(Stroke. 1995;26:1478-1489.)
© 1995 American Heart Association, Inc.
Articles |
Ischemic Delayed Neuronal Death
A Mitochondrial Hypothesis
From the Department of Neurology, Tohoku University School of Medicine, Sendai (K.A., M.A., J.K., Y.I.), and the Departments of Pathology at Mie University School of Medicine, Tsu (T.Y), Sapporo Medical College, Sapporo (A.H.), and the Institute of Neuropathology, Kumagaya (K.K.), Japan.
Correspondence to Koji Abe, MD, Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai 980-77, Japan.
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Abstract |
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Background A brief period of global brain ischemia causes cell death in hippocampal CA1 pyramidal neurons days after reperfusion in rodents and humans. Other neurons are much less vulnerable. This phenomenon is commonly referred to as delayed neuronal death, but the cause has not been fully understood although many mechanisms have been proposed.
Summary of Review Hippocampal CA1 neuronal death usually occurs 3 to 4 days after an initial ischemic insult. Such a delay is essential for the mechanism of this type of cell death. Previous hypotheses have not well explained the reason for the delay and the exact mechanism of the cell death, but a disturbance of mitochondrial gene expression could be a possibility. Reductions of mitochondrial RNA level and the activity of a mitochondrial protein, encoded partly by mitochondrial DNA, occurred exclusively in CA1 neurons at the early stage of reperfusion and were aggravated over time. In contrast, the activity of a nuclear DNA–encoded mitochondrial enzyme and the level of mitochondrial DNA remained intact in CA1 cells until death. Immunohistochemical staining for cytoplasmic dynein and kinesin, which are involved in the shuttle movement of mitochondria between cell body and the periphery, also showed early and progressive decreases after ischemia, and the decreases were found exclusively in the vulnerable CA1 subfield.
Conclusions A disturbance of mitochondrial DNA expression may be caused by dysfunction of the mitochondrial shuttle system and could cause progressive failure of energy production of CA1 neurons that eventually results in cell death. Thus, the mitochondrial hypothesis could provide a new and exciting potential for elucidating the mechanism of the delayed neuronal death of hippocampal CA1 neurons.
Key Words: cerebral ischemia • cytochrome c oxidase • mitochondria • neuronal death
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Introduction |
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TopAbstractIntroductionPrevious HypothesesThe Mitochondrial HypothesisFuture DirectionsReferences |
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Brain cells, especially neurons, are very sensitive to various injuries, such as ischemia, hypoxia, hypoglycemia, infection, and trauma. These vulnerabilities of neurons often make it difficult to cure patients suffering from injuries to the central nervous system in clinical situations. The vulnerability is different even within neuronal populations. It is well known that a brief period of global brain ischemia causes cell death in hippocampal CA1 pyramidal neurons days after reperfusion (Fig 1
). Other neurons,
such as parietal cortical or hippocampal CA3, are much less
vulnerable.1 2 This phenomenon is commonly referred to as
delayed neuronal death.1 3 A similar phenomenon occurs
after ischemic injury in humans.4 Prolonged ischemia
extends the area of neuronal death to the caudate and thalamic
nuclei.2 5 6 However, because hippocampal CA1 neurons are
most vulnerable to ischemia, the cell death has been thought to
represent a sensitivity of the neurons to injuries. Therefore, it is
important to know the exact mechanism of hippocampal CA1 neuronal cell
death after ischemia. The cause of such delayed neuronal damage in CA1
neurons has not been fully under-stood although many mechanisms have been proposed. Most of the
previous hypotheses have some problems in explaining the reason why the
eventual cell death occurs 3 to 4 days after the initial ischemic
insult, the mechanism that should be essential to this type of neuronal
death.
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The purpose of this review is to summarize these previous hypotheses in terms of the mechanism of delayed neuronal death and propose a new hypothesis based on the disturbance of mitochondrial gene expression. Although previous hypotheses have some difficulties in explaining the exact mechanism of cell death, they are partly related to the new hypothesis.
