO), respectively, and pranlukast and edaravone were used as controls. The neurological deficits, infarct volumes, brain edema, neuron density, and Evans blue extravasation in the brain were determined 24 h after MCAO. Pretreatments with multiple doses or a single dose of montelukast (0.1 and 1.0 mg/kg) before MCAO significantly attenuated all the ischemic insults. Post-treatment with a single dose of montelukast (0.1 and 1.0 mg/kg) at 30 min after MCAO also significantly decreased brain edema and infarct volume, but not neurological deficits. However, post-treatment with a single dose of montelukast at 1 h after MCAO had no significant effect. Pranlukast showed the same effects as montelukast, but edaravone attenuated the ischemic insults only with multiple doses before MCAO. Thus, montelukast has a dose- and time-dependent neuroprotective effect on permanent focal cerebral ischemia in mice, with an effective dose range of 0.1-1.0 mg/kg and a therapeutic window of 30 min. These findings further support the therapeutic potential of CysLT1 receptor antagonists in the treatment of cerebral ischemia at earlier phases.

Acetates↗

PubMed2003

[An improved quantitative method for evaluation of ischemic injury and neuroprotection in mouse brain slices].

OBJECTIVE: To establish a simpler and more accurate method for evaluating in vitro ischemic injury and neuroprotective effects of drugs through improving experimental instrument and quantitative index in mouse brain slices. METHODS: An incubation instrument was developed and its application tested. 2,3,5-triphenyltetrazolium chloride (TTC) was used as a substrate to biosynthesize formazan standard in mouse brain slices, and formazan was isolated, purified and identified. Ischemic injury of mouse brain slices was induced by oxygen/glucose deprivation (OGD), the produced formazan from TTC in the cortex and striatum was measured at 490 nm spectrophotometrically. Edaravone and ONO-1078 were added into the incubation medium to observe their neuroprotective effects. RESULT: The incubation instrument worked well for incubating brain slices and obtaining stable results efficiently. Standard formazan was biosynthesized and purified with a purity of 99.3%, and showed a linear range of 0.05 - 1 mg/ml in absorbance at 490 nm (r=0.9997). OGD decreased formazan production in the cortex and striatum in a duration-dependent manner. Edaravone (0.01 to 1 micromol/L) recovered OGD-induced decrease of formazan production, but ONO-1078 showed no effect. CONCLUSION: The incubation instrument and quantitative measurement of formazan developed in this study are efficient,accurate and simple for evaluating ischemic injury and neuroprotection,which can be used in screening of neuroprotective drugs in vitro.

Alprostadil↗

PubMed2002

[Current state on development of neuroprotective agents for cerebral ischemia].

The improvement of decreased cerebral blood flow using thrombolytic agents, anti-thrombin drugs, and antiplatelet drugs has been essential for acute ischemic stroke. Edaravone, a free radical scavenger, has been commercially available as a novel neuroprotective agent for ischemic stroke in Japan from 2001. The appearance of a neuroprotective agent implies that therapeutic strategy can be expanded through a combination with thrombolysis. In the previous development, several cases have reported that neuroprotective compounds failed in clinical trials. However, recent studies have clarified that the cerebral ischemia induced the neuronal cell death by mediating multiple mechanisms with necrosis and/or apoptosis. The cytotoxicity derived from the NO/peroxynitrite/free radical generating system, one of intracellular Ca2+ signaling, is a typical event in ischemic injury, which is protected by edaravone. Furthermore, it is suggested that suppression of excessively activated voltage-dependent Na+ and Ca2+ channels is effective as a strategy for neuroprotection, since abnormal excitatory stimuli in the neuronal network result in the cerebral infarction. The development of several compounds having different mechanisms of action for acute stroke is in progress. It is therefore prospected that the various novel neuroprotective agents will be provided for assuring the option of therapeutic strategy, since the reinforcement of medical stroke care including diagnosis contributes to the prolongation of the therapeutic time window.

