(Stroke. 1996;27:1124-1129.)
© 1996 American Heart Association, Inc.
Articles |
Role of Oxidants in Ischemic Brain Damage
From the Departments of Neurological Surgery and Neurology, University of California, School of Medicine, San Francisco.
Correspondence to Pak H. Chan, PhD, CNS Injury and Edema Research Center, University of California, 521 Parnassus, C-224, San Francisco, CA 94143-0651.
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Abstract |
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 Top Abstract IntroductionOxygen Radical Production in...Antioxidant Enzyme SODs and...Transgenic and Knockout Mutant...ConclusionReferences |
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Background and Purpose Oxygen free radicals or oxidants have been proposed to be involved in acute central nervous system injury that is produced by cerebral ischemia and reperfusion. Because of the transient nature of oxygen radicals and the technical difficulties inherent in accurately measuring their levels in the brain, experimental strategies have been focused on the use of pharmacological agents and antioxidants to seek a correlation between the exogenously supplied specific radical scavengers (ie, superoxide dismutase and catalase) and the subsequent protection of cerebral tissues from ischemic injury. However, this strategy entails problems (hemodynamic, pharmacokinetic, toxicity, blood-brain barrier permeability, etc) that may cloud the data interpretation. This mini-review will focus on the oxidant mechanisms in cerebral ischemic brain injury by using transgenic and knockout mice as an alternative approach.
Methods Transgenic and knockout mutants that either overexpress or are deficient in antioxidant enzyme/protein levels have been successfully produced. The availability of these genetically modified animals has made it possible to investigate the role of certain oxidants in ischemic brain cell damage in molecular fashion.
Results It has been shown that an increased level of CuZn–superoxide dismutase and antiapoptotic protein Bcl-2 in the brains of transgenic mice protects neurons from ischemic/reperfusion injury, whereas a deficiency in CuZn–superoxide dismutase or mitochondrial Mn–superoxide dismutase exacerbates ischemic brain damage. Target disruption of neuronal nitric oxide synthase in mice also provides neuronal protection against permanent and transient focal cerebral ischemia.
Conclusions I conclude that molecular genetic approaches in modifying antioxidant levels in the brain offer a unique tool for understanding the role of oxidants in ischemic brain damage.
Key Words: cerebral ischemia • free radicals • oxidants • reperfusion • superoxide dismutase • mice, transgenic • mice, knockout
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Introduction |
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TopAbstractIntroductionOxygen Radical Production in...Antioxidant Enzyme SODs and...Transgenic and Knockout Mutant...ConclusionReferences |
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Oxygen free radicals or oxidants have been implicated in the development of many neurological disorders and brain dysfunctions.1 2 3 One role of oxygen free radicals in brain injury appears to involve reperfusion after cerebral ischemia. In either global or focal cerebral ischemia, cerebral blood flow is significantly reduced in the brain regions that are supplied with oxygen by the occluded vessel. Reoxygenation during reperfusion provides oxygen to sustain neuronal viability and also provides oxygen as a substrate for numerous enzymatic oxidation reactions that produce reactive oxidants. In addition, reflow after occlusion often causes an increase in oxygen to levels that cannot be utilized by mitochondria under normal physiological flow conditions (Figure
). It has been demonstrated that about 2% to 5%
of the electron flow in isolated brain mitochondria produces superoxide
radicals and H2O2.4 These
constantly produced oxygen radicals are scavenged respectively by SODs
and by GSHPx and catalase. Other antioxidants, including glutathione,
ascorbic acid, and vitamin E, are also likely to be involved in the
detoxification of free radicals. During reperfusion, perturbation of
the antioxidative defense mechanisms is a result of the
overproduction of oxygen radicals, inactivation of
detoxification systems, consumption of antioxidants, and failure to
adequately replenish antioxidants in the ischemic brain tissue.
Because of technical difficulties, the level of oxygen free radicals in
brain tissue after ischemia is generally assessed by indirect
methods, including lipid peroxidation, protein oxidation, and DNA
damage (Figure). Recent advances in methodologies have allowed
investigators to measure hydroxyl radicals by salicylate
hydroxylation5 and NO radicals with a porphyrinic
microsensor6 and with electron paramagnetic resonance spin
trapping7 in ischemic brain tissue. In addition,
several chemical and biochemical methods have been developed to measure
superoxide radicals in neurons that undergo oxidative
stress.8 9 10 11 Despite these useful measurements for
superoxide, hydroxyl, and NO radicals, establishment of the causative
role of oxygen radicals in ischemic brain injury remains a
difficult task for stroke researchers and neuroscientists. This review
will attempt to assess the role of oxygen radicals in cerebral
ischemia and the molecular genetic approaches using transgenic
and knockout mutant mice and to dissect out the molecular and cellular
mechanisms involving oxygen radicals in ischemic brain
damage.
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Oxygen Radical Production in Ischemic Brain |
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TopAbstractIntroductionOxygen Radical Production in...Antioxidant Enzyme SODs and...Transgenic and Knockout Mutant...ConclusionReferences |
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Several oxygen radical species, including O2·-, HO2·, H2O2, and ·OH, are formed following the initial reduction of oxygen:
 | (1) |
 | (2) |
 | (3) |
 | (4) |
, SOD catalyzes this reaction at
physiological pH at an extremely fast, constant
rate (2x109 L·mol-1),
forming H2O2 that is then detoxified to
H2O and O2 by catalase in mammalian cells or in
the brain by GSHPx at the expense of reduced glutathione (Equation 4).
The oxidized glutathione can be recycled to reduced glutathione by
glutathione reductase in the presence of nicotinamide-adenine
dinucleotide phosphate.