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Previous Hypotheses |
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TopAbstractIntroductionPrevious HypothesesThe Mitochondrial HypothesisFuture DirectionsReferences |
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Glutamate Excitotoxicity
In 1969 Olney7 first suggested glutamate as a powerful excitotoxin to neurons. A remarkable increase of extracellular excitatory neurotransmitter levels such as glutamate and aspartate was reported during brain ischemia and the early period of reperfusion in microdialysis studies in vivo.8 9 The glutamate release is thought to be mainly from presynaptic terminals although some are from postsynaptic terminals.10 11 Experiments with deafferentation of the presynaptic fibers partly protected against CA1 cell death.12 13 14 Dense excitatory and fewer inhibitory innervations in the CA1 neurons provide a background of hyperactivity after ischemia caused by an excitotoxic mechanism.15 16 17 18 The opening of both voltage-dependent and receptor-operated calcium channels results in unregulated excessive calcium influx into the cytoplasm. Calcium is released also from intracellular stores during ischemia.19 Such an unregulated increase of intracellular calcium concentration causes an activation of calcium ATPase, which results in further consumption of cellular ATP and of calcium-dependent proteases, phospholipases, and nucleases. All these processes cause catastrophic consequences in cells.20 21
However, even though the amount of glutamate release was very high,8 9 excessive glutamate release was only transient and returned to normal levels in 10 to 20 minutes of reperfusion. Although a very short period of nonlethal ischemia resulted in high-frequency discharge in the CA1 neurons,22 the phenomenon was not observed after longer periods of ischemia that were severe enough to damage CA1 neurons.23 24 25 Furthermore, recent reports suggest that the amount of N-methyl-D-aspartate receptor and mRNA for the receptor is not very different between the CA1 and CA3 regions.26 27 Thus, the excitotoxic mechanism does not completely explain the eventual cell death occurring so long after insult. However, it should be noted that excessive glutamate release causes a transient increase of intracellular calcium concentration. Although there still is a possibility that extracellular levels of glutamate measured by brain microdialysis may not represent levels in the synaptic cleft, it is important that glutamate returned to baseline levels in the early period of reperfusion, and the level is presumed to persist until cell death.
Prolonged Inhibition of Protein Synthesis
It is well known that the threshold for disturbance of
protein synthesis is very sensitive28 and that the
translational step is much more vulnerable to ischemia or other
injuries than the transcriptional step.29 After a brief
period of ischemia, protein synthesis is markedly inhibited in
all neuronal cells but recovers during the course of reperfusion,
except in vulnerable neurons such as CA1 cells.30
Polyribosomes, in which proteins are synthesized in the
cell, become disaggregated into monosomes long after reperfusion. An
increase in intracellular calcium results in an inactivation of
eukaryotic initiation factor-2,20 21 29 and
the problem could be in the activations of eukaryotic
initiation factor-2 and guanine nucleotide exchange factor
in the initiation of protein synthesis at the ribosomes.31
If ischemic cells cannot efficiently replace important proteins
that are degraded by ischemic injury, the cells may eventually
die. Thus, prolonged inhibition of protein synthesis has been
recognized as an important aspect of delayed neuronal death.
However, this hypothesis did not specify particular proteins that play key roles in the mechanism of the death. Furthermore, this hypothesis does not explain why protein synthesis in the CA1 or other specific neuronal groups are selectively sensitive to ischemia. Although calcium overload was dominant in the CA1 area,5 the increase of calcium was also transient,32 making it difficult to explain the complete shutdown of protein synthesis for a long time. The process of protein synthesis requires extreme accuracy to avoid a mistake of amino acid sequence, which needs high energy consumption. Therefore, the prolonged inhibition of protein synthesis suggests that the neurons are in a condition in which they do not have enough energy to make most of the proteins or they have to save energy to use for another purpose.
