close

Вход

Забыли?

вход по аккаунту

?

Structural Features of Ischemic Damage in the Hippocampus.

код для вставкиСкачать
THE ANATOMICAL RECORD 292:1914–1921 (2009)
Structural Features of Ischemic Damage
in the Hippocampus
ALEXANDER G. NIKONENKO,1 LIDIJA RADENOVIC,2 PAVLE R. ANDJUS,2
1
AND GALYNA G. SKIBO *
1
Bogomoletz Institute of Physiology, Kiev, Ukraine
2
School of Biology, University of Belgrade, Belgrade, Serbia
ABSTRACT
Cerebral ischemic injury resulting from either focal or global circulatory arrests in the brain is one of the major causes of death and disability
in the adult population. The hippocampus, playing important roles in
learning and memory, is selectively vulnerable to ischemic insults. Distinct
populations of hippocampal neurons are targeted by ischemia and multiple
factors, including excitotoxicity, oxidative stress, and inflammation, are responsible for their damage and death. Modifications of synapses occur very
early after ischemia, reflecting related changes in synaptic transmission.
These modifications structurally relate to spatial patterns formed by synaptic vesicles, geometry of postsynaptic density, and so forth. Ischemiainduced changes of synaptic contacts can be implicated in the mechanisms
leading to delayed neuronal death. In this review, we summarize the available data on the structural aspects of ischemic injury of the hippocampus
obtained in tissue culture and animal models and discuss pathways of neurodegeneration common for cerebral ischemia and various neurodegeneraC 2009 Wiley-Liss, Inc.
tive disorders. Anat Rec, 292:1914–1921, 2009. V
Key words: astrocytes; cerebral ischemia; microglia; pyramidal
neurons; synapses
Cerebral ischemia is caused by major insufficiencies in
cerebral blood flow. Circulatory collapse due to cardiac
arrest leads to global cerebral ischemia, while a focal ischemic lesion may be produced by the occlusion of a
major brain artery. Prolonged circulatory deficits induce
irreversible changes in the brain tissue inflicting the
damage and death of neural cells. The primary effect of
ischemia is a loss of oxygen and energy substrates, for
example, glucose. In contrast to glucose, which has some
alternatives, oxygen has no substitute as the final electron acceptor in the oxidative phosphorylation pathway,
which is why its loss dramatically decreases ATP production and causes an electron leakage generating reactive oxygen species (ROS). Persisting glycolysis leads to
intracellular acidification further impairing cell functions (Rossi et al., 2007).
Soon after ischemia, the malfunction of ATP-dependent
processes causes a dramatic change in ion gradients and
membrane depolarization associated with a steady rise
in extracellular glutamate and other neurotransmitters
(Benveniste et al., 1984). As a result, high levels of intracellular Ca2þ trigger cell death. This process, known as
excitotoxicity, involves the synergistic action of proteases,
ROS, and Ca2þ overload (Choi and Rothman, 1990; Nikonenko et al., 2005). If an ischemic episode is relatively
short, then cell death tends to be delayed and selective
for neurons; whereas prolonged ischemia leads to a
broader and more rapid cellular destruction. Mild ischemia was reported to potentiate synaptic transmission,
while more severe ischemic insults were found to suppress it (Hammond et al., 1994; Jourdain et al., 2002).
The described events are most prominent in the focus of
ischemic injury. The situation is somewhat different in a
so-called penumbra, moderately hypoperfused region surrounding the core of injury. Here, energy production is
compromised to a lesser extent but ischemia triggers a series of events in the penumbra, which may eventually
*Correspondence to: Dr. Galyna G. Skibo, Prof., Department
of Cytology, Bogomoletz Institute of Physiology, Bogomoletz
street 4, 01024, Kiev, Ukraine. Fax: þ380-44-256-24-42.
E-mail: [email protected]
Received 18 February 2009; Accepted 9 June 2009
DOI 10.1002/ar.20969
Published online in Wiley InterScience (www.interscience.wiley.
com).
