Oxidants, antioxidants and the ischemic brain
-Haberle2
1 Department of Anesthesiology, The Multidisciplinary Neuroprotection
Laboratories, Duke University Medical Center, Durham, NC 27710, USA
2 Department of Radiation Oncology, The Multidisciplinary Neuroprotection
Laboratories, Duke University Medical Center, Durham, NC 27710, USA
3 Department of Neurobiology, The Multidisciplinary Neuroprotection
Laboratories, Duke University Medical Center, Durham, NC 27710, USA
4 Surgery (Neurosurgery), The Multidisciplinary Neuroprotection
Laboratories, Duke University Medical Center, Durham, NC 27710, USA
* Author for correspondence (e-mail: warne002{at}mc.duke.edu)
Accepted 13 April 2004
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Summary |
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Key words: brain, ischemia, oxidative stress, antioxidant
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Introduction |
---|
Principal sources of superoxide include electron leak during mitochondrial
electron transport, perturbed mitochondrial metabolism and inflammatory
responses to injury (Halliwell and
Gutteridge, 1999). The brain has potent defenses against
superoxide including dietary free-radical scavengers (ascorbate,
-tocopherol), the endogenous tripeptide glutathione, and enzymatic
antioxidants. Enzymatic antioxidants regulate superoxide concentration by
dismutation of superoxide to hydrogen peroxide (superoxide dismutase or SOD;
Fridovich, 1995
), which is
then converted to water (peroxidases such as glutathione peroxidase and
peroxiredoxin) or dismuted to water and oxygen (catalase).
Although increased expression of these enzymes can occur in response to
ischemia (Fukui et al., 2002),
endogenous antioxidant capacity can be overwhelmed, leading to increased
superoxide and hydrogen peroxide concentrations. Nitric oxide formation is
both constitutive and inducible. Ischemia-induced nitric oxide overproduction
is in part caused by glutamatergic-mediated increases in intracellular calcium
concentration, resulting in a calmodulin-dependent upregulation of nitric
oxide synthase (NOS; Dawson et al.,
1991
; Garthwaite et al.,
1988
,
1989
). Nitric oxide can be
consumed by reacting with hemoglobin
(Ignarro et al., 1987
;
Joshi et al., 2002
).
Flavohemoglobin-based enzymes (nitric oxide reductase, nitric oxide
dioxygenase) capable of specifically metabolizing nitric oxide have been
identified in bacteria (Hausladen et al.,
1998
), and flavohemoglobin-like activity has been identified in
mammalian cells (Gardner et al.,
2001
). Yet, an important non-enzymatic mechanism regulating nitric
oxide concentration is its reaction with superoxide yielding peroxynitrite
(Beckman et al., 1990
).
Under pathophysiological conditions, excessive nitric oxide production can
elicit nitrosative damage (Espey et al.,
2000) via independent nitrosylation of protein heme sites
(e.g. cytochrome c; Schonhoff et
al., 2003
) or through its reaction products with oxygen or other
nitrogen oxides. Superoxide can cause oxidative damage of iron/sulfur clusters
of aconitase (Gardner and Fridovich,
1991
), an important enzyme in the tricarboxylic acid cycle. The
major oxidative stress produced by superoxide, however, is derived from its
participation in peroxynitrite formation
(Beckman et al., 1990
) and its
involvement in the iron-catalyzed HaberWeiss reaction
(superoxide-driven Fenton chemistry;
Liochev and Fridovich, 2002
),
causing hydrogen peroxide to be converted to hydroxyl radical. Hydroxyl
radical, peroxynitrite and peroxynitrite-derived products (hydroxyl radical,
carbonate radical and nitrogen dioxide) all have the potential to react with
and damage most cellular targets including lipids, proteins and DNA.
Direct measurement of reactive oxygen (ROS) and nitrogen (RNS) species
concentrations in tissue subjected to ischemia/reperfusion is problematic
(Tarpey and Fridovich, 2001).