Disturbed HSP Expression
HSPs are induced under stressful cell conditions when general
protein syntheses are inhibited although some HSPs, such as HSC70, are
normally expressed.33 34 35 36 37 HSPs are essentially involved in
protein folding and therefore have been recognized as a "molecular
chaperone."36 37 The cell-protective roles of HSPs have
been shown in vitro by injection of antibody against HSP70 or
transfection of a gene that constitutively expresses
HSP70.38 39 Nowak40 first reported HSP70
synthesis after cerebral ischemia in gerbils in 1985. HSP70 is
induced mainly in neurons but can also be induced in astroglial and
capillary endothelial cells.41 42 43 44
Subsequent reports showed that CA1 neurons expressed a large
amount of mRNA for HSP70 with less immunostaining of
the protein.45 46 47 Although HSP70 gene expression
genetically has priority over other general or housekeeping proteins
under stressful conditions,33 48 HSP70 gene expression was
disturbed at the translational level in CA1 neurons probably because of
the severe injury.45 46 47 Recent reports have showed that
pretreatment of animal brain with a very short period of
ischemia that does not cause neuronal death partly saved the
CA1 neuronal loss, with prominent expression of
HSP70.49 50 51 52 53 54 These results suggest that the preexistence of
HSP70 after pretreatment was related to the acceleration of subsequent
robust and fast induction of HSP70 mRNA and to its effective
translation into the protein.54
However, experiments with rats raised a question about the significance of the role of HSP70.52 55 Contrary to the case in gerbils, CA1 neurons of rats expressed a large amount of immunoreactive HSP70 with the mRNA,52 55 but such neurons eventually die like those in gerbils.2 52 55 Because immunoreactive staining does not provide a quantity of protein, it is difficult to know the significance of the protective effect of HSP70 and the difference of the protein induction between rat and gerbil. However, it can be said that a translational disturbance of HSP70 gene expression may not be a major cause of CA1 cell death in rats and perhaps not in gerbils. In addition, not only HSP70 gene expression is changed after pretreatment54 ; the setting level of many other gene expressions might also be changed.
Lipid Metabolism and Free Radicals
Free fatty acids are liberated from membrane phospholipids during
ischemia.56 57 58 59 The level of free fatty acids
decreases, and peroxidative derivatives of arachidonic
acid increase during reperfusion.60 61 62 Activation of
xanthine oxidase and dysfunction of mitochondria also generate free
radicals. Because liberation of arachidonic acid during
ischemia differs regionally63 and free
arachidonic acid inhibits the reuptake of released
gluamate without inhibition of that of 
-aminobutyric
acid,64 arachidonic acid may
transneuronally enhance the differences in regional damage seen between
CA1 and CA3 cells. Hillered and Chan65 reported that
arachidonic acid was a potent uncoupler of and induced
swelling in mitochondria. However, the difference in the amount of free
arachidonic acid between CA1 and CA3 areas was only
10% to 30%,63 making it difficult to accept the
essential differences in the prognosis for the neurons. Furthermore,
free fatty acids returned to normal levels quickly, by 30 minutes to 1
hour.57
NO is a free radical produced in vascular endothelium and serves as an endothelium-derived relaxing factor that maintains and regulates vascular tone.66 67 68 69 However, it is also produced in neurons and glial cells.70 71 72 73 74 NO may mediate neuronal death caused by excitotoxic and hypoxic insults,75 76 77 and mice with knockouts of NO synthase were resistant to ischemia.78 However, inhibition of NO synthase showed dual effects on infarction size depending on the dose of the inhibitor.79 80 81 82 83 84 NO released from glial cells is long-lasting and could be cytotoxic.75 85 86 87 However, NO synthase is not rich in CA1 neurons88 89 and is inducible after a brief period of ischemia, with a peak at 1 day.89 Neurons that contain NO synthase are resistant to excitotoxic and ischemic injuries.90 91 Direct evidence of the relation between CA1 cell death and NO has not been reported.
Free radical scavengers including superoxide dismutase are induced during and after ischemia92 93 94 probably in response to superoxide generation.95 96 Administration of superoxide dismutase ameliorated the damage of CA1 neurons,96 reducing traumatic and ischemic damage.97 98 Transgenic mice with overexpression of human superoxide dismutase showed a reduction of infarcted size.99 100 The effects of the superoxide dismutase transgene on delayed neuronal death is under investigation by Chan et al. Recent data suggest that reaction of peroxynitrite (ONOO-) with superoxide dismutase may degenerate neuronal cells.101 102 103 However, protein tyrosine nitration by the reaction has not yet been reported in terms of delayed neuronal death.
Energy Metabolism and Cerebral
Circulation
Immediately after the findings of delayed neuronal death in gerbil
and rat, many groups examined changes of energy metabolism
and cerebral blood flow. Many reports suggested that energy
metabolism recovered quickly after
reperfusion.104 105 106 107 108 Several reports indicated that
vascular supply to the hippocampus is inferior to that of
other regions of the brain109 and that perfused
capillaries and the volume of circulating blood are 20% to 30% lower
in the CA1 than CA3 region.110 However, the data of
microcirculatory capacity were obtained only at 3 minutes and 7 days
after reperfusion,110 which does not explain why cell
death takes 3 to 4 days. In addition, cerebral blood flow was not
significantly different between vulnerable and more resistant
areas during and after ischemia.111 112 Thus, it
is now commonly thought that disturbances of energy
metabolism and cerebral circulation are not mainly involved
in the mechanism of delayed neuronal death. However, it should be noted
that Munekata and Hossmann107 have reported a relative
delay of recovery from acidosis in the CA1 area compared with the CA3
and cortical areas. This suggests an enhanced glycolysis, with possible
impairment of mitochondrial functions.
