1086
Current Concepts of Cerebrovascular Disease and Stroke
Free Radicals in Central Nervous
System Ischemia
J.W. Schmidley, MD
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Free radicals have been implicated in a wide
variety of diseases and in the toxic and therapeutic
effects of antineoplastic drugs and radiation, the
deleterious consequences of environmental pollutants, and "degenerative" processes such as aging and
Parkinson's disease.1-2 Their involvement in myocardial and intestinal as well as central nervous system
(CNS) ischemia is under intensive study.3
A free radical is any molecule, atom, or group of
atoms with an unpaired electron in its outermost
orbital. Since covalent chemical bonds usually consist of
a pair of electrons sharing an orbital, free radicals can
be thought of as molecules with an "open" or "half
bond, which accounts for their extreme reactivity.3
Free radical species of potential importance in
cerebral ischemia include superoxide (O2~-) and
hydroxyl (OH-). [By convention, the single unpaired
electron in a free radical is represented by a dot.] In
the acidic conditions of ischemic brain, O2~- is probably protonated (HO2~-). The OH- radical is the
more reactive and more toxic of these two molecules.
Hydrogen peroxide (H2O2), while not a free radical
per se, has the potential to generate OH- radicals in
reactions with O2~-, catalyzed by iron (or other
transition metals): O2~+H2O2-»O2+OH~+OH-. In
order to function as a catalyst for this reaction, the Fe
must not be bound to proteins. Since unlike most
extracellular fluids the cerebrospinal fluid (CSF) has
low concentrations of Fe-binding proteins, iron
released from damaged brain cells is more likely to
be readily available to catalyze the generation of
OH-. Fe can also donate electrons to H2O2 to form
OH-: H 2 O 2 +Fe 2 + ^Fe 3 + +OH-+0H". Because H2O2
is nonpolar, it readily crosses membranes unlike O2~\
Free radicals are produced in small amounts by
normal cellular processes. The mitochondrial electron transport system is designed to add four electrons to O2, reducing it to H2O and avoiding the
reactive species produced by single electron reduction of O2. However, "leaks" in mitochondrial electron transport allow O2 to accept single electrons,
forming O2~\ Free radicals are produced in the
reactions catalyzed by prostaglandin hydroperoxi-
dase and are byproducts of the normal or pathologic
function of several other enzymes. They are also
produced in cells by the auto-oxidation of various
small molecules including catecholamines and by the
microsomal cytochrome P-450 reductase system.4
The features of free radical chemistry central to
any potential role in cerebral ischemia are their
extreme reactivity and their tendency to initiate and
participate in chain reactions. When a free radical
with its lone electron reacts with another molecule,
another free radical must be produced (Figure 1).
This free radical in turn can react with another
molecule and so on until the chain of reactions is
terminated either by the random collision of two free
radicals to form a molecule with a stable bond or by
one of the cellular defense mechanisms discussed
below (references 3-8 should be consulted for details
of free radical chemistry).
Free radicals can react with and damage proteins,
nucleic acids, lipids, and other classes of molecules
such as the extracellular matrix glycosaminoglycans
(e.g., hyaluronic acid). The sulfur-containing amino
acids and the polyunsaturated fatty acids are particularly vulnerable. Because the latter are found in
high concentrations in the CNS, most research on the
role of free radicals in cerebral ischemia has concentrated on these molecules. Fatty acids are most
susceptible to free radical attack at alpha methylene
carbons, those adjacent to carbon-carbon double
bonds (Figure 1). Polyunsaturated fatty acids with
several double bonds per molecule are therefore
particularly liable to free radical damage.5
Unicellular and multicellular organisms have a
variety of defenses against free radicals, among them
the low molecular weight "scavengers" such as alphatocopherol and ascorbate. Alpha-tocopherol (vitamin
E) is lipid soluble and therefore easily crosses the
blood-brain barrier and enters cell membranes.