Hydroxyl radicals are extremely active oxidants. These radicals are
known to initiate lipid peroxidation and to cause protein oxidation and
DNA damage in cells (Figure). Superoxide radicals, on the other hand,
are much less reactive but have a longer half-life and can form
hydroxyl radicals through a Haber-Weiss reaction (see Equation 5).
 | (5) |
 | (6) |
 | (7) |
 | (8) |
It is generally believed that this reaction (Equation 5) proceeds
rapidly in the presence of trace metal iron (Fenton reaction). Another
pathway for forming ·OH is through the reaction of
O2·- and NO· (a gas radical that is
constantly being formed in the brain by neuronal,
endothelial, and glial NOS).12 The
product of this reaction is ONOO-.13
This reaction (Equation 6) is extremely rapid, and the constant rate of
ONOO- formation (6.7x109
L·mol-1·s-1)
is diffusion-limited.14 At
physiological pH, ONOO- degrades
instantly to ·OH and nitrogen dioxide (NO2·) (see
Equation 8). ONOO-, a stronger
pro-oxidant, can react with SOD to form a powerful nitrating agent,
resulting in the nitration of tyrosines of cellular proteins and
initiation of cellular dysfunction and death (Figure).15
However, the role of ONOO- in ischemic brain
injury has only recently been investigated. On the other hand,
contradictory reports have surfaced with regard to the role of NO· in
ischemic neuronal injury, primarily because of its dual role as
a vasodilator (ie, increases in cerebral blood flow)16 and
as a free radical that can injure neuronal cells.17 Other
studies have suggested that the redox state of NO· may determine its
role as either neuronal protector or injurious mediator after
activation of N-methyl-D-aspartate
receptors.18 It is of interest to note that
downregulation of CuZn-SOD activity in PC12 cells by exposure to
antisense oligonucleotides leads to apoptotic
cell death via the NO·-ONOO-
pathway.19
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Antioxidant Enzyme SODs and Cerebral Ischemia |
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TopAbstractIntroductionOxygen Radical Production in...Antioxidant Enzyme SODs and...Transgenic and Knockout Mutant...ConclusionReferences |
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Several enzymes, including SOD, GSHPx, glutathione reductase, and catalase, are endogenous antioxidants that process specific free radical scavenging properties. SODs, in particular, have been used extensively to reduce superoxide radical–associated ischemic brain damage.
Based on the metal ion requirements and the anatomic distribution,
three types of SODs exist in brain cells. CuZn-SOD is a cytosolic
enzyme that requires both copper and zinc ions as cofactors. It is a
dimeric protein that is coded by the human CuZn-SOD transgene
(SOD-1) on chromosome 21 in human cells. Manganese (Mn-SOD)
is a mitochondrial enzyme with requirements for
Mn2+.20 It is a tetrameric protein that is
coded by the SOD-2 gene in chromosome 4 in human cells. Both
CuZn-SOD and Mn-SOD from various sources have been fully characterized
biochemically, and the cDNAs of both human enzymes have been
successfully cloned.21 A copper-containing SOD
(sod-3) has been identified in the extracellular
space, and its gene has been successfully cloned (Table 1).22 As specified for superoxide radicals,
CuZn-SOD has been used extensively to reduce brain injury induced by
ischemia and reperfusion. Unfortunately, investigators have
obtained various degrees of success and failure when free nonmodified
SOD was used to ameliorate ischemic brain
injury.23 The extremely short half-life of CuZn-SOD (6
minutes) in circulating blood and its failure to pass the
blood-brain barrier make it difficult to use enzyme therapy in
cerebral ischemia. However, a modified enzyme with an increased
half-life, such as polyethylene glycol–conjugated SOD, has
been successfully used to reduce infarct volume in rats that have been
subjected to focal cerebral ischemia.24
Liposome-entrapped SOD has an increased half-life (4.2 hours),
blood-brain barrier permeability, and cellular uptake, and it has
also proved to be an effective treatment in reducing the severity of
traumatic and focal ischemic brain injuries.25 26
Yet, in some instances, modified SOD (ie, polyethylene
glycol–conjugated SOD) has been used with conflicting
results.24 The fact that the results are mixed make it
imperative to use other experimental strategies so the role of SOD can
be fully established in cerebral ischemia.
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Transgenic and Knockout Mutant Mice as Useful Tools to Study the Role of Oxidants in Ischemic Brain Injury |
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TopAbstractIntroductionOxygen Radical Production in...Antioxidant Enzyme SODs and...Transgenic and Knockout Mutant...ConclusionReferences |
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One strategy is to use transgenic/knockout technology to alter the levels of pro-oxidants, antioxidants, and oxidant-related enzymes or proteins and to use these transgenic animals to study the role of a specific oxidant or antioxidant in ischemic brain injury.
The most commonly used method for creating transgenic mice is the
microinjection of DNA of interest (transgene) into the pronuclei of
fertilized mouse oocytes.27 This technique is used to
introduce a linear DNA fragment (genomic or cDNA with proper promoter)
that contains sequences required for directing correct transcriptional
initiation and for encoding a gene product (protein, enzyme) that
can be readily identified using various biochemical assays. Pronuclear
microinjection of DNA leads to random integration of various copies of
the injected DNA into a single site on a mouse chromosome. The
integrated DNA can be passed on to future generations. Another way to
produce transgenic mice is to introduce foreign genes to embryonic stem
cells.28 The embryonic stem cells are subsequently
screened for the integration of transgenes. These embryonic stem cells
with the transgene (active or inactive knockout) can then be
microinjected into the blastocytes to further produce chimeric mice.
The mating of chimeric mice with wild types produces heterozygous
offspring (+/-) that contain the transgene. Furthermore, breeding
among heterozygous mice generates homozygous animals (+/+ for
overexpression, -/- for knockout). By use of this
transgenic technology, several mice strains with various
genotypes that relate to oxidant/antioxidant enzymes/proteins
have been successfully developed. Most of these transgenic and knockout
mutant animals have been used in the study of the role of oxidants in
ischemic brain injury (Table 2).