Apoptosis and Neurotrophic Factors
Apoptosis requires active synthesis of mRNA and protein
and has been observed typically in the processes of lymphocyte
maturation in thymus, of cultured cells, and of developing central
nervous system.113 114 115 On the other hand, necrosis
involves destruction of tissue, including neurons, glial cells, and
capillary blood vessels. Deprivation of neurotrophic
factors activates a putative "killer protein" that causes
cell death with an apoptotic mechanism.116 117 118 Fas
antigen mediates apoptosis,119 and a
proto-oncogene product, bcl-2, inhibits
apoptotic cell death in vitro.120 121 The
apoptotic cell death takes a few days without the formation of
edema, and a 180-bp DNA ladder produced by
Ca2+-dependent endonuclease usually precedes cell
death.114 115 Several lines of evidence have suggested an
apoptotic mechanism of CA1 cell death, including a protective
effect of administration of protein synthesis
inhibitor122 or nerve growth
factor,123 124 an observation of a DNA
ladder,125 decreases of neurotrophic
factors,126 127 128 129 and bcl-2
inductions.130 Thus, hippocampal CA1 neuronal death has
some aspects that are similar to apoptotic cell death.
However, ultrastructural analyses suggest that CA1 cell death was not accompanied by typical pathological changes seen in apoptosis, such as early extensive chromatin condensation and nuclear displacement.131 132 133 Inhibitors of protein and RNA syntheses did not reproducibly prevent neuronal damage.133 134 An infusion of nerve growth factor did not rescue CA1 neurons in rats.135 DNA ladders can also be found in other types of neuronal cell death, such as cold injury and necrosis.136 137 The profile of bcl-2 expression was not specific to this protein and was similar to other proto-oncogenes, such as c-fos, in the CA1 region.130 138 Glutamate-related neuronal death was not a programmed cell death in cerebellar culture.139 Apoptotic cells may not express a stress response such as HSP70 for survival. In fact, cultured neurons died days after withdrawal of serum, with an apoptotic mechanism expressing no HSP70 inductions (F.R. Sharp, personal communication, 1994). Furthermore, there is no compensatory advantage, which is required of cells dying with the apoptotic mechanism, to the brain or the individual animals for losing important CA1 neurons. These data provide evidence against the apoptotic hypothesis. Thus, the exact mechanism should be essentially different from that of apoptotic cell death as well as from typical necrosis.
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The Mitochondrial Hypothesis |
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TopAbstractIntroductionPrevious HypothesesThe Mitochondrial HypothesisFuture DirectionsReferences |
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Characteristics of the mtDNA System
Most mitochondrial proteins are encoded by nuclear DNA, synthesized on the cytoplasmic ribosomes, and then imported into mitochondria (Fig 2
). However, unlike other organelles
in the cell, mitochondria have a DNA system that is different from the
nuclear DNA system. Some proteins encoded by mtDNA are synthesized on
the mitochondrial ribosomes. Although mitochondria have their own
genome, the gene expression is completely controlled by the nuclear DNA
system. The protein traffic seems to be unidirectional from cytoplasm
to mitochondria. However, the nuclear and mitochondrial genetic systems
communicate to coordinate their contributions to form the
energy-converting enzyme complexes.140 Transcription of
mRNA from mtDNA needs mitochondrial transcription factor and
mitochondrial RNA polymerase, which are entirely encoded by nuclear
DNA. mtDNA is different from nuclear DNA in several ways: (1) mtDNA is
circular and nuclear DNA is linear; the size is approximately 16.5 kb
in mammals, which is 105 times smaller than that of nuclear
DNA; (2) each mitochondrion has multiple copies of mtDNA, ranging from
100 to 1000 in a cell, which makes up to 1% of the total cellular DNA;
(3) mtDNA is packaged without histones and is usually distributed in
several clusters in the matrix of the mitochondria, where they are
thought to be attached to the inner membrane; and (4) because of the
low fidelity of replication and lack of repair of mtDNA, the amount of
normal mtDNA may decrease and deleted mtDNA increases during cell
aging, which may cause a problem in nondividing cells such as neurons
and cardiac cells.141 142 143
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The mitochondrial respiratory complex is essential for the
production of ATP by oxidative phosphorylation
and consists of complex proteins that are encoded by both mtDNA and
nuclear DNA. The mtDNA encodes for 13 essential oxidative
phosphorylation polypeptides as well as containing 2
rRNA and 22 tRNA genes.144 COX is a mitochondrial enzyme
forming complex IV for the electron transfer system and is composed of
13 subunits; three of them (COX-I, -II, and -III) are encoded by mtDNA.
