Effect of Ebselen on Contractile Responses in Perfused Rabbit Basilar Artery

Takase, Takashi; Ohta, Tomio; Ogawa, Ryusuke; Tsuji, Masao; Tamura, Yoji; Kazuki, Shuji; Miyamoto, Takashi

doi:10.1097/00006123-199902000-00073

Cited by 7 publications

(3 citation statements)

References 41 publications

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“…Ebselen has since been demonstrated to exhibit some beneficial effects on neurons, and provide some protection against ischemic insults. 3,4,13,20,27,28) Some evidence has been found showing that ebselen protects neurons against ischemic brain injury, but the mechanisms that account for the effects of this antioxidant remain unclear.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…This selenium compound mimics the reactivity of glutathione peroxidase, reacting rapidly with peroxynitrite (k ϭ 2 ϫ 10 6 M Ϫ1 s Ϫ1 , pH Ն 8, 25 °C (90)) and being reduced back to its original form by glutathione. Experiments in clinical trials on ebselen have shown important plasma concentration of the drug ranging from 10 M at 2 h after administration to a baseline level of 5.1 M after 7 days oral administration of a daily dose of 400 mg (91). Under these conditions, k[T] is 10Ϫ20 s Ϫ1 .…”

Section: Box 1 Diffusion As a Kinetic Contendermentioning

confidence: 99%

Chemical Biology of Peroxynitrite: Kinetics, Diffusion, and Radicals

2009

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Peroxynitrite is formed by the very fast reaction of nitric oxide and superoxide radicals, a reaction that kinetically competes with other routes that chemically consume or physically sequester the reagents. It can behave either as an endogenous cytotoxin toward host tissues or a cytotoxic effector molecule against invading pathogens, depending on the cellular source and pathophysiological setting. Peroxynitrite is in itself very reactive against a few specific targets that range from efficient detoxification systems, such as peroxiredoxins, to reactions eventually leading to enhanced radical formation (e.g., nitrogen dioxide and carbonate radicals), such as the reaction with carbon dioxide. Thus, the chemical biology of peroxynitrite is dictated by the chemical kinetics of its formation and decay and by the diffusion across membranes of the species involved, including peroxynitrite itself. On the other hand, most durable traces of peroxynitrite passing (such as 3-nitrotyrosine) are derived from radicals formed from peroxynitrite by routes that represent extremely low-yield processes but that have potentially critical biological consequences. Here we have reviewed the chemical kinetics of peroxynitrite as a biochemical transient species in order to estimate its rates of formation and decay and then its steady-state concentration in different intra- or extracellular compartments, trying to provide a quantitative basis for its reactivity; additionally, we have considered diffusion across membranes to locate its possible effects. Finally, we have assessed the most successful attempts to intercept peroxynitrite by pharmacological intervention in their potential to increment the existing biological defenses that routinely deal with this cytotoxin.

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“…Similar considerations may be apply to the synthetic compound ebselen [2-phenyl-1,2-benzisoselenazol-3-(2H)one], a lipid soluble selenium compound that exhibits glutathione peroxidase-like activity, which reduce peroxynitrite by two-electrons with a significant rate constant of 2 × 10 6 M −1 s −1 [143]. Experimental models after drug administration have determined ebselen plasma concentrations in the range of 5–10 μM, which represents a k T [T] value ~ 10–20 s −1 and could account for the reported protective effects of ebselen in several models of inflammation and reperfusion injury mediated by peroxynitrite [21,144,145,146]. Other organo selenium compounds were also reported to react with peroxynitrite.…”

Section: Modulation Of the Steady State Concentration Of Peroxynitmentioning

confidence: 99%

Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite

Carballal

Bartesaghi

Radí

2014

Biochimica et Biophysica Acta (BBA) - General Subjects

137

122

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Background Peroxynitrite, the product of the reaction between superoxide radicals and nitric oxide, is an elusive oxidant of short half-life and low steady-state concentration in biological systems; it promotes nitroxidative damage. Scope of Review We will consider kinetic and mechanistic aspects that allow rationalizing the biological fate of peroxynitrite from data obtained by a combination of methods that include fast kinetic techniques, electron paramagnetic resonance and kinetic simulations. In addition, we provide a quantitative analysis of peroxynitrite production rates and conceivable state-state levels in living systems. Major Conclusions The preferential reactions of peroxynitrite in vivo include those with carbon dioxide, thiols and metalloproteins; its homolysis represents only < 1 % of its fate. To note, carbon dioxide accounts for a significant fraction of peroxynitrite consumption leading to the formation of strong one-electron oxidants, carbonate radicals and nitrogen dioxide. On the other hand, peroxynitrite is rapidly reduced by peroxiredoxins, which represent efficient thiol-based peroxynitrite detoxification systems. Glutathione, present at mM concentration in cells and frequently considered a direct scavenger of peroxynitrite, does not react sufficiently fast with it in vivo; glutathione mainly inhibits peroxynitrite-dependent processes by reactions with secondary radicals. The detection of protein 3-nitrotyrosine, a molecular footprint, can demonstrate peroxynitrite formation in vivo. Basal peroxynitrite formation rates in cells can be estimated in the order of 0.1 to 0.5 μM s−1 and its steady-state concentration ~ 1 nM. General Significance The analysis provides a handle to predict the preferential fate and steady-state levels of peroxynitrite in living systems. This is useful to understand pathophysiological aspects and pharmacological prospects connected to peroxynitrite.

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Effect of Ebselen on Contractile Responses in Perfused Rabbit Basilar Artery

Cited by 7 publications

References 41 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

Chemical Biology of Peroxynitrite: Kinetics, Diffusion, and Radicals

Kinetic and mechanistic considerations to assess the biological fate of peroxynitrite

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