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In the studies using transgenic mice overexpressing SOD-1,42 two models of focal cerebral ischemia are used. One model is achieved by permanent occlusion of the left MCA just proximal to the piriform branch of the anesthetized mouse. Immediately after occlusion of the MCA, the left CCA is permanently ligated, and the right CCA is temporarily occluded for 1 hour followed by additional reperfusion for 24 hours. The total infarct volume (in cubic millimeters) is reduced by 36% in SOD-1 transgenic mice compared with nontransgenic mice. The brain edema is also reduced in both the MCA territory and the anterior cerebral artery area, a region that corresponds to the "ischemic penumbra." Antioxidants, both reduced glutathione and ascorbic acid, are maintained at higher levels in the penumbra area than in the same anatomic regions in nontransgenic mouse brains.29 In another study that involved the use of SOD-1 transgenic mice, MCA occlusion was achieved with a 5-0 rounded nylon suture placed within the internal cerebral artery followed by withdrawal of the suture to allow reperfusion. The infarct volume was reduced by 26% in SOD-1 transgenic mice at 3 hours of reperfusion after 3 hours of ischemia30 and by 40% in SOD-1 transgenic mice compared with nontransgenic mice at 24 hours after 1 hour of MCA occlusion.43 The decrease in the infarct volume in SOD-1 transgenic mice clearly parallels the reduction of neurological deficits and is not related to the changes in cerebral blood flow. On the other hand, the infarct volume produced in SOD-1 transgenic mice that are subjected to 24 hours of permanent MCA occlusion using intraluminal suture blockade is not different from that in nontransgenic mice,31 suggesting that the increased ischemic severity resulting from prolonged cerebral ischemia will limit the protective role of CuZn-SOD against neuronal injury.
In addition to the SOD-1 transgenic mice, transgenic mice overexpressing bFGF when subjected to right CCA ligation, hyperglycemia, and 20 minutes of 1% carbon monoxide contained more viable hippocampal CA1 neurons than nontransgenic mice.33 Although the mechanism by which the bFGF protects hippocampal CA1 is unknown, it is possible that increased antioxidant enzyme activities in hippocampal neurons by bFGF overexpression44 may account for the neuronal protection.45 Transgenic mice in which neurons overexpress the human BCL-2 protein under the control of the neuron-specific enolase or phosphoglycerate kinase promoters are protected against cerebral ischemia produced by permanent MCA occlusion.32 BCL-2, a membranous protein that is encoded by bcl-2, a mammalian homologue of the nematode antiapoptotic gene ced-9,46 has been known to interfere with neuronal apoptosis by acting as an antioxidant.47 48 49 It has been demonstrated that the neurons that survive focal cerebral ischemic insult also express BCL-2 protein.50
In a recent study, Lawrence et al51 demonstrated that overexpression of BCL-2 with herpes simplex virus vectors protects the central nervous system neurons against focal cerebral ischemia in rats and against glutamate-induced injury in hippocampal neurons in culture. Thus, these studies enforce the antioxidative concept in cerebral ischemia, since both transgenic mice and rats overexpressing antioxidant protein BCL-2 are more resistant to cerebral ischemia–induced brain damage.
On the other hand, a limited number of mutant mice that contain a null mutation of a specific gene have been developed and used for the study of molecular and cellular mechanisms of cerebrovascular diseases. It has been demonstrated that ischemic infarction is significantly reduced in neuronal NOS knockout mice35 that were developed by Huang et al,52 clearly indicating that NO radicals produced by neuronal NOS are major determinants of the pathogenesis of the infarct after permanent focal ischemia. These same investigators have recently developed knockout mice that are deficient in endothelial NOS.36 37 Inducible NOS has been implicated in cerebral ischemic damage,53 and mutant mice deficient in inducible NOS have been successfully produced.38 It is anticipated that the role of inducible NOS in cerebral ischemia can be fully elucidated by using these mutant mice. In another study using knockout mice, the ischemic infarct volume was significantly reduced in p53 mutant mice (both homozygous and heterozygous) after focal cerebral ischemia compared with the wild type.39 Since the loss of p53 tumor suppressor gene has been shown to protect neurons from kainate-induced cell death,54 the neuronal protection offered by p53-deficient mutants may be related to the reduction of oxidative stress induced by kainate.55
Using the knockout mutant mice, preliminary studies have been carried out to address the role of mouse cytosolic CuZn-SOD (sod-1) and Mn-SOD (sod-2)40 in ischemic brain injury. It has recently been shown that ischemic infarct is significantly increased in mice that lack the sod-1 (homozygous and heterozygous) or sod-2 (heterozygous) gene.41 These studies, albeit preliminary, did point to the involvement of superoxide radicals in ischemic brain damage and to the important role these antioxidant enzymes play in neuronal protection after a focal ischemic insult.
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Conclusion |
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TopAbstractIntroductionOxygen Radical Production in...Antioxidant Enzyme SODs and...Transgenic and Knockout Mutant...ConclusionReferences |
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It is now clear that oxidants play a major role in brain damage in cerebrovascular diseases. The successful development of SOD-1 transgenic mice, as well as sod-1, sod-2, neuronal NOS knockout mutants, and many other transgenic and knockout mutant mice, has afforded stroke researchers and neuroscientists a unique opportunity to study the oxidant mechanisms underlying the complex neuronal responses to ischemic insults. It is clear that these genetically modified mice could also be useful for the study of neurodegenerative diseases and neurological disorders other than cerebrovascular diseases. Despite these successful beginnings, there are obvious advantages to using larger animal species (ie, rats) for transgenic animals and knockout mutants, since many models for stroke and cerebrovascular disease have been developed mainly in rats.56 The successful creation of transgenic and knockout mutant rats will be an invaluable addition to the study of the mechanisms underlying ischemic brain damage in the well-established focal, thrombolytic, and global ischemia models.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work is supported by National Institutes of Health grants NS-14543, NS-25372, AG-08938, and NO1 NS-5-2334. I thank Cheryl Christensen for editorial assistance.
Received April 12, 1996; accepted April 19, 1996.