Low intracellular concentrations, short half-lives and the efficient and
redundant systems that have evolved to scavenge ROS/RNS require that any
detection technique must be sensitive and specific enough to compete with
antioxidant defenses against the species in question
(Fridovich, 2003
;
Glebska and Koppenol, 2003
;
Myhre et al., 2003
;
Zhao et al., 2003
).
Additionally, the methods applied must have intracellular access to monitor
the intracellular milieu. This undoubtedly has contributed to confusion
surrounding the roles of these species in disease. Most commonly, ROS/RNS have
been tracked by measuring stable metabolites (e.g. nitrates/nitrites) or
`footprints' of the reactions of these molecules with lipids (e.g.
thiobarbituric acid adducts, 4-hydroxynonenal), DNA (e.g. 8-hydroxyguanine) or
proteins (e.g. nitrotyrosine). Electrochemical and microdialysis approaches
have also proven useful in tracking superoxide
(Fabian et al., 1995
) and
hydroxyl radical (Globus et al.,
1995
) concentrations.
An alternative approach to the study of ROS/RNS in ischemic brain is the
use of either transgenic animals or pharmacological agents to alter
antioxidant potential. For example, if targeted disruption of a specific SOD
genetic coding sequence increases ischemic tissue damage, evidence is provided
that the enzyme plays a beneficial role in the response of brain to oxidative
stress. This is further supported if overexpression of the same gene results
in increased tissue tolerance to ischemia. There are two major limitations to
the use of transgenic mice in study of oxidative stress. First, compensatory
mechanisms, perhaps developed during ontogeny so as to allow survival in the
absence/overexpression of the gene, are rarely considered, particularly in the
context of the experiment being performed
(Ibrahim et al., 2000;
Przedborski et al., 1992
).
Second, although progress is being made in the use of conditional `knock-outs'
and `overexpressors', in which a selected gene's expression is
decreased/increased in response to a specific pharmacological stimulus, most
work continues to be performed with animals that retain their knock-out (or
overexpressing) status throughout the entire ischemia/reperfusion interval.
This makes it difficult to determine when and how the gene product influences
ischemic injury.
The ultimate goal for understanding the mechanism of oxidative stress in brain ischemia is to develop therapeutic interventions. To this end, innumerable pharmacological antioxidants have been evaluated. Although these agents have received the greatest scrutiny for therapeutic potential, the same agents can also be used to dissect the role of oxidative stress in ischemic brain injury by assessing the impact of their purported mechanism of action on ischemia-induced intracellular cascades and outcome. On the other hand, the study of pharmacological agents is limited by bioavailability and undefined secondary effects when introduced into an in vivo environment. Thus, transgenic and pharmacological interventions can be viewed as complimentary tools to examine the role of oxidative stress in ischemic brain injury. This review will consider various possible contributions of oxidative stress to ischemic brain injury, with a focus on validation of the mechanism via either transgenic or pharmacological intervention (Fig. 1).
|
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Inhibition of lipid peroxidation |
---|
Increased nitric oxide concentrations associated with ischemia may have
dual effects on lipid peroxidation. Reaction of nitric oxide with superoxide
causes formation of peroxynitrite that initiates lipid peroxidation
via reaction of lipids with its decomposition products hydroxyl
radical and nitrogen dioxide (Brookes et
al., 1998; Rubbo et al.,
1994
). In contrast, nitric oxide itself may directly inhibit lipid
peroxidation by intercepting alkoxyl and peroxyl radical intermediates thereby
terminating chain propagation reactions
(Nicolescu et al., 2002
;
Niziolek et al., 2003
;
Rubbo et al., 1994
).
Despite this, it has been difficult to confirm that lipid peroxidation is a
primary and critical contributor to ischemic cell death as opposed to being a
result of intracellular organelle dysfunction mediated by oxidative stress
(Watson, 1998). Indeed,
numerous pharmacological inhibitors of lipid peroxidation have been tested.