Ascorbate (vitamin C) crosses the blood-brain barrier less easily but is actively transported into CSF by
the choroid plexus and is further concentrated in
neuronal cytoplasm by a second active system. Vitamin C actually exists in a relatively unreactive free
radical form, which by reacting with O2~- and OHFrom the Department of Neurology, Case Western Reserve
radicals can prevent further propagation of chain
University, School of Medicine, Cleveland, Ohio.
Reprinted from Current Concepts of Cerebrovascular Disease and reactions such as that illustrated in Figure 1. Vitamin
Stroke 1990;25:7-12.
E neutralizes free radicals by donating hydrogen
Schmidley
(1)
AJSJU
H*+ .OH — H2O
/UUU
(2)
o) \r\=/w
-o2
(4) V = \ = A = /
o
o
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\ruu
FIGURE 1. In (I), part of a polyunsaturated fatty acid
(PUFA) chain is shown with three double bonds. A -OH
radical "abstracts" a hydrogen atom, forming H2O and an
alkyl free radical center on the PUFA molecule (2), which then
rearranges to form (3) a "conjugated diene" (a saturated C no
longer stands between C atoms with double bonds). Molecular
O2 then adds to form a peroxy radical (4), which can then
abstract a hydrogen atom from a second PUFA molecule,
creating another free radical as in (2) and propagating the
reaction.
atoms; this reaction, of course, leaves an unpaired
electron on the vitamin E molecule, but the free
radical thus created is harmless. Specific enzymes
have also evolved to deal with free radicals. Superoxide dismutase, which exists in mitochondrial and
cytoplasmic forms, catalyzes the conversion of 2 O2~molecules into H2O2 and O2. Because H2O2 is a
potential source of OH- radical, two additional protective enzymes, catalase and glutathione peroxidase,
destroy it. The former converts H2O2 molecules into
O2 and H2O, and the latter catalyzes the oxidation of
reduced glutathione by 2 H2O2. Another enzyme,
glutathione reductase, then regenerates reduced glutathione. Glutathione peroxidase detoxifies lipid
hydroperoxides (see below), as well as H2O2. The
CNS is relatively poorly endowed with superoxide
dismutase, catalase, and glutathione peroxidase and
is also relatively lacking in vitamin E. However, it is
rich in Fe, whose important role in production of
free radicals has already been discussed, and in
polyunsaturated fatty acids,
which are prime targets
for free radical attack.5
Free Radical Involvement in Tissue Damage in
Cerebral Ischemia
The bulk of experimental work on free radicals in
cerebral ischemia has concentrated on damage to
Free Radicals in CNS Ischemia
1087
membrane lipids.9-12 As already noted, neuronal
membranes are rich in polyunsaturated fatty acids,
which are particularly susceptible to free radical
attack at carbons adjacent to double bonds. Figure 1
indicates how this is thought to occur. The lipid
hydroperoxides shown in Figure 1 are not completely
stable in vivo and, in the presence of metals or metal
complexes (e.g., Fe), can further decompose to reactive radicals which will propagate the chain reactions
started by the initial free radical attack. Lipid
hydroperoxides also fragment to produce aldehydes
which can in turn cross-link proteins, rendering them
useless as receptors or enzymes. Potential consequences of damage to membrane lipids include
changes in fluidity and permeability and in the orientation of proteins embedded in the bilayer of the
plasma membrane and other cellular endomembranes. The shape and function of many intrinsic
membrane proteins depend on specific interactions
between their hydrophobic domains and membrane
phospholipids.511 The function of these phospholipid-dependent proteins would be particularly susceptible to free radical damage of the fatty acid
component of membrane phospholipids.11 It is not
surprising that receptor function is also compromised
by lipid peroxidation.12 The consequences of these
alterations for cellular function are potentially lethal.