Therefore, COX-I mRNA is transcribed from mtDNA and translated into the
protein within mitochondria. The activity of COX protein is an overall
activity of these 13 subunits. COX activity is high in the oriens
layer, stratum radiatum, and lacunosum moleculare layer of the CA1
subfield as well as in the molecular layer of dentate gyrus in gerbils
(Fig 3a). With in situ hybridization, the amount of
COX-I mRNA and DNA can be measured.145 COX-I mRNA is
abundantly present in hippocampal neuronal cell layers in control
brain (Fig 3b); COX-I DNA is scarcely present in hippocampal
pyramidal cell layers in control brain (Fig 3c). It is rich
in the oriens layer and stratum radiatum of the CA1 subfield and
especially dense in the lacunosum moleculare layer of the CA1 subfield
and molecular layer of dentate gyrus, similar to the case of COX
activity. COX activity, COX-I mRNA, and COX-I DNA should be in the same
mitochondrial capsules. Therefore, these different regional
distributions between COX activity and COX-I DNA and COX-I mRNA (Fig 3)
support the previous hypothesis of the presence of a mitochondrial
shuttle system.146 Mitochondria are periodically shuttled
to and from the cell body to obtain newly synthesized nuclear-encoded
mitochondrial proteins, such as other COX subunits (COX-IV through
-XIII), succinate dehydrogenase, and mitochondrial transcription
factor.
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Disturbance of mtDNA Expression
Many biochemical analyses of the activities of
mitochondrial respiratory function have been reported in brains with
experimental ischemia.147 148 149 However,
regional changes of mitochondrial enzyme activity, mRNA, and DNA after
ischemia have not been extensively examined in relation to the
delayed neuronal death of CA1 neurons. Recent reports suggest a
selective and progressive decrease of mtDNA expression in CA1 neurons
after 3.5 minutes of forebrain ischemia.150 151 152
Compared with other areas of hippocampal neurons such as CA3 and
dentate granule cells, COX-I mRNA level began to decrease at an early
stage of reperfusion in the CA1 subfield (Fig 4, left,
arrowheads), progressively deteriorated, and was completely gone at 7
days (arrowheads), whereas other hippocampal neurons showed almost no
change during the reperfusion period. A previous report with a
biotinylated probe suggested no change of COX-I mRNA levels in
hippocampal CA1 neurons up to 48 hours after
reperfusion.153 However, nonspecific signals after RNase
treatment seem to be too high to detect small changes of COX-I
mRNA.153
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In contrast, the amount of COX-I DNA began to decrease in the oriens
layer of the CA1 subfield at 2 days and significantly decreased in the
entire CA1 subfield at 7 days (Fig 4
, middle, arrowheads). Unlike COX-I
mRNA, COX-I DNA did not completely disappear even at 7 days. The amount
of COX-I DNA remained normal in other areas of hippocampus and cerebral
cortex during the reperfusion period. Southern blot analysis
confirmed the change in the CA1 region.151 These data may
be consistent with data from brain mtDNA, which was not damaged
after prolonged cardiac arrest and reperfusion.154
HSP60, also known as cpn60, is an E coli GroEL homologue and
works in conjunction with the 10-kD chaperonin (cpn10) in the
mitochondrial matrix.36 37 HSP60 is a mitochondrial
protein but is encoded by nuclear DNA; therefore, the protein is
synthesized on cytoplasmic ribosomes and is imported in mitochondria.
HSP60 mRNA is also induced in CA1 neurons with a peak at 1 day (Fig 4,
right), and the increase may be related to the interaction with
denatured or unfolded protein in mitochondria by analogy with the roles
of HSP70 and HSC70.36 37 152 In fact, the increase of
HSP60 mRNA is associated with the inductions of HSP70 and HSC70 mRNAs
and the decrease of COX-I mRNA,152 which may
represent the mitochondrial damage.