Brain Ischemia↗

PubMed2003

Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on transient global cerebral ischemia in rats.

AIM: To determine whether ONO-1078 [pranlukast, 4-oxo-8-[p-(4-phenylbutyloxy)benzoyl-amono]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate], a potent leukotriene receptor antagonist, possesses a neuroprotective effect on global cerebral ischemia in rats, and to explore its possible mechanism of action. METHODS: Transient global cerebral ischemia was induced by four-vessel occlusion for 10 min and followed by 72-h reperfusion. ONO-1078 (0.03-0.3 mg/kg) and edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one, a neuroprotective agent) 10 mg/kg were ip injected 30 min before ischemia and 1 h after reperfusion, and once a day afterward. Neurological outcome was evaluated before ischemia and 24, 48, 72 h after reperfusion. Neuron density, the expressions of N-methyl-D-aspartate (NMDA) receptor subunit proteins (NR1, NR2A, NA2B) and vascular cell adhesion molecule 1 (VCAM-1) in the cerebral cortex and hippocampus were measured at 72 h after reperfusion. RESULTS: ONO-1078 (0.1, 0.3 mg/kg) and edaravone (10 mg/kg) improved ischemia-induced neurological deficiency and reduced neuron death. ONO-1078 (0.1, 0.3 mg/kg) significantly inhibited the enhanced expression of NMDA receptor subunit protein NR2A in the cortex and VCAM-1 in the hippocampus of ischemic rats. CONCLUSION: ONO-1078 possesses a neuroprotective effect on global cerebral ischemia in rats, and its mechanism may be partly related to the inhibition of the upregulation of NR2A and VCAM-1 in different regions of the brain.

Animals↗

PubMed2006

Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia.

Nine-day-old harlequin (Hq) mice carrying the hypomorphic apoptosis-inducing factor (AIF)(Hq) mutation expressed 60% less AIF, 18% less respiratory chain complex I and 30% less catalase than their wild-type (Wt) littermates. Compared with Wt, the infarct volume after hypoxia-ischemia (HI) was reduced by 53 and 43% in male (YX(Hq)) and female (X(Hq)X(Hq)) mice, respectively (P<0.001). The Hq mutation did not inhibit HI-induced mitochondrial release of cytochrome c or activation of calpain and caspase-3. The broad-spectrum caspase inhibitor quinoline-Val-Asp(OMe)-CH(2)-PH (Q-VD-OPh) decreased the activation of all detectable caspases after HI, both in Wt and Hq mice. Q-VD-OPh reduced the infarct volume equally in Hq and in Wt mice, and the combination of Hq mutation and Q-VD-OPh treatment showed an additive neuroprotective effect. Oxidative stress leading to nitrosylation and lipid peroxidation was more pronounced in ischemic brain areas from Hq than Wt mice. The antioxidant edaravone decreased oxidative stress in damaged brains, more pronounced in the Hq mice, and further reduced brain injury in Hq but not in Wt mice. Thus, two distinct strategies can enhance the neuroprotection conferred by the Hq mutation, antioxidants, presumably compensating for a defect in AIF-dependent redox detoxification, and caspase inhibitors, presumably interrupting a parallel pathway leading to cellular demise.

Amino Acid Chloromethyl Ketones↗

PubMed2006

MCI-186 administered to the maternal circulation inhibits fetal brain injury resulting from total umbilical cord occlusion in the chronically instrumented fetal lamb.