Because they are extremely short lived and produced only in minute quantities, free radicals are
difficult to measure directly.12 Alternative approaches
to demonstrate their involvement in cerebral ischemic
damage have concentrated on measuring the rate of
consumption of endogenous protective molecules,
such as vitamins C and E, and reduced glutathione or
the formation of by-products of lipid peroxidation,
such as malondialdehyde (MDA), or conjugated
dienes (Figure 1). The MDA assay has several shortcomings, not the least being its lack of specificity for
free radical mediated injury.7 Lastly, in many experimental systems free radical involvement has been
inferred from the protective effects of vitamins C or E,
iron chelators such as deferoxamine, inhibitors of lipid
peroxidation, or enzymes like superoxide dismutase
and catalase. In view of the need to rely on these
indirect or inferential methods and of the well-known
vagaries of animal models of cerebrovascular disorders, it is not surprising that unequivocal evidence of
free radical mechanisms in cerebral ischemia has been
hard to come by. More recently, "trapping" techniques have been applied to the study of free radicals
in cerebral ischemia. These techniques rely on the
reaction of free radicals with reagents to produce
longer lived products which can be detected using
electron spin resonance spectroscopy or high performance liquid chromatography with electrochemical
detection.1314 However, even these newer techniques
may not be free of artifact, particularly in biologic
systems.15
In vitro incubation of brain slices, cell cultures,
homogenates, or subcellular fractions with free radical
generating systems results in various combinations of
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Stroke Vol 21, No 7, July 1990
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diene conjugation, MDA production, destruction of
membrane phospholipids with concomitant release of
free fatty acids, particularly polyunsaturated fatty
acids, and depletion of vitamin E. These changes are
accompanied by histologic, ultrastructural, and neurochemical evidence of tissue damage and edema. The
activity of both neuronal and blood-brain barrier
endothelial Na+-K+ ATPase is impaired, as are synaptosomal uptake of serotonin and GABA and mitochondrial function. These results (summarized in reference 12) establish that free radicals are clearly
capable of damaging CNS tissue but leave unanswered
questions about whether (and where) free radical
mechanisms contribute to cerebral ischemic damage
in vivo.
We have not yet addressed the question of how
O2-derived free radicals might be generated in ischemic tissues. In nearly complete ischemia insufficient
O2 is available to accept electrons passed along the
mitochondrial electron transport chain, leading to
eventual reduction ("electron saturation") of components of this system, such as flavin adenine dinucleotide and coenzyme Q (CoQ). In the presence of
small amounts of O2, these molecules can then
auto-oxidize to produce, for example, O2~*:CoQ
(reduced)+O2->CoQ-+O2~\ The residual O2 molecules in severely ischemic brain cannot act as electron
acceptors in the "normal" fashion because oxidationreduction ("redox") potential sufficient to favor stepwise electron transfer to them cannot be generated
by such low concentrations of molecular oxygen.11
With reperfusion reactive oxygen radicals may be
generated as by-products of the reactions of arachidonic acid to produce prostaglandins and leukotrienes. These enzymes would be particularly active
during reperfusion because an abundance of their
substrate, free arachidonic acid, would have been
released from membrane phospholipids during ischemia, and with reperfusion O2 would also be available. During reduction of the hydroperoxide group of
prostaglandin G2 (PGG2) to form prostaglandin H2
(PGH2), a free radical intermediate forms which in
turn is reduced by nicotinamide adenine dinucleotide
(NAD) or NAD-phosphate, generating free radical
forms of these compounds which could then donate
an electron to O2 to form O2~\ The issue of reperfusion injury to brain or its microvessels assumes new
importance in view of recently developed thrombolytic therapies for CNS ischemia.
Experiments using depletion of vitamin C, reduced
glutathione, or MDA production as indicators of in
vivo free radical production in ischemic CNS tissues
have produced contradictory results. Recent work
using the more sensitive conjugated diene technique
has demonstrated lipid peroxidation during recirculation following global and focal cerebral ischemia.