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  Q.-G. Zhang, L. Raz, R. Wang, D. Han, L. De Sevilla, F. Yang, R. K. Vadlamudi, and D. W. Brann Estrogen Attenuates Ischemic Oxidative Damage via an Estrogen Receptor {alpha}-Mediated Inhibition of NADPH Oxidase Activation J. Neurosci., November 4, 2009; 29(44): 13823 - 13836. [Abstract] [Full Text] [PDF]
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J. E. Jung, G. S. Kim, P. Narasimhan, Y. S. Song, and P. H. Chan Regulation of Mn-Superoxide Dismutase Activity and Neuroprotection by STAT3 in Mice after Cerebral Ischemia J. Neurosci., May 27, 2009; 29(21): 7003 - 7014. [Abstract] [Full Text] [PDF]
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 P. Narasimhan, J. Liu, Y. S. Song, J. L. Massengale, and P. H. Chan VEGF Stimulates the ERK 1/2 Signaling Pathway and Apoptosis in Cerebral Endothelial Cells After Ischemic Conditions Stroke, April 1, 2009; 40(4): 1467 - 1473. [Abstract] [Full Text] [PDF]
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B. Xing, H. Chen, M. Zhang, D. Zhao, R. Jiang, X. Liu, and S. Zhang Ischemic Postconditioning Inhibits Apoptosis After Focal Cerebral Ischemia/Reperfusion Injury in the Rat Stroke, August 1, 2008; 39(8): 2362 - 2369. [Abstract] [Full Text] [PDF]
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 J. Suzuki, F. Broeyer, A. Cohen, M. Takebe, J. Burggraaf, and Y. Mizushima Pharmacokinetics of PC-SOD, a Lecithinized Recombinant Superoxide Dismutase, After Single- and Multiple-Dose Administration to Healthy Japanese and Caucasian Volunteers J. Clin. Pharmacol., February 1, 2008; 48(2): 184 - 192. [Abstract] [Full Text] [PDF]
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 T. P. Obrenovitch Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia Physiol Rev, January 1, 2008; 88(1): 211 - 247. [Abstract] [Full Text] [PDF]
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 C. Wakade, M. M. Khan, L. M. De Sevilla, Q.-G. Zhang, V. B. Mahesh, and D. W. Brann Tamoxifen Neuroprotection in Cerebral Ischemia Involves Attenuation of Kinase Activation and Superoxide Production and Potentiation of Mitochondrial Superoxide Dismutase Endocrinology, January 1, 2008; 149(1): 367 - 379. [Abstract] [Full Text] [PDF]
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H. Endo, H. Kamada, C. Nito, T. Nishi, and P. H. Chan Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J. Neurosci., July 26, 2006; 26(30): 7974 - 7983. [Abstract] [Full Text] [PDF]
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J. Liu, P. Narasimhan, Y.-S. Lee, Y. Seon Song, H. Endo, F. Yu, and P. H. Chan Mild hypoxia promotes survival and proliferation of SOD2-deficient astrocytes via c-Myc activation. J. Neurosci., April 19, 2006; 26(16): 4329 - 4337. [Abstract] [Full Text] [PDF]
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 P. K Shukla, V. K Khanna, M M. Ali, R. Maurya, M Y Khan, and R. C Srimal Neuroprotective effect of Acorus calamus against middle cerebral artery occlusion-induced ischaemia in rat Human and Experimental Toxicology, April 1, 2006; 25(4): 187 - 194. [Abstract] [PDF]
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O. Farkas, J. Lifshitz, and J. T. Povlishock Mechanoporation induced by diffuse traumatic brain injury: an irreversible or reversible response to injury? J. Neurosci., March 22, 2006; 26(12): 3130 - 3140. [Abstract] [Full Text] [PDF]
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 M. Shimazawa, S. Chikamatsu, N. Morimoto, S. Mishima, H. Nagai, and H. Hara Neuroprotection by Brazilian Green Propolis against In vitro and In vivo Ischemic Neuronal Damage Evid. Based Complement. Altern. Med., June 1, 2005; 2(2): 201 - 207. [Abstract] [Full Text] [PDF]
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J. Liu, P. Narasimhan, F. Yu, and P. H. Chan Neuroprotection by Hypoxic Preconditioning Involves Oxidative Stress-Mediated Expression of Hypoxia-Inducible Factor and Erythropoietin Stroke, June 1, 2005; 36(6): 1264 - 1269. [Abstract] [Full Text] [PDF]
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 R. E. Haskew-Layton, A. A. Mongin, and H. K. Kimelberg Hydrogen Peroxide Potentiates Volume-sensitive Excitatory Amino Acid Release via a Mechanism Involving Ca2+/Calmodulin-dependent Protein Kinase II J. Biol. Chem., February 4, 2005; 280(5): 3548 - 3554. [Abstract] [Full Text] [PDF]
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 H. Kolsch, M. Linnebank, D. Lutjohann, F. Jessen, U. Wullner, U. Harbrecht, K. M. Thelen, M. Kreis, F. Hentschel, A. Schulz, et al. Polymorphisms in glutathione S-transferase omega-1 and AD, vascular dementia, and stroke Neurology, December 28, 2004; 63(12): 2255 - 2260. [Abstract] [Full Text] [PDF]
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 S.-K. Lee, D. I. Kim, S. Y. Kim, D. J. Kim, J. E. Lee, and J. H. Kim Reperfusion Cellular Injury in an Animal Model of Transient Ischemia AJNR Am. J. Neuroradiol., September 1, 2004; 25(8): 1342 - 1347. [Abstract] [Full Text] [PDF]
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 S. J. Vannucci and H. Hagberg Hypoxia-ischemia in the immature brain J. Exp. Biol., August 15, 2004; 207(18): 3149 - 3154. [Abstract] [Full Text] [PDF]
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 A. Iwashita, N. Tojo, S. Matsuura, S. Yamazaki, K. Kamijo, J. Ishida, H. Yamamoto, K. Hattori, N. Matsuoka, and S. Mutoh A Novel and Potent Poly(ADP-Ribose) Polymerase-1 Inhibitor, FR247304 (5-Chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 425 - 436. [Abstract] [Full Text] [PDF]
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 K.M.A. Welch Statins for the prevention of cerebrovascular disease: the rationale for robust intervention Eur. Heart J. Suppl., July 1, 2004; 6(suppl_C): C34 - C42. [Abstract] [Full Text] [PDF]