OBJECTIVE: To evaluate the transplacental effects of MCI-186 (edaravone), a potent hydroxyl radical scavenger, administered to the maternal circulation to inhibit fetal brain injury caused by umbilical cord occlusion. METHODS: Nine chronically instrumented lambs were prepared. In three cases, 10-min persistent total umbilical cord occlusion (group A) was performed. Another three cases underwent occlusion and were administered 60 mg of MCI-186 through the maternal femoral vein prior to the end of occlusion (group B). The remaining three cases underwent sham operation (group C). On day 3 after insult, fetal brains were extirpated. Paraffin-embedded brain tissue sections were stained with hematoxylin and eosin, Bodian, Kluver-Barrera, and TUNEL. Neuronal cellular damage was evaluated by two pathologists blinded to the experimental conditions. RESULTS: Group A displayed numerous cells with eosinophilic condensation of nuclear chromatin and proliferation of microglia in the hippocampus and basal ganglia. TUNEL-positive cells were observed in the periventricular area. Group B showed microglial proliferations, but no marked changes. No pathological changes were apparent in group C. CONCLUSIONS: MCI-186 administered to the maternal circulation could inhibit fetal brain injury resulting from hypoxia-reperfusion induced by umbilical cord occlusion.

Animals↗

PubMed2006

Voltage-dependent sodium channels in spinal cord motor neurons display rapid recovery from fast inactivation in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a substantial loss of motor neurons in the spinal cord, brain stem, and motor cortex. Previous evidence showed that in a mouse model of a familial form of ALS expressing high levels of the human mutated protein Cu,Zn superoxide dismutase (Gly(93)-->Ala, G93A), the firing properties of single motor neurons are altered to induce neuronal hyperexcitability. To determine whether the functionality of the macroscopic voltage-dependent Na(+) currents is modified in G93A motor neurons, in the present work their physiological properties were examined. The voltage-dependent sodium channels were studied in dissociated motor neurons in culture from nontransgenic mice (Control), from transgenic mice expressing high levels of the human wild-type protein [superoxide dismutase 1 (SOD1)], and from G93A mice, using the whole cell configuration of the patch-clamp recording technique. The voltage dependency of activation and of steady-state inactivation, the kinetics of fast inactivation and slow inactivation of the voltage-dependent Na(+) channels were not modified in the mutated mice. Conversely, the recovery from fast inactivation was significantly faster in G93A motor neurons than that in Control and SOD1. The recovery from fast inactivation was still significantly faster in G93A motor neurons exposed for different times (3-48 h) and concentrations (5-500 microM) to edaravone, a free-radical scavenger. Clarification of the importance of these changes in membrane ion channel functionality may have diagnostic and therapeutic implications in the pathogenesis of ALS.

Algorithms↗

PubMed2006

The production of hydroxyl radicals in the fetal lamb brain resulting from occlusion of the umbilical circulation and the transplacental effect of MCI-186 to inhibit hydroxyl radical production.

The present study evaluated hydroxyl radical production in fetal lamb brain during and after umbilical cord occlusion and examined the effects of injecting MCI-186 (3-metyl-1-phenyl-2-pyrazolin-5-one; Edaravone), a hydroxyl radical scavenger, into the maternal circulation. In 11 chronically instrumented lambs, intermittent total umbilical cord occlusions 1 min out of every 3 min for 1 h and 10-min persistent total umbilical cord occlusion were performed with brain microdialysis using 5 mM of sodium salicylate. In the remaining four lambs, 60 mg of MCI-186 was administered into the maternal circulation from shortly before the end of 10-min persistent total umbilical cord occlusion. Concentrations of 2,3-dihydroxy-benzoic acid (2,3-DHBA), produced by hydroxyl radical reactions with sodium salicylate, were measured in perfusate by HPLC. Concentration of 2,3-DHBA in perfusate was 23.05 +/- 10.95 nM before umbilical cord occlusion. Levels of 2,3-DHBA tended to increase slightly during and after intermittent umbilical cord occlusion, and were significantly increased by the end of 10-min occlusion (40.06 +/- 21.36 nM) and after occlusion (93.74 +/- 29.17 nM). Infusion of MCI-186 suppressed 2,3-DHBA concentration to 29.35 +/- 14.95 nM after occlusion. Administration of MCI-186 into the maternal circulation reduces hydroxyl radical production induced by umbilical cord occlusion in the fetal lamb brain.

