Effects of ebselen on cerebral ischemia and reperfusion evaluated by microdialysis

Kondoh, Susumu; Nagasawa, S; Kawanishi, Masahiro; Yamaguchi, Kazunobu; Kajimoto, Sachiko; Ohta, Tomio

doi:10.1080/01616412.1999.11740998

Cited by 24 publications

(8 citation statements)

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“…Previously, an in vivo microdialysis study measured extracellular lactate, pyruvate, and purine catabolite levels were measured in the brain of rats subjected to transient, fourvessel occlusion after administration of ebselen. 17) In that study, ebselen significantly reduced the maximum levels of lactate and purine catabolites. Ebselen has since been demonstrated to exhibit some beneficial effects on neurons, and provide some protection against ischemic insults.…”

Section: Discussionmentioning

confidence: 73%

Neuroprotective Effects of Ebselen Following Forebrain Ischemia: Involvement of Glutamate and Nitric Oxide

Koizumi

Fujisawa

Suehiro

et al. 2011

Neurol. Med. Chir.(Tokyo)

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Ebselen is a mimic of glutathione peroxidase that reacts with peroxynitrite and inhibits nitric oxide (NO) synthase. Ebselen has beneficial effects on the neurological outcome of patients with stroke. In this study, the mechanisms by which ebselen can elicit neuroprotective effects against ischemic brain injury were investigated in male Wistar rats. Experimental forebrain ischemia was induced by bilateral common carotid artery occlusion with hemorrhagic hypotension. Ebselen was administered to animals in the treatment group 2 hours prior to the induction of forebrain ischemia, and placebo was administered in the control group. Cerebral blood flow (CBF) was measured by the hydrogen clearance method. Cortical extracellular levels of excitatory amino acids (EAAs) and NO were evaluated using in vivo microdialysis. Neuronal damage in the CA1 subfield of the hippocampus was assessed in brains harvested after a 24-hour period of survival. CBF did not recover to normal physiological levels after ischemic insults in either the control or treatment groups. The differences in the sequential changes in extracellular EAA and NO levels between groups were not statistically significant. There was a significantly larger mean density of intact, undamaged neurons in the CA1 subfield in the treatment group than in the control group. The neuroprotective effects of ebselen were reflected in the histological findings, without significant inhibition of glutamate release or NO synthesis during the acute phase of experimentally induced cerebral ischemia.

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Section: Discussionmentioning

confidence: 73%

Neuroprotective Effects of Ebselen Following Forebrain Ischemia: Involvement of Glutamate and Nitric Oxide

Koizumi

Fujisawa

Suehiro

et al. 2011

Neurol. Med. Chir.(Tokyo)

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“…The observation that ebselen is neuroprotective in the RS-CEM is consistent with earlier findings in rodent stroke models. 6,[27][28][29][30] However, with the highest dose tested, ebselen did not significantly affect the P 50 compared with controls, perhaps because of the detrimental effects mediated by its activity on many enzymes and proteins. 1 Nevertheless, the neuroprotective properties of ebselen in the RSCEM are comparable to those of the spin-trap agent NXY-059 in the same model.…”

Section: Discussionmentioning

confidence: 94%

Ebselen, a Seleno-Organic Antioxidant, Is Neuroprotective After Embolic Strokes in Rabbits