ISCHEMIC DAMAGE IN THE HIPPOCAMPUS
evolve into cell death (Lo, 2008). Some brain regions,
including the hippocampus, are more vulnerable to ischemia than others. Here, structural ischemia-related
changes can be observed at different levels. To study these
changes, the various in vivo (Petito and Pulsinelli, 1984;
Ishimaru et al., 2001) and in vitro (Skibo et al., 2000,
2005; Jourdain et al., 2002) models were used.
ISCHEMIA-RELATED CHANGES IN NEURONS
Cerebral ischemia leads to diverse structural changes
in neural cells. Early electron microscopic studies
showed transient mitochondrial swelling, disaggregation
of polyribosomes, decreases in rough endoplasmic reticulum, and Golgi apparatus in postischemic hippocampal
neurons. The recovery of these cells was associated with
a marked proliferation of smooth endoplasmic reticulum
(Petito and Pulsinelli, 1984). Ischemia causes a dramatic
loss of extracellular fluid and concomitant swelling of
hippocampal cells (Liu et al., 2001; Kovalenko et al.,
2006). These findings are consistent with diffusion data
showing that the volume fraction of intracellular space
in the brain tissue which is severely affected by ischemia
drops fivefold, from 20% to 4% (Nicholson and Sykova,
1998). Mitochondrial swelling is one of the initial postischemic changes. In mild cases, swollen mitochondria
regain their normal shape soon. In severe cases, these
organelles demonstrate condensation, increased matrix
density, and deposits of an electron-dense material followed by the disintegration of mitochondria (Solenski
et al., 2002; Kovalenko et al., 2006).
Transient hypoxia slightly decreases active respiration
in mitochondria, but together with a rise in intracellular
Ca2þ, it causes dramatic effects. Ca2þ should enter the mitochondrial matrix to mediate ischemic injury (Schild et al.,
2003). There are alterations in membrane contact points, a
rise in intra-mitochondrial Zn2þ level, and activation of
large, multi-conductance channels disrupting the functional
integrity of the mitochondrial outer membrane in postischemic hippocampal neurons (Bonanni et al., 2006).
Cerebral ischemia was shown to inhibit protein synthesis. The increase in the number of so-called stress
granules—sites of inactive protein synthesis machinery—was observed within 10–90 min of reperfusion in
some areas of the rat hippocampus (Kayali et al., 2005).
In the penumbra, protein synthesis gets irreversibly
inhibited several hours after ischemia (Zhang et al.,
2006). A marked increase in ubiquitin immunoreactivity
was shown in postischemic hippocampal neurons (Gubellini et al., 1997). Ubiquitin is used as a tag to label proteins committed to be hydrolyzed, and components of
translational complex seem to be heavily ubiquitinated
after ischemia (Zhang et al., 2006).
In ischemic conditions imbalances between proteases
and their inhibitors occur. Ca2þ-dependent cytoplasmic
cysteine proteases, calpains, play important roles in
cytoskeletal remodeling processes. In neurons, a calpaindependent degradation of the cytoskeleton starts very
early after ischemia and fodrin (Yokota et al., 2003), aspectrin (Neumar et al., 2001), MAP2 (Buddle et al.,
2003), and other cytoskeletal proteins are being
degraded. Another protease—caspase-3 is upregulated
mostly in apoptotic neurons (Rami, 2003). In the CA1
area of the postischemic hippocampus caspase-3 overexpression is associated mostly with degenerating pyrami-
1915
dal neurons showing DNA fragmentation. The inhibition
of this enzyme significantly reduces ischemia-related cell
death (Chen et al., 1998).
In gerbils, prolonged global cerebral ischemia kills
96% of CA1 neurons by day 4 (Colbourne et al., 1999).