However, the results suggested spotty, focal involvement and were more impressive for global than
for focal ischemia.910 The "trapping" techniques
described earlier have been used by two groups
recently to detect free radical production after 8
minutes of global ischemia and 15 minutes of reperfusion in the rat13 and after 5-15 minutes of severe
forebrain ischemia and 5-15 minutes of reperfusion
in the gerbil.14 Thus, conclusive evidence that free
radicals play an important direct role in focal cerebral ischemia is still lacking at this time.
The part played by the O2~- generating enzyme,
xanthine oxidase (XO), in cerebral ischemia has also
not been defined. In ischemia of other viscera including gut and heart, xanthine dehydrogenase (XDH),
an enzyme which ordinarily cannot produce free
radical species, is converted to XO, probably by
Ca2+-activated proteolysis.3 With reperfusion XO
then catalyzes the conversion of hypoxanthine to
urate, forming O2~* as a byproduct. O2~* can, of
course, be scavenged by superoxide dismutase but
with the creation of a molecule of H2O2, which, as we
have seen, can react with further O2~- molecules in an
iron-catalyzed reaction to form OH-. Substrate for
XO is present in abundance because it accumulates
as ATP is depleted. Brain content of XDH/XO is
low, but the enzyme is present in the microvessels of
the blood-brain barrier.16
Cerebral Vasculature as Target for Free Radicals
Up to this point we have considered only the brain
parenchyma as a target for free radical damage. The
experiments of Kontos and colleagues,17-19 however,
strongly suggest that free radical mechanisms are
important in mediating the response of small cerebral arterioles to acute hypertension and perhaps in
the changes of hypertensive encephalopathy. These
studies began with the observation that cyclooxygenase inhibitors eliminated and direct application of
arachidonic acid reproduced the cerebral arteriolar
responses to acute hypertension, including dilatation,
diminished responsiveness to CO2, morphologic
changes in endothelium and smooth muscle, and
increased permeability. These responses could be
elicited not only by topical arachidonic acid but also
by PGG? and 15 HPETE (15 hydroperoxyeicosatetraenoic acid), substrates for hydroperoxidase
enzymes, whereas the stable PGs and 15 HPETE had
no effect. The hypothesis that O2~- radical produced
during the PG hydroperoxidase reactions was
responsible was further strengthened by the demonstration that superoxide dismutase and catalase
blunted or eliminated the arterial responses induced
by topical arachidonic acid, PGG2, and 15 HPETE. It
was proposed that in acute hypertension release of
arachidonic acid from phospholipids is the initial
event, stimulated by activation of phospholipase A2.
The arachidonic acid is then metabolized by cyclooxygenase to PGG2 and thence to PGH2 by PG
hydroperoxidase, producing O2~\ The charged O2~*
molecules probably escape via an anion channel in
the cell membrane to enter the CSF and brain
extracellular fluid. More recently, the same group has
demonstrated O2~' production in vascular smooth
muscle and endothelium during reperfusion following complete ischemia.19
Schmidley Free Radicals in CNS Ischemia
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The effects of O2 • on the microvessels of the CNS
have been studied in capillaries of the frog, which, in
addition to being somewhat larger than those of
mammals, are present on the pial surface as well as
within the neural parenchyma. These features allow
penetration of intact microvessels with microelectrodes and determination of the electrical resistance
of the endothelial layer.20 Topical application of
xanthine/XO to the pial surface of the frog brain
causes a reversible decrease in electrical resistance of
the endothelium, presumably reflecting increased
permeability of tight junctions.
The changes induced by xanthine/XO were inhibitable by allopurinol and superoxide dismutase+
catalase but not by corticosteroids, which act by inhibiting phospholipase A2, nor by cyclooxygenase or lipoxygenase inhibitors, suggesting that they were evoked by
O2~g radicals generated by XO, rather than via arachidonic acid pathways.21 The relevance of these free
radical mechanisms to human hypertensive encephalopathy, loss of autoregulation in ischemic tissue, ischemic brain edema, or vasospasm following subarachnoid hemorrhage (SAH) is unsettled but of potential
interest. Although the arteriolar change evoked by free
radicals in this experimental system is dilation, it is
possible that arteriolar smooth muscle damage following SAH might be enough to produce a necrotizing
arteriopathy. Post-SAH CSF would contain abundant
iron to catalyze production of OH- radicals.