Lapchak

Zivin

2003

Stroke

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Background and Purpose-It has been proposed that antioxidants and spin-trap agents may be neuroprotective after acute ischemia stroke. Although the antioxidant ebselen is currently in clinical trials, little is known about the effectiveness of ebselen, which has glutathione peroxidase-like and anti-inflammatory properties in embolic stroke models. Therefore, we determined the effects of ebselen when administered alone or with the thrombolytic tissue plasminogen activator (tPA), the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke. Methods-Male New Zealand White rabbits were embolized by injection of a suspension of small blood clots into the middle cerebral artery via a catheter. Five minutes after embolization, ebselen (10 to 50 mg/kg) was infused intravenously. Control rabbits received infusions of the vehicle required to solubilize ebselen. In additional rabbits, ebselen (20 mg/kg) was administered 60 minutes after embolization, either alone or in combination with tPA (0.9 or 3.3 mg/kg tPA). Behavioral analysis was conducted 24 hours after embolization, allowing determination of the effective stroke dose (P 50 ) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Results-A drug is considered neuroprotective if it significantly increases the P 50 compared with the vehicle-treated control group. The P 50 of controls 24 hours after embolization was 1.35Ϯ0.30 mg. Rabbits treated 5 minutes after embolization with 10, 20, or 50 mg/kg ebselen had P 50 values of 2.12Ϯ0.56, 2.82Ϯ0.75 (PϽ0.05), and 0.49Ϯ0.54 mg, respectively. A significant neuroprotective effect was observed with the 20-mg/kg dose, but not if there was a 60-minute delay before administration (P 50 ϭ1.69Ϯ0.32 mg). When tPA (3.3 mg/kg) was infused 60 minutes after embolization and ebselen (20 mg/kg) was injected at either 5 (P 50 ϭ2.98Ϯ0.18 mg) or 60 (P 50 ϭ3.60Ϯ0.79 mg) minutes, there was no additional neuroprotective effect compared with tPA alone (P 50 ϭ3.38Ϯ0.55 mg). However, if ebselen (20 mg/kg) was administered concomitantly with low-dose tPA (0.9 mg/kg) 60 minutes after embolization, the P 50 was 3.52Ϯ0.73 mg (PϽ0.05), indicating a synergistic effect of the drug combination because neither alone was effective (P 50 ϭ1.69Ϯ0.32 and 1.54Ϯ0.36 mg, respectively). Conclusions-This study indicates that ebselen may be neuroprotective when administered shortly after an embolic stroke, but the time-and dose-response analyses suggest that it has a narrow therapeutic window. Nevertheless, ebselen may be beneficial if administered concomitantly with a thrombolytic because it significantly enhanced the neuroprotective activity of low-dose tPA.

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“…The observation that in vitro ebselen scavenges peroxynitrite [11,12] needs its clear significance in vivo confirmed [13,14]. Animal inflammatory and cerebral, cardiac, hepatic, and renal ischemia-reperfusion or toxic injury models as well as protection from noise exposure demonstrated its anti-inflammatory or organ-preserving pharmacological potential [7,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. In models of alveolar inflammation, edema generation was virtually blocked, and bronchoalveolar lavage TNF-a was dose-dependently reduced [13,[30][31][32].…”

Section: Introductionmentioning

confidence: 89%

Ebselen Improves Ischemia-Reperfusion Injury After Rat Lung Transplantation

Hamacher

Stammberger

Weber

et al. 2009

Lung

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The heterocyclic organic compound ebselen (2-phenyl-1,2-benizsoselenazol-3(2H)-one) is a glutathione peroxidase mimick with protective properties against oxidative injury. Ebselen also has anti-inflammatory activity, including attenuation of tumor necrosis factor release and increase of interleukin-10, as shown in vivo, in inflammatory and ischemia-reperfusion injuries, including those of the lung. This study was designed to assess its effect on severe ischemia-reperfusion injury in a model of left-sided rat lung isotransplantation. Orthotopic single left-sided lung allotransplantation (Wistar to Wistar) was performed in female rats after a total ischemic time of 18 h. In nine recipients given 500 mg/kg oral ebselen 1 h before transplantation, graft PaO(2)/FiO(2) was improved 24 h after transplantation, as evidenced with a mean (standard deviation) PaO(2) of 139 (61) mmHg vs. eight controls with 65 (33) mmHg (p = 0.009). Bronchoalveolar PMN count was reduced to approximately 50% in the ebselen group compared with controls, whereas no difference in the tumor necrosis factor content was found. We conclude that the improvement of lung function in ebselen-treated transplanted rats is mainly the result of the anti-inflammatory activity of the drug during reperfusion.

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Effects of ebselen on cerebral ischemia and reperfusion evaluated by microdialysis

Cited by 24 publications

References 0 publications

Neuroprotective Effects of Ebselen Following Forebrain Ischemia: Involvement of Glutamate and Nitric Oxide

Neuroprotective Effects of Ebselen Following Forebrain Ischemia: Involvement of Glutamate and Nitric Oxide

Ebselen, a Seleno-Organic Antioxidant, Is Neuroprotective After Embolic Strokes in Rabbits

Ebselen Improves Ischemia-Reperfusion Injury After Rat Lung Transplantation

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