Changes in Mitochondrial Enzyme Activities
COX activities also show an early, selective, and progressive
decrease in the hippocampal CA1 subfield until 7 days after
ischemia (Fig 5, left, arrowheads).
Developmental changes of COX activity in brain regions and marked
decreases of the activity in hyperglycemic brain after anoxia have been
reported in cats.149 155 However, such an early decrease
in the CA1 region has not been reported. The early decrease of
mitochondrial COX activity in the stratum radiatum may be related to
the high glucose uptake in the same region at the early period of
reperfusion,156 suggesting an enhanced glycolysis in
the region with a disturbed mitochondrial function. The delayed
recovery from acidosis in the CA1 region107 might be
related to this possible upregulation of glycolysis.
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Distribution of succinate dehydrogenase activity (Fig 5, right) in the
sham control hippocampus is almost the same as that of the COX activity
(Fig 5, left). In contrast to the change of COX activity, succinate
dehydrogenase activity begins to decrease in the oriens layer at 2 days
and markedly decreases at 7 days in the entire CA1 subfield, especially
in the lacunosum moleculare layer (arrowheads). An activity of pyruvate
dehydrogenase complex that is also encoded by nuclear DNA was increased
during the early period of reperfusion.157 158
Histological examination shows that most of the CA1
cells are still present at 2 days although the staining began to
decrease compared with staining in sham controls.150 151 152
Only the CA1 cells were completely gone at 7 days (Fig 1) in the
present study after 3.5 minutes of
ischemia.150 151 152
Motor Proteins
So-called motor proteins, such as CD and kinesin, are linear
motors that convert the energy of ATP hydrolysis into mechanical work
and move cellular organelles such as mitochondria along microtubules
(Fig 6). CD, also referred to as MAP1C,159
translocates organelles to the "minus" (proximal) end of
microtubules.159 160 161 162 163 Kinesin is thought to mediate an
axonal transport to the "plus" (peripheral) end of
microtubules. The heavy chain contains all of the mechanochemical
elements necessary for generating microtubule-based movements and has
microtubule-stimulated ATP activity.164 165 166 167 168 169
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Immunohistochemical analyses for CD and kinesin are shown in
Fig 7 (left and middle). Immunoreactivity for CD is
observed in all hippocampal pyramidal cells, whereas it is
scarcely expressed in dentate granule cells.170 The
immunoreactivity begins to decrease at 1 hour in CA1 cells; the
decrease becomes more evident at 3 hours after ischemia,
whereas in other neurons immunoreactivity remains at normal levels (Fig 7 left). The immunoreactivity progressively decreased and was almost
gone as early as 1 day. Immunoreactive kinesin is present
in all hippocampal cells, especially in cell bodies, of control
brain. Immunoreactivity for kinesin shows an apparent change in
hippocampal CA1 cells after 8 hours of reperfusion and continuously
decreases (Fig 7, middle). However, other hippocampal neurons show
almost no change during the reperfusion period. Thus, CD shows a
progressive decrease from 1 to 3 hours, and kinesin shows a decrease
from 8 hours of reperfusion; these changes in CD and kinesin are found
only in the vulnerable CA1 sector. Two minutes of ischemia did
not significantly change the immunoreactivities of CD and kinesin in
CA1 cells.170 MAP2, which is abundant in neuronal
dendrites, is thought to be one of the microtubule cross-linking
proteins.171 Previous studies revealed that
immunoreactivity of MAP2 was more susceptible to ischemia than
that of 
-tubulin and should serve as a marker of cell injury after
ischemia.172 173 174 175 176 However, staining of MAP2 was
maintained at control levels in CA1 cells until 2 days but was
completely gone at 7 days.
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Thus, the motor proteins CD and kinesin are much more susceptible to ischemia compared with nonmotor or constitutive proteins such as MAP2 and tubulin. CD and kinesin are thought to be normally attached to the lipid membrane of cell organelles. The early reduction of immunoreactivity suggests that CD and kinesin become translocated from the lipid membrane or that these motor proteins are sensitive to a transient increase of calcium during and after ischemia. Recent works identified a new kinesin superfamily (KIF1-5), and some of the members are involved in mitochondrial movement (KIF1b).177 178 The present data provide evidence for the early disturbance of the mitochondrial shuttle system in CA1 neurons.