Animals↗

PubMed2001

[Neuroprotective therapy for the treatment of acute ischemic stroke].

Following cerebral ischemia, various biochemical reactions are provoked in a stepwise manner leading neuronal cells to ischemic death. The prevention of these biochemical reactions may exert neuroprotective actions and consequently reduce the magnitude of ischemic cerebral injury. On the basis of such a view, numerous neuroprotective drugs have been developed during the last decade. Quite a few drugs were found effective in reducing the infarct volume in experimental studies, and more than 15 of them were subjected to clinical phase III trials to see a therapeutic effectiveness. However, the results of phase III trials were disappointing in the majority drugs. Only three drugs, nicaravene, ebselen and edaravone, all radical scavengers, were judged effective by small-sized trials with a wide therapeutic window, 48-72 hours after stroke, in Japan. The fact suggests that a one-point prevention of biochemical reactions by single drug is unable to rescue ischemic neuronal cells. Ischemic insult causes damages of vascular wall including the endothelium which play an important role in the development of hemorrhagic changes or cerebral edema. Vascular protection is considered as important as neuroprotection in treatment of clinical stroke. Mild hypothermia has neuroprotective and vascular protective actions and hence may be more effective than neuroprotective drugs for the treatment of stroke. The prevention of fever, which often occurs in severe stroke, may exert the similar effect as hypothermia in neuroprotection. Neuroprotective therapy in the future should proceed toward the simultaneous protections of neurons and vessels using combination of multiple drugs.

Animals↗

PubMed2003

[Gene therapy and neuroprotection for cerebral infarction].

Topical application of GDNF protein greatly reduced the infarct size and brain edema at 24 hr of continuous MCAO in rats. The reduction of the infarct size was not related to a change of cerebral blood flow (CBF), but was accompanied by marked reduction of positive cells for TUNEL and caspases in the affected area. GDNF protein showed a direct protective effect against ischemic brain damage, but not secondary by improving CBF. Pretreatment of animals with Ad-GDNF 24 hr before the subsequent 90 min of transient MCAO effectively reduced infract volume and area without affecting regional CBF compared to the vehicle or Ad-LacZ animal groups. Free radical scavenger edaravone effectively reduced brain edema, infarct size, and peroxidative markers of protein, lipid and DNA. Thus, gene therapy and neuroprotective strategy have a great potential for reducing ischemic brain damage of human stroke patients in the near future.

Adenoviridae↗

PubMed2006

Reactive oxygen species generated by mitochondrial injury in human brain microvessel endothelial cells.

Generation of reactive oxygen species (ROS) and their detrimental effects on the brain after transient ischemia are widely recognized. We studied ROS production from mitochondria in human brain microvessel endothelial cells (HBEC) under chemical hypoxia. HBEC in confluent conditions were incubated for 30 min with 10 microM 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein (DCF) diacetate, which was hydrolyzed and trapped inside the cells. ROS were measured with a fluorescent microscope, a CCD camera and an image analyzing system. Injury to mitochondrial respiratory chain was induced either with rotenone (an inhibitor of mitochondrial complex I) or with m-chlorocarbonyl cyanide phenylhydrazone (CCCP) (an uncoupler of ATP synthetase). Shortly after application of 10 microM rotenone, fluorescent intensity started to increase and the gradual increase continued for 10 min. Similarly, CCCP (10, 50 and 100 microM) dose-dependently increased the fluorescent intensity (p<0.01). Edaravone, a free radical scavenger widely used for treatment of cerebral infarction in Japan, at 100 microM successfully suppressed this ROS production (p<0.05). These data show that chemical hypoxia with normal concentration of oxygen in the medium induced free radicals generation in HBEC. Importance of endothelial mitochondria as a source of free radicals after reperfusion is suggested.

Antipyrine↗