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A. Saito, T. Hayashi, S. Okuno, T. Nishi, and P. H. Chan Oxidative Stress Is Associated With XIAP and Smac/DIABLO Signaling Pathways in Mouse Brains After Transient Focal Cerebral Ischemia Stroke, June 1, 2004; 35(6): 1443 - 1448. [Abstract] [Full Text] [PDF]
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C. M. Maier, L. Hsieh, F. Yu, P. Bracci, and P. H. Chan Matrix Metalloproteinase-9 and Myeloperoxidase Expression: Quantitative Analysis by Antigen Immunohistochemistry in a Model of Transient Focal Cerebral Ischemia Stroke, May 1, 2004; 35(5): 1169 - 1174. [Abstract] [Full Text] [PDF]
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 G. Y. Sun, J. Xu, M. D. Jensen, and A. Simonyi Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases J. Lipid Res., February 1, 2004; 45(2): 205 - 213. [Abstract] [Full Text] [PDF]
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A. Iwashita, T. Maemoto, H. Nakada, I. Shima, N. Matsuoka, and H. Hisajima A Novel Potent Radical Scavenger, 8-(4-Fluorophenyl)-2-((2E)-3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c] [1,2,4]triazine (FR210575), Prevents Neuronal Cell Death in Cultured Primary Neurons and Attenuates Brain Injury after Focal Ischemia in Rats J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 961 - 968. [Abstract] [Full Text] [PDF]
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A. Saito, T. Hayashi, S. Okuno, M. Ferrand-Drake, and P. H. Chan Overexpression of Copper/Zinc Superoxide Dismutase in Transgenic Mice Protects against Neuronal Cell Death after Transient Focal Ischemia by Blocking Activation of the Bad Cell Death Signaling Pathway J. Neurosci., March 1, 2003; 23(5): 1710 - 1718. [Abstract] [Full Text] [PDF]
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 E. Martelin, R. Lapatto, and K. O. Raivio Regulation of xanthine oxidoreductase by intracellular iron Am J Physiol Cell Physiol, December 1, 2002; 283(6): C1722 - C1728. [Abstract] [Full Text] [PDF]
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N. Noshita, T. Sugawara, T. Hayashi, A. Lewen, G. Omar, and P. H. Chan Copper/Zinc Superoxide Dismutase Attenuates Neuronal Cell Death by Preventing Extracellular Signal-Regulated Kinase Activation after Transient Focal Cerebral Ischemia in Mice J. Neurosci., September 15, 2002; 22(18): 7923 - 7930. [Abstract] [Full Text] [PDF]
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 M. V. Avshalumov and M. E. Rice NMDA Receptor Activation Mediates Hydrogen Peroxide-Induced Pathophysiology in Rat Hippocampal Slices J Neurophysiol, June 1, 2002; 87(6): 2896 - 2903. [Abstract] [Full Text] [PDF]
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K. W. Hong, K. Y. Kim, J. H. Lee, H. K. Shin, Y. G. Kwak, S.-O. Kim, H. Lim, and S.-E. Yoo Neuroprotective Effect of (2S,3S,4R)-N""-cyano-N-(6-amino-3, 4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378), a Benzopyran Analog, against Focal Ischemic Brain Damage in Rats J. Pharmacol. Exp. Ther., April 1, 2002; 301(1): 210 - 216. [Abstract] [Full Text] [PDF]
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Y. Suzaki, M. Yoshizumi, S. Kagami, A. H. Koyama, Y. Taketani, H. Houchi, K. Tsuchiya, E. Takeda, and T. Tamaki Hydrogen Peroxide Stimulates c-Src-mediated Big Mitogen-activated Protein Kinase 1 (BMK1) and the MEF2C Signaling Pathway in PC12 Cells. POTENTIAL ROLE IN CELL SURVIVAL FOLLOWING OXIDATIVE INSULTS J. Biol. Chem., March 8, 2002; 277(11): 9614 - 9621. [Abstract] [Full Text] [PDF]
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 B. Krishnadasan, C. R. Hampton, J. Griscavage-Ennis, R. J. Dabal, and E. D. Verrier Molecular Mechanisms of Neurologic Injury Following Cardiopulmonary Bypass Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2002; 6(1): 43 - 53. [Abstract] [PDF]
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G. W. Kim, T. Kondo, N. Noshita, and P. H. Chan Manganese Superoxide Dismutase Deficiency Exacerbates Cerebral Infarction After Focal Cerebral Ischemia/Reperfusion in Mice: Implications for the Production and Role of Superoxide Radicals Stroke, March 1, 2002; 33(3): 809 - 815. [Abstract] [Full Text] [PDF]
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T. Sumii and E. H. Lo Involvement of Matrix Metalloproteinase in Thrombolysis-Associated Hemorrhagic Transformation After Embolic Focal Ischemia in Rats Stroke, March 1, 2002; 33(3): 831 - 836. [Abstract] [Full Text] [PDF]
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T. Sugawara, N. Noshita, A. Lewen, Y. Gasche, M. Ferrand-Drake, M. Fujimura, Y. Morita-Fujimura, and P. H. Chan Overexpression of Copper/Zinc Superoxide Dismutase in Transgenic Rats Protects Vulnerable Neurons against Ischemic Damage by Blocking the Mitochondrial Pathway of Caspase Activation J. Neurosci., January 1, 2002; 22(1): 209 - 217. [Abstract] [Full Text] [PDF]
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W. Droge Free Radicals in the Physiological Control of Cell Function Physiol Rev, January 1, 2002; 82(1): 47 - 95. [Abstract] [Full Text] [PDF]
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H. A. Kontos Oxygen Radicals in Cerebral Ischemia: The 2001 Willis Lecture Stroke, November 1, 2001; 32(11): 2712 - 2716. [Abstract] [Full Text] [PDF]
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 W. Ying, M. B. Sevigny, Y. Chen, and R. A. Swanson Poly(ADP-ribose) glycohydrolase mediates oxidative and excitotoxic neuronal death PNAS, October 9, 2001; 98(21): 12227 - 12232. [Abstract] [Full Text] [PDF]
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Y. Morita-Fujimura, M. Fujimura, T. Yoshimoto, and P. H. Chan Superoxide During Reperfusion Contributes to Caspase-8 Expression and Apoptosis After Transient Focal Stroke Stroke, October 1, 2001; 32(10): 2356 - 2361. [Abstract] [Full Text] [PDF]