The most notable is tirilazad, a non-glucocorticoid steroid. Despite abundant
preclinical evidence that tirilazad improved ischemic outcome via its
putative action as inhibitor of lipid peroxidation
(Kavanagh and Kam, 2001
), no
effect on outcome from human stroke was observed
(Haley, 1998
). It should be
noted that virtually all of the positive preclinical studies recorded only a
short-term outcome (i.e. several days post-ischemia), while human trials
measured the outcome after 3 months. Although it is clear that lipid
peroxidation occurs in response to oxidative stress and that membrane
disruption is disadvantageous to the cell, the available outcome data are
insufficient to allow the conclusion that this mechanism is critical in
defining ischemic outcome.
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Inhibition of xanthine oxidase |
---|
Allopurinol decreases post-ischemic cerebral uric acid, xanthine and
conjugated diene concentrations (Marro et
al., 1994; Nihei et al.,
1989
), preserves ATP
(Williams et al., 1992
), and
reduces edema (Patt et al.,
1988
). Despite this, studies employing the requisite physiological
control and longterm outcome analysis of effects of xanthine oxidase
inhibitors on post-ischemic behavior and histology have not been performed.
The results from short-term outcome studies in adult rats have been mixed
(Lindsay et al., 1991
;
Martz et al., 1989
). More
encouraging results have been observed in perinatal brain (Palmer et al.,
1993
,
1990
;
van Bel et al., 1998
), but no
long-term outcome studies have been reported. As a result, despite biochemical
evidence of diminished oxidative stress from inhibition of hypoxanthine
metabolism, evidence supporting xanthine dehydrogenase/oxidase activity as a
major contributor to ischemic outcome is modest. This is not surprising
because many other avenues for superoxide and hydrogen peroxide generation
(e.g. inflammation) are unaffected by xanthine oxidase inhibitors.
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The superoxide dismutases and their mimetics |
---|
Extracellular SOD (SOD3) is also expressed in brain but in substantially
lower concentrations than SOD1 or SOD2
(Marklund, 1984). EC-SOD, a
tetrameric protein, is secreted into the extracellular compartment
(Tibell et al., 1987
). EC-SOD
has a heparin binding domain that allows adherence to the glycocalyx
(Sandstrom et al., 1992
).
EC-SOD is presumed to provide defense against superoxide present in the
extracellular space (e.g. produced by membrane-bound NAD(P)H oxidase or
secreted by inflammatory cells; Oury et
al., 1992
). The relatively low EC-SOD concentration in whole brain
may be misleading with respect to its importance to ischemic events. The
extracellular compartment is small and thus EC-SOD concentration in the
extracellular compartment may be sufficient to provide biological relevance.
Indeed, EC-SOD overexpressing mice have increased tolerance to both focal and
global cerebral ischemia (Sheng et al.,
1999a
,
2000
), while EC-SOD
knock-outs exhibit enhanced damage (Sheng
et al., 1999b
). These data implicate an important role for
extracellular superoxide in the pathogenesis of ischemia/reperfusion and
suggest a therapeutic role for SOD mimetics that localize in the extracellular
compartment.