Neuronal death in the penumbra occurs at a slower rate
taking days to mature (Zhang et al., 2006). Delayed and
rapid neuronal death appear to follow a similar sequence
of cellular events. The lag between an ischemic episode
and neuronal death depends upon the severity and/or
duration of ischemia (Rosenblum, 1997).
Distinct populations of hippocampal neurons demonstrate
differential vulnerability to ischemia (Harry and Lefebvre
d’Hellencourt, 2003). Transient cerebral ischemia selectively
damaged CA1 pyramidal neurons but left neurons in the
CA3 area and dentate gyrus largely intact. Manifestations
of cell death in the rat hippocampal CA1 area became quite
prominent 1 day after a short ischemic episode. Later, the
degeneration of pyramidal cell bodies increased progressively leading to injury and death in 79.5% of CA1 neurons
within 7 days (Kovalenko et al., 2006).
Hippocampal interneurons are generally more resistant than pyramidal cells to excitotoxic insults possibly
because of differences in NMDA receptor expression
and/or subunit composition (Avignone et al., 2005). However, some interneurons are more ischemia-sensitive
than others, namely, somatostatin (SST)- and neuropeptide Y (NPY)-positive interneurons located in the dentate hilus (Johansen, 1993; Larsson et al., 2001),
calretin-positive interneurons in the CA3 area (Hsu
et al., 1994), and a small number of interneurons located
in the mossy fiber layer (Johansen, 1993).
SST-positive interneurons have their soma in the hilus
and project to the outer molecular layer onto dendrites
of dentate granule cells, adjacent to perforant path
input. These interneurons, which are very sensitive to
excitotoxicity, reduce the likelihood of generating longterm potentiation (LTP) (Tallent, 2007). Calretin-positive
CA3 interneurons are characterized by their spiny dendrites and receive more innervation from mossy fibers.
Data suggest that the degeneration of CA1 interneurons
and CA3 pyramidal cells may occur secondary to the
ischemia-related delayed cell death of CA1 pyramidal
neurons (Hsu et al., 1994).
In contrast, hippocampal GABAergic interneurons,
NPY-positive interneurons in the CA1 and CA3 areas as
well as parvalbumin-positive cells survive ischemia
(Johansen, 1993; Larsson et al., 2001). However, altered
GABA neurotransmission may contribute to ischemiarelated neuronal death by enhancing the excitability of
CA1 pyramidal cells (Zhan et al., 2006).
Mechanisms underlying ischemia-related cell death
include necrosis, apoptosis, autophagic death, and hybrid
forms of cell death. The distinction between apoptosis and
necrosis still relies primarily on morphological criteria
(Martin et al., 1998). Cellular necrosis is initiated by the
departure from normal physiology and starts with ATP
depletion and impairments in membrane permeability.
Then nuclear pyknosis follows and the structural integrity of organelles is affected. The resulting release of intracellular debris is accompanied by an inflammatory
reaction. In contrast, apoptosis is an ordered set of
changes in gene expression and protein activity. It starts
from chromatin condensation and disintegration of nucleoli. Then dying cells get fragmented forming so-called
1916
NIKONENKO ET AL.
apoptotic bodies and cellular debris are phagocytozed by
nearby resident cells, typically without generating an
acute inflammatory response.
Apoptotic cells represent a minor fraction of dying
postischemic neurons, while the rest follow a necrosislike pathway (Martin et al., 1998; Müller et al., 2004).
Upregulation of phospho-c-Jun is viewed as an early
sign of apoptosis in CA1 neurons and caspase-3 is upregulated in the majority of apoptotic cells (Müller et al.,
2004). The release of cytochrome c from mitochondria to
the cytosol is considered to be a critical step in the apoptotic death of CA1 neurons after focal cerebral ischemia
(Sugawara et al., 1999).