A Speculative Synthesis
The previous150 151 152 and present data show an
early onset and progressive reduction of COX-I mRNA levels and COX
activity in contrast to succinate dehydrogenase activity and COX-I DNA
level. Because the mitochondrial shuttle system is essential in mtDNA
expressions and the renewal of proteins, disturbances of motor
proteins must result in the progressive failure of energy
production in CA1 neurons that eventually causes a final
catastrophe and cell death. Although the reason why the
immunoreactivities of motor proteins are susceptible to
ischemia remains to be resolved, it is possible that biological
activities of motor proteins are disturbed. Because CA1 neurons may
need more ATP to repair the disturbed intracellular environment and
denatured protein and lipids, ATP may be difficult to be sufficiently
distributed to motor proteins (Fig 6). Impairment of kinesin activity
caused by mutations decreased action potential propagation and
neurotransmitter release in Drosophila.179
Kirino et al180 suggested that a slight
reduction of membrane resting potential (25% of control) persisted in
CA1 neurons after ischemia and preceded cell death. Recent data
suggest that ambient levels of glutamate become toxic to cells under
mild energy failure.181 182 183 184 After an initial increase,
normal glutamate levels were maintained long after reperfusion,
probably until cell death at 3 to 4 days.8 9 Hippocampal
CA1 neurons have uniquely longer dendrites and axonal projects than
other hippocampal neurons, making them more vulnerable to the
disturbance of motor proteins and mild energy failure.
The present hypothesis is not contrary to previous hypotheses. An initial increase of intracellular calcium concentration caused by excitatory neurotransmission first damages motor proteins; then the mitochondrial shuttle system is disturbed, followed by a gradual decrease of energy production in mitochondria that eventually causes an energy crisis of the cells, which are increasingly demanding ATP for recovery. These processes finally result in cell death. Thus, this hypothesis cooperates with the previous hypotheses and explains the reason why cell death takes 3 to 4 days after the initial ischemic insult. The delayed neuronal death of hippocampal CA1 neurons seems to be a particular type of necrosis.
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Future Directions |
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TopAbstractIntroductionPrevious HypothesesThe Mitochondrial HypothesisFuture DirectionsReferences |
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The present data suggest a progressive change of energy metabolism within a specific region of the CA1 area. Therefore, further analyses on regional energy metabolism and quantitative topographic measurement of ATP that are more detailed than previous reports104 105 106 107 108 185 and possible measurement of the intracellular regional metabolic rate of ATP will be required to understand the mechanism more clearly. Recent data suggest that an mtDNA deletion and the reduction of mitochondrial enzyme activity are also associated with ischemic, hypoxic, and aged tissue.186 187 188 189 190 191 192 Although COX-I DNA is not located in the hot spot of such mtDNA deletions,141 142 143 193 194 deleted mtDNA might be increasing in CA1 neurons after ischemia if it is examined with probes that detect hot spots. Problems in mitochondrial transcription factor and mitochondrial RNA polymerase could also take part in the disturbances of mtDNA expression.195 196 197 Delayed neuronal death is found in other neuronal populations, such as small neurons in lateral caudate, neurons in cortical 4-6 layers, and Purkinje cells.1 2 3 5 Further studies are required to determine whether the present hypothesis could also be applied to those cells with a longer duration of ischemia.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was partly supported by Grant-in-Aid for Scientific Research on Priority Areas (I. Kanazawa) 06272204; Grant-in-Aid for Scientific Research (C) 06807055 from the Ministry of Education, Science and Culture of Japan; and a grant (S. Hirai) from the Ministry of Health and Welfare of Japan. The authors would like to thank Profs T. Kirino, T. Yoshimoto, A. Tamura, and T. Yanagihara and Drs T. Tominaga, H. Kinouchi, and H. Kato for helpful discussions and support. The authors also thank Profs B.K. Siesjö, K.A. Hossmann, W.A. Pulsinelli, M.D. Ginsberg, D. Choi, P.H. Chan, F.R. Sharp, T. Wieloch, M.A. Moskowitz, N.G. Bazan, and T.S. Nowak, Jr, for their suggestions to the present hypothesis.
Received November 9, 1994; revision received January 11, 1995; accepted March 30, 1995.
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References |
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TopAbstractIntroductionPrevious HypothesesThe Mitochondrial HypothesisFuture DirectionsReferences |
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