Recent pharmacological advances have allowed the advent of potent SOD
mimetics. Although bovine SOD has shown some therapeutic potential
(Liu et al., 1989), its
short-half life in circulation, inability to penetrate the bloodbrain
barrier and potential antigenicity have limited its appeal. Several major
classes of SOD mimetics have been reported to date
(Sheng et al., 2002a
): Mn(II)
cyclic polyamines (Riley,
2000
), Mn(III) salen derivatives
(Baker et al., 1998
), Mn(III)
porphyrins (Batinic-Haberle,
2002
; Batinic-Haberle et al.,
2002
) and stable cyclic nitroxides
(Goldstein et al., 2003a
;
Kwon et al., 2003
;
Sugawara et al., 2001
). All
eliminate superoxide in catalytic fashion, with catalytic rate constants being
in excess of 106 M1 s1, except
in the case of nitroxides. With nitroxides the catalytic rate constant,
involving nitroxide/oxoammonium cation redox couple, is limited by the very
slow nitroxide oxidation with superoxide (<103
M1 s1) and is <106
M1 s1 at pH 7.4
(Goldstein et al., 2003a
). The
compounds variously have selective SOD-like properties [Mn cyclic(II)
polyamines (Salvemini et al.,
1999
)], modest catalase-like activity [Mn(III) salen derivatives
(Baker et al., 1998
) and
Mn(III) porphyrins (Day et al.,
1997
)], potential to oxidize nitric oxide [oxoMn(V) salen
derivatives) (Sharpe et al.,
2002
) and Mn(III) porphyrins
(Spasojevic et al., 2000
) and
oxidized nitroxides, i.e. oxoammonium cations
(Goldstein et al., 2004
)], and
ability to eliminate peroxynitrite [Mn(III) salen derivatives
(Sharpe et al., 2002
),
Mn(III) porphyrins (Ferrer-Sueta et al.,
2003
) and oxoammonium cations
(Goldstein et al., 2004
)] or
peroxynitrite-derived products such as nitrogen dioxide radical (nitroxides;
Goldstein et al., 2004
,
2003b
) and carbonate radical
[Mn(III) porphyrins (Ferrer-Sueta et al.,
2003
) and nitroxides
(Goldstein et al., 2004
)].
Reactivity of antioxidants towards a wide range of ROS/RNS would make them
more versatile antioxidants, i.e. protective in different cellular
environments. Mn(III) porphyrins have been most intensively investigated in
models of cerebral ischemia/reperfusion. The cationic Mn(III) porphyrins,
ortho N-ethylpyridylporphyrin (MnTE-2-PyP5+, AEOL 10113)
and di-ortho N,N'-diethylimidazolylporphyrin
(MnTDE-2-ImP5+, AEOL 10150) have both been shown to provide potent
protection against infarct formation when given as late as 6 h after onset of
reperfusion from 90 min of temporary middle cerebral artery occlusion
(Mackensen et al., 2001
;
Sheng et al., 2002b
). This
was associated with post-ischemic decreases in aconitase inactivation,
8-hydroxyguanine formation and cytokine expression
(Bowler et al., 2002
;
Mackensen et al., 2001
).
Long-term outcome studies and effects on apoptotic responses have not yet been
reported for these drugs.
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Catalase and glutathione peroxidase |
---|
Both glutathione peroxidase-overexpressing and knock-out mice have been
studied in the context of focal cerebral ischemia/reperfusion. Overexpression
reduces necrotic and apoptotic cell death, astrocytic/microglial activation
and inflammatory cell infiltration
(Ishibashi et al., 2002;
Weisbrot-Lefkowitz et al.,
1998
). In contrast, intracerebroventricular infusion of exogenous
glutathione peroxidase failed to improve outcome from global forebrain
ischemia/reperfusion (Yano et al.,
1998
). This difference might be attributable to differences in
model type (focal versus global) or intracellular bioavailability of
glutathione peroxidase when administered intracerebroventricularly. The
progeny of cross-breeding a glutathione peroxidase knock-out and a Cu,Zn-SOD
overexpressor caused a loss of protection that was otherwise afforded by
overexpression of Cu,Zn-SOD (Crack et al.,
2001
). However, the glutathione peroxidase knockout alone was
insufficient to worsen cerebral ischemia/reperfusion injury
(Crack et al., 2001
),
consistent with overlap in function with catalase. Cumulatively, these data
implicate an important role for glutathione peroxidase in brain
ischemia/reperfusion, although the relative contributions of glutathione
peroxidase and catalase have not been clarified.
Selective pharmacological antagonists of glutathione peroxidase have not
been studied. Ebselen is a synthetic mimetic of glutathione peroxidase
(Muller et al., 1984). It is
not selective in that it also inhibits protein kinase C, 5-lipooxygenase,
cyclooxygenase and NADPH oxidase (Schewe,
1995
). Thus, inferences from the efficacy of this drug in the
context of ischemia/reperfusion regarding the role of glutathione peroxidase
must be limited. Ebselen has been shown to be protective in several ischemia
models (Imai et al., 2003
;
Kondoh et al., 1999
) and is
currently being studied in ongoing clinical trials
(Saito et al., 1998
;
Yamaguchi et al., 1998
).