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H. Chen, C.-J. Hu, Y. Y. He, D.-I Yang, J. Xu, and C. Y. Hsu Reduction and Restoration of Mitochondrial DNA Content After Focal Cerebral Ischemia/Reperfusion Stroke, October 1, 2001; 32(10): 2382 - 2387. [Abstract] [Full Text] [PDF]
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H. Imai, H. Masayasu, D. Dewar, D. I. Graham, and I. M. Macrae Ebselen Protects Both Gray and White Matter in a Rodent Model of Focal Cerebral Ischemia Stroke, September 1, 2001; 32(9): 2149 - 2154. [Abstract] [Full Text] [PDF]
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C.-Y. Huang, M. Fujimura, Y.-Y. Chang, and P. H. Chan Overexpression of Copper-Zinc Superoxide Dismutase Attenuates Acute Activation of Activator Protein-1 After Transient Focal Cerebral Ischemia in Mice Stroke, March 1, 2001; 32(3): 741 - 747. [Abstract] [Full Text] [PDF]
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 T. Hoshi and S. H Heinemann Regulation of cell function by methionine oxidation and reduction J. Physiol., February 15, 2001; 531(1): 1 - 11. [Abstract] [Full Text] [PDF]
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L. Belayev, Y. Liu, W. Zhao, R. Busto, and M. D. Ginsberg Human Albumin Therapy of Acute Ischemic Stroke : Marked Neuroprotective Efficacy at Moderate Doses and With a Broad Therapeutic Window Stroke, February 1, 2001; 32(2): 553 - 560. [Abstract] [Full Text] [PDF]
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C. Iadecola, K. Niwa, S. Nogawa, X. Zhao, M. Nagayama, E. Araki, S. Morham, and M. E. Ross Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice PNAS, January 30, 2001; 98(3): 1294 - 1299. [Abstract] [Full Text] [PDF]
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 W.-D. Heiss, L. W. Kracht, A. Thiel, M. Grond, and G. Pawlik Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia Brain, January 1, 2001; 124(1): 20 - 29. [Abstract] [Full Text] [PDF]
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H. Nakane, Y. Chu, F. M. Faraci, L. W. Oberley, D. D. Heistad, and P. H. Chan Gene Transfer of Extracellular Superoxide Dismutase Increases Superoxide Dismutase Activity in Cerebrospinal Fluid Editorial Comment Stroke, January 1, 2001; 32(1): 184 - 189. [Abstract] [Full Text] [PDF]
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K. Sampei, A. S. Mandir, Y. Asano, P. C. Wong, R. J. Traystman, V. L. Dawson, T. M. Dawson, P. D. Hurn, and C. Y. Hsu Stroke Outcome in Double-Mutant Antioxidant Transgenic Mice Editorial Comment Stroke, November 1, 2000; 31(11): 2685 - 2691. [Abstract] [Full Text] [PDF]
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T. Neumann-Haefelin, A. Kastrup, A. de Crespigny, M. A. Yenari, T. Ringer, G. H. Sun, M. E. Moseley, and M. Fisher Serial MRI After Transient Focal Cerebral Ischemia in Rats : Dynamics of Tissue Injury, Blood-Brain Barrier Damage, and Edema Formation Editorial Comment: Dynamics of Tissue Injury, Blood-Brain Barrier Damage, and Edema Formation Stroke, August 1, 2000; 31(8): 1965 - 1973. [Abstract] [Full Text] [PDF]
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Y. Gursoy-Ozdemir, H. Bolay, O. Saribas, T. Dalkara, and J. S. Beckman Role of Endothelial Nitric Oxide Generation and Peroxynitrite Formation in Reperfusion Injury After Focal Cerebral Ischemia Editorial Comment Stroke, August 1, 2000; 31(8): 1974 - 1981. [Abstract] [Full Text] [PDF]
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M. v. L. Campagne, H. Thibodeaux, N. van Bruggen, B. Cairns, and D. G. Lowe Increased Binding Activity at an Antioxidant-Responsive Element in the Metallothionein-1 Promoter and Rapid Induction of Metallothionein-1 and -2 in Response to Cerebral Ischemia and Reperfusion J. Neurosci., July 15, 2000; 20(14): 5200 - 5207. [Abstract] [Full Text] [PDF]
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C. E. Weaver, M. B. Land, R. H. Purdy, K. G. Richards, T. T. Gibbs, and D. H. Farb Geometry and Charge Determine Pharmacological Effects of Steroids on N-Methyl-D-aspartate Receptor-Induced Ca2+ Accumulation and Cell Death J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 747 - 754. [Abstract] [Full Text]
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B. R. Hu, M. E. Martone, Y. Z. Jones, and C. L. Liu Protein Aggregation after Transient Cerebral Ischemia J. Neurosci., May 1, 2000; 20(9): 3191 - 3199. [Abstract] [Full Text] [PDF]
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A. Davalos, J. Castillo, J. Marrugat, J. M. Fernandez-Real, A. Armengou, P. Cacabelos, and R. Rama Body iron stores and early neurologic deterioration in acute cerebral infarction Neurology, April 25, 2000; 54(8): 1568 - 1574. [Abstract] [Full Text] [PDF]
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M. Fujimura, Y. Morita-Fujimura, N. Noshita, T. Sugawara, M. Kawase, and P. H. Chan The Cytosolic Antioxidant Copper/Zinc-Superoxide Dismutase Prevents the Early Release of Mitochondrial Cytochrome c in Ischemic Brain after Transient Focal Cerebral Ischemia in Mice J. Neurosci., April 15, 2000; 20(8): 2817 - 2824. [Abstract] [Full Text] [PDF]
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D. Ito, M. Murata, K. Watanabe, T. Yoshida, I. Saito, N. Tanahashi, and Y. Fukuuchi C242T Polymorphism of NADPH Oxidase p22 PHOX Gene and Ischemic Cerebrovascular Disease in the Japanese Population Stroke, April 1, 2000; 31(4): 936 - 939. [Abstract] [Full Text] [PDF]
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 M. OZAKI, S. S. DESHPANDE, P. ANGKEOW, J. BELLAN, C. J. LOWENSTEIN, M. C. DINAUER, P. J. GOLDSCHMIDT-CLERMONT, and K. IRANI Inhibition of the Rac1 GTPase protects against nonlethal ischemia/reperfusion-induced necrosis and apoptosis in vivo FASEB J, February 1, 2000; 14(2): 418 - 429. [Abstract] [Full Text]