There is some evidence that ischemia-related neuronal
death may involve the elements of autophagy—a homeostatic process required for the recycling of proteins and
damaged organelles. It was shown that focal ischemia is
associated with the enhanced expression of the autophagy regulator Beclin1 and subcellular redistribution of
the autophagic marker LC3 (Rami and Kögel, 2008). In
addition, it was found that some cells in the penumbra
may display hybrid cell death features combining various apoptotic and necrotic alterations: a marked caspase-3 activation, nuclear condensation/ fragmentation,
swollen cytoplasm, damaged organelles, and deteriorated
membranes (Wei et al., 2004).
It is interesting that mild ischemia may stimulate cell
proliferation in the subgranular zone of the dentate
gyrus. The number of DNA-synthesizing cells expressing
a marker of neural stem/progenitor cells was dramatically increased in this region 8 days after ischemia
(Yagita et al., 2001). The expression of an inducible nitric oxide synthase (iNOS) seems to be necessary for
ischemia-stimulated cell birth, because the latter is not
observed after focal cerebral ischemia in mutant mice
lacking the iNOS gene (Zhu et al., 2003).
Fig. 1. Micrographs of hippocampal tissue in the CA1 area
str.radiatum of intact rats (A) and rats subjected to a short episode of
transient global cerebral ischemia (B). Scale bar ¼ 200 nm.
ISCHEMIA-RELATED CHANGES IN SYNAPSES
Synaptic remodeling takes place in hippocampal tissue
early after ischemia. A short ischemic episode induces a
progressive decrease in synaptic numbers in the rat CA1
area, exceeding 30% at 1 day and 65% at 7 days after
the occlusion. Nearly half of the remaining synapses display degenerative features (Kovalenko et al., 2006). In
addition, there is a rapid ischemia-related increase in
the number of perforated synapses and multiple synapse
boutons (Ito et al., 2006; Kovalenko et al., 2006). Perforations are thought to correlate with reactive synaptogenesis, supporting a suggestion that few remaining
synapses increase their efficacy in response to ischemia
(Jourdain et al., 2002).
A significant, threefold, increase in the frequency of
concave-shaped synapses is observed 1 day after ischemia presumably reflecting the enhanced rate of synaptic
vesicle exocytosis (Hammond et al., 1994). Consistent
with this interpretation, ischemia-related potentiation of
excitatory transmission similar to LTP has been reported
in vitro (Jourdain et al., 2002).
The proportion of perforated synapses dropped almost to
control values 7 days after ischemia correlating with the
decrease in the frequency of concave-shaped synapses
(Kovalenko et al., 2006). It is interesting to observe that the
ischemia-related increase in perforated synapse numbers
was found in the CA1 area but not in the dentate gyrus af-
ter 24 hr of reperfusion (Martone et al., 1999). The number
of synapses in the ischemic penumbra was reported to
recover 1–12 weeks after ischemia (Ito et al., 2006).
Such structural features of a synaptic contact as numbers and spatial distribution of synaptic vesicles (SV)
directly relate to the efficacy of synaptic transmission
(Fig. 1). SV constitute an integral component of a chemical synapse specializing in the storage of a neurotransmitter and their availability for release determines some
presynaptic properties. SV can be divided into three
pools characterized by different release-competence: the
readily releasable pool (RRP), reserve pool, and resting
pool (Sudhof, 2000). RRP vesicles are in close proximity
to active zones and have the highest release-competence.
Vesicles of the reserve pool are more distant from release
sites but can move closer under stimulation. The resting
pool contains the organelles that are most distant from
active zones and rarely participate in neurotransmitter
release. Thus, the position of SV relative to active zones
seems to be a reasonable morphological correlate for the
probability of neurotransmitter release from a vesicle
(Tyler and Pozzo-Miller, 2001). The clustered arrangement of SV is another feature typical of a normally functioning chemical synapse (Kim et al., 2002). Special
software was designed to quantify these features in electron micrographs (Fig. 2) (Nikonenko and Skibo, 2004).