Although a catalase-overexpressing mouse strain exists
(Chen et al., 2003), it has
not been studied in the context of cerebral ischemia/reperfusion. An
alternative method is to examine catalase deficiency. The developing brain
provides a natural model for this in that both catalase and glutathione
peroxidase are poorly expressed. Cu,Zn-SOD overexpression in neonatal mice
worsens the outcome from ischemia/reperfusion
(Fullerton et al., 1998
). In
contrast Cu,Zn-SOD overexpression in adult mice improves the outcome
(Yang et al., 1994
). This
difference is probably attributable to inadequate catalase and glutathione
peroxidase enzymatic activity available to the developing brain for the
conversion of superoxide-generated hydrogen peroxide to water and oxygen
(Fullerton et al., 1998
). The
same argument suggests that endogenous concentrations of catalase and
glutathione concentrations are sufficient in the adult brain to process
superoxide, should its dismutation to hydrogen peroxide be enhanced by a SOD
mimetic.
There has been some attempt to test efficacy of exogenously administered
catalase in adult ischemia/reperfusion models with mixed results, possibly due
to the question of bioavailability of proteins that must cross the
bloodbrain barrier (Forsman et al.,
1988; Liu et al.,
1989
). Catalase inhibitors, such as 3-aminotriazole, have not been
evaluated in the context of ischemia. Therefore, there is insufficient
pharmacological information to conclude that catalase, particularly in the
presence of normal glutathione peroxidase concentrations, plays a central role
in the response of brain to ischemia. This, however, should be tempered by the
possibility that the importance of catalase may increase if superoxide
production and SOD activity are increased.
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Glutathione depletion |
---|
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Nitric oxide synthase inhibition |
---|
The relevance of nitric oxide was increased with the report that the
diffusion-limited reaction between superoxide and nitric oxide gives rise to
peroxynitrite (Beckman et al.,
1990). The highly reactive peroxynitrite provided a mechanistic
basis for oxidative stress derived from increased nitric oxide production
caused by ischemia/reperfusion (Eliasson
et al., 1999
). Studies confirmed increased peroxynitrite formation
occurring in parallel with upregulation of iNOS
(Suzuki et al., 2002
) and
lack of peroxynitrite formation in nNOS knockouts
(Eliasson et al., 1999
).
Nitric oxide has also been shown to inhibit mitochondrial respiration
via competition with oxygen for cytochrome oxidase
(Brown and Borutaite, 1999
)
and play a role in the initiation of apoptosis
(Bonfoco et al., 1995
).
Although little has been reported on efforts to bring nitric oxide inhibitors
to clinical investigation, there is no doubt that nitric oxide plays a pivotal
role in mediating oxidative stress
(Mikkelsen and Wardman,
2003
).
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Metal chelators |
---|
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Poly(ADP-ribose) polymerase inhibitors |
---|
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Mitochondrial permeability transition inhibitors |
---|
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Spin traps |
---|
Mechanistically, in the presence of free radicals, nitrones undergo
oxidation to nitroxide radicals. Goldstein et al.
(2003a) have shown that stable
nitroxides can be reduced to hydroxylamine and oxidized to oxammonium cation,
and thus can act catalytically to eliminate superoxide. However, no data are
presently available to justify the catalytic role of nitrones based on the
formation of nitroxides. Based on its poor bloodbrain barrier
penetration, the protection afforded by NXY-059 against transient focal
cerebral ischemia may be the result of the events occurring at the
blood/endothelial interface (Kuroda et
al., 1999
), or indicate that the drug enters the brain after
bloodbrain barrier breakdown. This distinction is important. More
important is the implication that because commencement of treatment at 4 h
after onset of ischemia was efficacious, only oxidative stress occurring more
than 4 h after onset of ischemia has importance for ischemic outcome.
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Conclusions |
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Acknowledgments |
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