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Recommendations for Standards Regarding Preclinical Neuroprotective and Restorative Drug Development Stroke, December 1, 1999; 30(12): 2752 - 2758. [Abstract] [Full Text] [PDF]
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M. Fujimura, Y. Morita-Fujimura, P. Narasimhan, J.-C. Copin, M. Kawase, P. H. Chan, and C. Y. Hsu Copper-Zinc Superoxide Dismutase Prevents the Early Decrease of Apurinic/Apyrimidinic Endonuclease and Subsequent DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice • Editorial Comment Stroke, November 1, 1999; 30(11): 2408 - 2415. [Abstract] [Full Text] [PDF]
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M. Fujimura, Y. Morita-Fujimura, T. Sugawara, P. H. Chan, and C. Y. Hsu Early Decrease of XRCC1, a DNA Base Excision Repair Protein, May Contribute to DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice • Editorial Comment Stroke, November 1, 1999; 30(11): 2456 - 2463. [Abstract] [Full Text] [PDF]
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M. van Lookeren Campagne, H. Thibodeaux, N. van Bruggen, B. Cairns, R. Gerlai, J. T. Palmer, S. P. Williams, and D. G. Lowe Evidence for a protective role of metallothionein-1 in focal cerebral ischemia PNAS, October 26, 1999; 96(22): 12870 - 12875. [Abstract] [Full Text] [PDF]
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P. Lipton Ischemic Cell Death in Brain Neurons Physiol Rev, October 1, 1999; 79(4): 1431 - 1568. [Abstract] [Full Text] [PDF]
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P.-E. Chabrier, M. Auguet, B. Spinnewyn, S. Auvin, S. Cornet, C. Demerle-Pallardy, C. Guilmard-Favre, J.-G. Marin, B. Pignol, V. Gillard-Roubert, et al. BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: A promising neuroprotective strategy PNAS, September 14, 1999; 96(19): 10824 - 10829. [Abstract] [Full Text] [PDF]
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C. Napoli, S. Salomone, T. Godfraind, W. Palinski, D. M. Capuzzi, G. Palumbo, F. P. D'Armiento, R. Donzelli, F. de Nigris, R. L. Capizzi, et al. 1,4-Dihydropyridine Calcium Channel Blockers Inhibit Plasma and LDL Oxidation and Formation of Oxidation-Specific Epitopes in the Arterial Wall and Prolong Survival in Stroke-Prone Spontaneously Hypertensive Rats • Editorial Comment Stroke, September 1, 1999; 30(9): 1907 - 1915. [Abstract] [Full Text] [PDF]
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N. Benjelloun, S. Renolleau, A. Represa, Y. Ben-Ari, C. Charriaut-Marlangue, and G. Z. Feuerstein Inflammatory Responses in the Cerebral Cortex After Ischemia in the P7 Neonatal Rat • Editorial Comment Stroke, September 1, 1999; 30(9): 1916 - 1924. [Abstract] [Full Text] [PDF]
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M. Kawase, K. Murakami, M. Fujimura, Y. Morita-Fujimura, Y. Gasche, T. Kondo, R. W. Scott, P. H. Chan, and M. S. Wolin Exacerbation of Delayed Cell Injury After Transient Global Ischemia in Mutant Mice With CuZn Superoxide Dismutase Deficiency • Editorial Comment Stroke, September 1, 1999; 30(9): 1962 - 1968. [Abstract] [Full Text] [PDF]
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C. J. Vaughan and N. Delanty Neuroprotective Properties of Statins in Cerebral Ischemia and Stroke Stroke, September 1, 1999; 30(9): 1969 - 1973. [Abstract] [Full Text] [PDF]
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 D. O'MAHONY and M. J KENDALL Nitric oxide in acute ischaemic stroke: a target for neuroprotection J. Neurol. Neurosurg. Psychiatry, July 1, 1999; 67(1): 1 - 3. [Full Text]
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W.-D. Heiss, A. Thiel, M. Grond, and R. Graf Which Targets Are Relevant for Therapy of Acute Ischemic Stroke? Stroke, July 1, 1999; 30(7): 1486 - 1489. [Abstract] [Full Text] [PDF]
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D. A. Shackelford, T. Tobaru, S. Zhang, and J. A. Zivin Changes in Expression of the DNA Repair Protein Complex DNA-Dependent Protein Kinase after Ischemia and Reperfusion J. Neurosci., June 15, 1999; 19(12): 4727 - 4738. [Abstract] [Full Text] [PDF]
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M. Fujimura, Y. Morita-Fujimura, M. Kawase, J.-C. Copin, B. Calagui, C. J. Epstein, and P. H. Chan Manganese Superoxide Dismutase Mediates the Early Release of Mitochondrial Cytochrome C and Subsequent DNA Fragmentation after Permanent Focal Cerebral Ischemia in Mice J. Neurosci., May 1, 1999; 19(9): 3414 - 3422. [Abstract] [Full Text] [PDF]
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 C. Iadecola, C. A. Salkowski, F. Zhang, T. Aber, M. Nagayama, S. N. Vogel, and M. Elizabeth Ross The Transcription Factor Interferon Regulatory Factor 1 Is Expressed after Cerebral Ischemia and Contributes to Ischemic Brain Injury J. Exp. Med., February 15, 1999; 189(4): 719 - 727. [Abstract] [Full Text] [PDF]
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M. A. Weigand, A. Laipple, K. Plaschke, H.-H. Eckstein, E. Martin, and H. J. Bardenheuer Concentration Changes of Malondialdehyde Across the Cerebral Vascular Bed and Shedding of L-Selectin During Carotid Endarterectomy Stroke, February 1, 1999; 30(2): 306 - 311. [Abstract] [Full Text] [PDF]
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M. Kawase, M. Fujimura, Y. Morita-Fujimura, P. H. Chan, and C. Iadecola Reduction of Apurinic/Apyrimidinic Endonuclease Expression After Transient Global Cerebral Ischemia in Rats : Implication of the Failure of DNA Repair in Neuronal Apoptosis • Editorial Comment: Implication of the Failure of DNA Repair in Neuronal Apoptosis Stroke, February 1, 1999; 30(2): 441 - 449. [Abstract] [Full Text] [PDF]