ISCHEMIC DAMAGE IN THE HIPPOCAMPUS
1917
Fig. 3. Scatterplots visualizing a relation between the distance to
the nearest-neighbor vesicle (NND) and shortest distance to the active
zone (AZD) for vesicles from control (A) and postischemic synapses
(B) (Nikonenko and Skibo, 2004). The ischemia-induced spatial rearrangement of synaptic vesicles can be observed as soon as 15 min
after ischemia.
Fig. 2. Spatial arrangement of synaptic vesicles relates to the efficacy of synaptic transmission (A). Quantified by the specialized software the shortest distance from a vesicle to the active zone of a
synapse is used as a correlate of a vesicle release-competence (B).
Similar formalism is applied to determine spatial proximity of vesicles to
each other, that is, their clustering potential (C). Scale bar ¼ 200 nm.
In synapses of the rat CA1 area, SV numbers tend to
decrease 2 hr after ischemia. This decrease was equal to
20% at 1 day and 44% at 7 days after the insult (Kovalenko et al., 2006). It is consistent with the data showing
that cerebral ischemia activates Ca2þ-dependent exocytosis of SV (Hammond et al., 1994). Similarly, SV numbers
experienced a 13% drop at 15 min and 25% at 2 hr after
an oxygen/glucose deprivation (OGD) episode in vitro.
However, one should be cautious when comparing quantities obtained in vivo and in vitro because in the latter case
synapses lack proper stimulation, are larger and contain
more sparsely distributed SV (Kovalenko et al., 2006).
The ischemia-induced spatial rearrangement of SV
can be observed in vivo after 15 min of reperfusion,
when the average distance from these organelles to
active zones increases by 24% (Fig. 3). Later, the value
of this parameter gets smaller becoming insignificantly
different from the control 7 days after ischemia. An
in vitro ischemia model demonstrates similar changes in
the spatial patterns formed by SV. It has to be noted that
these changes reflect mainly the disappearance of those
vesicles which are in close proximity to active zones (Nikonenko and Skibo, 2004; Kovalenko et al., 2006).
The inter-vesicle distance may be used as a measure
of SV clustering potential. It is of interest that in vivo
1918
NIKONENKO ET AL.
this parameter experiences a 10% increase at 15 min
(Fig. 3) and 40% increase at 7 days after ischemia. This
effect was more pronounced for RRP and part of the
reserve pool cluster facing an active zone, the core of a
reserve pool cluster being less affected. Despite larger
initial values of the parameter for the in vitro ischemia
model, its changes were similar in vitro and in vivo. The
increase in inter-vesicle spacings indicates the impaired
integrity of the spatial clusters of SV and may point to
abnormal interactions between SV proteins. The expression of SNAP-25 and synaptophysin implicated in the
regulation of synaptic transmission and SV cycling has
been modified following transient ischemia (Ishimaru
et al., 2001). A postischemic increase in calpain proteolytic activity and related degradation of cytoskeletal proteins may be responsible for the impairments of SV
transport (Sulkowski et al., 2006).
The postsynaptic density (PSD) is apposed to a presynaptic active zone being separated from it by a synaptic
cleft. PSD is composed of a cytoskeletal frame, in which
proteins, including neurotransmitter receptors, ion channels, and adaptor proteins, are anchored. The ischemiarelated activation of proteases results in a partial degradation of certain cross-linker proteins in PSD such as
spectrin and MAP2. In addition, unfolding proteins may
aggregate here resulting in a more diffuse and irregular
PSD structure (Martone et al., 1999).
Rapid enlargement of PSD was shown in excitatory
spine synapses in the CA1 area in vivo within 24 hr after
ischemia, followed by later degeneration of 80% of synaptic contacts. Postsynaptic structures contained numerous
vacuoles and lysosomes, and their cytoskeletal elements
and membranes demonstrated signs of lysis. A severalfold increase in PSD size was observed 7 days after ischemia. In vitro a transient OGD episode induced changes in
PSD similar to those observed in vivo (Kovalenko et al.,
2006). It should be stressed that the ischemia-related
increase in PSD size was both larger and longer-term in
the CA1 area than in the dentate gyrus. Although in the
latter, the change was reversed after 4 hr of reperfusion,
in the CA1 area, it persisted for at least 24 hr.