Recent Developments in Therapy
The 21-aminosteroids are a recently synthesized
class of molecules which, because of the 21-amino
substitution, lack glucocorticoid or other "classic"
steroid hormone activity. They cross the blood-brain
barrier after systemic administration and are powerful inhibitors of lipid peroxidation of CNS tissues in
vitro. Intraperitoneal injection of gerbils with these
agents, U74006F and U74500A, before and after
unilateral carotid occlusion protects hippocampal
CA! neurons and certain neocortical areas against
ischemic damage and, at high doses, improves
survival.2223 This protective effect was not seen in a
15-minute bilateral carotid occlusion model in the
gerbil.23 In the rat MCA occlusion model, U74006F
given at 10 minutes and again at 3 hours after
occlusion reduced ischemic brain edema.24 In the cat
posttreatment with U74006F attenuated postischemic hypoperfusion following 5 minutes of global
ischemia, which suggested a protective effect on the
microcirculation. However, in this system animals
given U74006F also had much higher blood pressures
in the postischemic period, an effect not noted in
other models, which may have increased cerebral
perfusion pressure.25 U74006F is capable of scavenging and thereby neutralizing the potentially deleterious effects of O2~- and lipid hydroperoxides. It also
blocks the release of arachidonic acid from membranes, which may also indirectly contribute to generation of free radicals (see above).21 U74500A has
iron-binding properties which may explain its greater
1089
efficacy in vitro against lipid peroxidation.23 It remains to be shown that any 21-aminosteroid actually
reduces free radical generation or lipid peroxidation
in vivo. The exact locus (microcirculation versus
neuron) and mechanism of action of these exciting
new molecules still must be elucidated.
Although superoxide dismutase has been used to
modify ischemia-reperfusion injury of the lung, gut,
and myocardium, several obstacles seem to block its
use in cerebral ischemia. These include a negative
charge and high molecular weight, which mean exclusion by the blood-brain barrier, as well as a short
plasma half-life and the inability of neurons and
astrocytes to internalize the enzyme. The bloodbrain barrier problem can be circumvented by using
liposome-entrapped enzyme. This approach has been
used in focal models of cerebral ischemia with reduction of edema and infarct size.26 Another potential
delivery system, consisting of superoxide dismutase
or catalase conjugated to polyethylene glycol, has
also been effective in reducing the size of focal
ischemic brain lesions.2728
This review ends on a somewhat paradoxic note,
reporting exciting new potential therapies which
seem to act by scavenging free radicals or blocking
lipid peroxidation in CNS. Yet unequivocal evidence
supporting production of free radicals in cerebral
ischemia has only recently emerged, and proof of
their importance vis a vis other putative mechanisms
in focal CNS ischemia, such as Ca2+ influx, acidosis,
and excitatory neurotransmitters, is still lacking.29
Perhaps one way to reconcile these seemingly disparate results is the concept that free radical mechanisms
damage the microvasculature, primarily during reperfusion, causing further parenchymal damage as a result
of increased permeability or platelet aggregation.19
Since the microvasculature is quantitatively a very
minor fraction of the brain mass, even severe damage
might not be evident on sensitive assays for the products of lipid peroxidation, which would explain the
largely negative results reported above.30
Acknowledgments
The author wishes to thank Drs. P.H. Chan and
R.A. Fishman for nurturing his interest in this subject, Dr. M.D. Winkelman for a critical review of the
manuscript, and Barbara First for tireless and technically superb word processing.
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KEY WORDS
cerebral ischemia • free radicals
Free radicals in central nervous system ischemia.
J W Schmidley
Stroke. 1990;21:1086-1090
doi: 10.1161/01.STR.21.7.1086
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