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P. H. Chan, M. Kawase, K. Murakami, S. F. Chen, Y. Li, B. Calagui, L. Reola, E. Carlson, and C. J. Epstein Overexpression of SOD1 in Transgenic Rats Protects Vulnerable Neurons Against Ischemic Damage After Global Cerebral Ischemia and Reperfusion J. Neurosci., October 15, 1998; 18(20): 8292 - 8299. [Abstract] [Full Text] [PDF]
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A. Li, J. Segui, S. H. Heinemann, and T. Hoshi Oxidation Regulates Cloned Neuronal Voltage-Dependent Ca2+ Channels Expressed in Xenopus Oocytes J. Neurosci., September 1, 1998; 18(17): 6740 - 6747. [Abstract] [Full Text] [PDF]
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G. J DEL ZOPPO, R. VON KUMMER, and G. F HAMANN Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke J. Neurol. Neurosurg. Psychiatry, July 1, 1998; 65(1): 1 - 9. [Full Text]
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J. M. Gidday, T.S. Park, A. R. Shah, E. R. Gonzales, P. M. Kochanek, R. S.B. Clark, and M. J. Whalen Modulation of Basal and Postischemic Leukocyte-Endothelial Adherence by Nitric Oxide • Editorial Comment Stroke, July 1, 1998; 29(7): 1423 - 1430. [Abstract] [Full Text] [PDF]
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 K.-A. Hossmann Experimental models for the investigation of brain ischemia Cardiovasc Res, July 1, 1998; 39(1): 106 - 120. [Full Text] [PDF]
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B. Ancona, L. Facci, D. Franceschini, and P. Giusti Melatonin prevents the delayed death of hippocampal neurons induced by enhanced excitatory neurotransmission and the nitridergic pathway FASEB J, June 1, 1998; 12(9): 725 - 731. [Abstract] [Full Text]
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M. Soehle, A. Heimann, O. Kempski, and C. Iadecola Postischemic Application of Lipid Peroxidation Inhibitor U-101033E Reduces Neuronal Damage After Global Cerebral Ischemia in Rats • Editorial Comment Stroke, June 1, 1998; 29(6): 1240 - 1247. [Abstract] [Full Text] [PDF]
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E. H. Lo, P. Bosque-Hamilton, W. Meng, and N. Panahian Inhibition of Poly(ADP-Ribose) Polymerase : Reduction of Ischemic Injury and Attenuation of N-Methyl-D-Aspartate–Induced Neurotransmitter Dysregulation • Editorial Comment: Reduction of Ischemic Injury and Attenuation of N-Methyl-D-Aspartate–Induced Neurotransmitter Dysregulation Stroke, April 1, 1998; 29(4): 830 - 836. [Abstract] [Full Text] [PDF]
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B.-R. Hu, M. Park, M. E. Martone, W. H. Fischer, M. H. Ellisman, and J. A. Zivin Assembly of Proteins to Postsynaptic Densities after Transient Cerebral Ischemia J. Neurosci., January 15, 1998; 18(2): 625 - 633. [Abstract] [Full Text] [PDF]
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G. T. Gobbel, M. Bellinzona, A. R. Vogt, N. Gupta, J. R. Fike, and P. H. Chan Response of Postmitotic Neurons to X-Irradiation: Implications for the Role of DNA Damage in Neuronal Apoptosis J. Neurosci., January 1, 1998; 18(1): 147 - 155. [Abstract] [Full Text] [PDF]
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H.-J. Bidmon, K. Kato, A. Schleicher, O. W. Witte, K. Zilles, and R. J. Traystman Transient Increase of Manganese–Superoxide Dismutase in Remote Brain Areas After Focal Photothrombotic Cortical Lesion • Editorial Comment Stroke, January 1, 1998; 29(1): 203 - 211. [Abstract] [Full Text] [PDF]
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A. Armengou, A. Davalos, J. M. Fernandez-Real, and J. Castillo Serum Ferritin Concentrations Are Not Modified in the Acute Phase of Ischemic Stroke Stroke, January 1, 1998; 29(1): 258 - 260. [Full Text]
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C. Iadecola, F. Zhang, R. Casey, M. Nagayama, and M. E. Ross Delayed Reduction of Ischemic Brain Injury and Neurological Deficits in Mice Lacking the Inducible Nitric Oxide Synthase Gene J. Neurosci., December 1, 1997; 17(23): 9157 - 9164. [Abstract] [Full Text] [PDF]
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M. Spranger, S. Krempien, S. Schwab, S. Donneberg, and W. Hacke Superoxide Dismutase Activity in Serum of Patients With Acute Cerebral Ischemic Injury : Correlation With Clinical Course and Infarct Size Stroke, December 1, 1997; 28(12): 2425 - 2428. [Abstract] [Full Text]
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R. Schmid-Elsaesser, S. Zausinger, E. Hungerhuber, N. Plesnila, A. Baethmann, and H.-J. Reulen Superior Neuroprotective Efficacy of a Novel Antioxidant (U-101033E) With Improved Blood-Brain Barrier Permeability in Focal Cerebral Ischemia Stroke, October 1, 1997; 28(10): 2018 - 2024. [Abstract] [Full Text]
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I. Kruman, A. J. Bruce-Keller, D. Bredesen, G. Waeg, and M. P. Mattson Evidence that 4-Hydroxynonenal Mediates Oxidative Stress-Induced Neuronal Apoptosis J. Neurosci., July 1, 1997; 17(13): 5089 - 5100. [Abstract] [Full Text] [PDF]
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S. Nogawa, F. Zhang, M. E. Ross, and C. Iadecola Cyclo-Oxygenase-2 Gene Expression in Neurons Contributes to Ischemic Brain Damage J. Neurosci., April 15, 1997; 17(8): 2746 - 2755. [Abstract] [Full Text] [PDF]
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 A. I. Faden Pharmacologic Treatment of Acute Traumatic Brain Injury JAMA, August 21, 1996; 276(7): 569 - 570. [Abstract] [PDF]
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E. H. Lo, H. Hara, J. Rogowska, M. Trocha, A. R. Pierce, P. L. Huang, M. C. Fishman, G. L. Wolf, M. A. Moskowitz, and P. H. Chan Temporal Correlation Mapping Analysis of the Hemodynamic Penumbra in Mutant Mice Deficient in Endothelial Nitric Oxide Synthase Gene Expression Stroke, August 1, 1996; 27(8): 1381 - 1385. [Abstract] [Full Text]
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