It was shown earlier that several protein kinases and
ATPases are translocated to synapses after ischemia (Hu
et al., 1998). The increased amount of material associated with PSD in the postischemic brain can represent
denatured and aggregated proteins. PSD proteins in the
CA1 area are heavily ubiquitinized, indicating that they
are going to degrade (Hu et al., 2000). These changes
may cause persistent alteration in synaptic transmission
and subsequently contribute to delayed neuronal injury.
ISCHEMIA-RELATED CHANGES IN
NON-NEURONAL CELLS IN
HIPPOCAMPAL TISSUE
Despite the fact that neuronal dysfunction is central
in the mechanisms of cerebral ischemic injury, other cells
also play important roles in the reaction to ischemic
insults. Cerebral ischemia causes endothelial cells to form
numerous microvilli that may increase microvascular resistance and result in moderate hemodynamic impediments. The injury of endotheliocytes leads to platelet
aggregation and formation of occlusive thrombi (Dietrich
et al., 1986). Progressive ischemia-related swelling of
perivascular astrocytic processes is associated with the
narrowing of microvascular lumen (Naganuma, 1990). On
the other hand, chronic cerebral ischemia can induce collateral circulation with the formation of new microvessels
in ischemic brain regions (Taguchi et al., 2004). The ischemia-related increase in superoxide production induces
a vasodilation, abnormal vascular reactivity, and bloodbrain barrier breakdown (Kontos, 2001), which may
result in a vasogenic edema (Nagy et al., 2005).
Inflammatory mechanisms play an important role during the acute phase of cerebral ischemia. Several cytokines and cell adhesion molecules are implicated in
early neurological deterioration influencing infarct volume, while metalloproteinases participate in the development of hemorrhagic transformations (RodriguezYanez and Castillo, 2008). The blockage of interleukin-1
(IL-1) receptors as well as knock-out inactivation of IL-1
gene significantly reduced neuronal loss after transient
ischemia. There is some evidence that IL-1 may act
through the release of nitric oxide by iNOS (Mizushima
et al., 2002). It was shown also that interleukin-6 exerts
trophic effects on postischemic hippocampal neurons
(Matsuda et al., 1996). A metalloproteinase inhibitor significantly reduced the ischemia-related injury of these
cells. Additionally, ischemic damage was also significantly reduced in metalloproteinase-9-deficient mice
(Lee et al., 2004). There is a biphasic increase in prostaglandin 2 levels after transient global cerebral ischemia
in gerbils, providing the evidence that isoforms of cyclooxygenase are also involved in the progression of ischemic injury (Candelario-Jalil et al., 2003).
Glial cells are far less susceptible to ischemic injury
than neurons. For example, astrocytes are able to maintain ATP levels longer than neurons; they have fewer
ionotropic glutamate receptors and may have better ion
buffering and antioxidant capacity. Astrocytes are the
only glycogen-storing cells in the brain tissue and can
use glycogen as a temporary substitute for glucose in ischemic conditions. Finally, they can release some transmitters, glutamate, D-serine, and adenosine, which have
roles in ischemic brain damage (Rossi et al., 2007).
Astrocytes provide metabolic and trophic support to
neurons and modulate synaptic activity. That is why
their impaired functions can critically influence neuronal
survival. Astrocytes respond to ischemia by the increase
in the number and size together with elongation of cytoplasmic processes (Kajihara et al., 2001), increase in the
expression of glial fibrillary acidic protein (GFAP) of the
intermediate filaments (Rossi et al., 2007), reorganization of their gap junctions supporting a functional syncytium (Li et al., 1998) and transient accumulation of
glycogen (Kajihara et al., 2001). Data show that ischemia induces astrocytes to renew the expression of
nexin—a potent protease inhibitor with neurite-promoting activity, which is mainly present in the adult olfactory system (Hoffmann et al., 1992). Severe ischemia
can induce apoptosis in astrocytes (Yu et al., 2001), however other data suggest that these cells mostly die by a
nonapoptotic mechanism (Chu et al., 2007).
In gerbils, transient global cerebral ischemia induced
an increase in the number of GFAP-positive (astrocytes)
and Iba-1-positive (microglia) cells in the CA1 area. This
increase was most evident in the str.lacunosum-moleculare, str.moleculare, and hilus 3–7 days after ischemia.
On day 28, the reactivity of astrocytes decreased in all
layers of the CA1 area. Changes in the intensity of
ISCHEMIC DAMAGE IN THE HIPPOCAMPUS
1919
reactive gliosis were consistent with the dynamics of pyramidal cell degeneration. Ameboid, sparsely arranged
Iba-1-positive microglial cells were seen in the CA1 area
starting one day after the occlusion. On day 3, their
numbers had increased more than sixfold in str.pyramidale, but changed little in str.radiatum (Pivneva et al.,
2005). Nevertheless, recent evidence indicates that
microglia monitor the functional status of synapses and
contribute to the subsequent increased turnover of synaptic contacts in the brain tissue affected by ischemia
(Wake et al., 2009). In contrast to astrocytes and microglia, ischemia was shown to cause a drop in the number
of hippocampal oligodendrocytes (Petito, 1986).
RELATION TO NEURODEGENERATIVE
DISEASES
Despite the fact that cerebral ischemic injury develops
much faster than chronic neurodegenerative disorders,
they share many common features. Neurodegeneration
similar to that observed after cerebral ischemia can also
be found in various diseases including Alzheimer’s disease (AD), Parkinson’s disease, and multiple sclerosis.
One causative factor typical of all these disorders is an
oxidative stress which triggers a cascade of events leading to cell death. Neurodegenerative diseases and cerebral ischemia share the accumulation of oxidative DNA
damage (Hill et al., 2008) as well as excitotoxic neuronal
degeneration leading to impaired function and ultimate
loss of specific neuronal populations (Arundine and
Tymianski, 2003).
Interestingly, transient ischemia was shown to cause
an abnormal accumulation of b-amyloid peptides in the
rat brain tissue (Makinen et al., 2008). The incidence of
AD is increased following ischemic episodes, and after
chronic hypoxia b-amyloid peptide-mediated increases in
L-type Ca2þ channel activity contribute to the Ca2þ
impairments seen in AD (Brown et al., 2005). Deposits
of a hyperphosphorylated tau protein—a pathological
hallmark of many neurodegenerative diseases—accumulate in postischemic neurons in a site-specific manner
(Wen et al., 2004).
The development and maturation of neurodegenerative
pathologies and ischemic lesions in the brain are characterized by the activation of glial cells and upregulation of
inflammatory mediators (Akundi et al., 2005; Koistinaho
and Koistinaho, 2005). Inflammation results in increased
nitric oxide formation and nitrosative stress which can inhibit components of the mitochondrial respiratory chain
and lead to energy metabolism impairments. This scenario is valid for various neurodegenerative disorders and
cerebral ischemic injury (Calabrese et al., 2004). Common
features include also Ca2þ-dependent enzymatic proteolysis (Higuchi et al., 2005) and blood-brain barrier breakdown (Willis et al., 2004). Finally, neurodegenerative
disorders and ischemic injury share common cell death
pathways which basically include a molecularly regulated
necrosis (Vanlangenakker et al., 2008) and caspase-mediated apoptosis (Hitomi et al., 2004).
CONCLUSIONS
It can be concluded that ischemic injury of the hippocampus unrolls at different levels and has both functional and structural implications. The deficiency in
Fig. 4. A scheme illustrating multiple factors which determine temporal and spatial dynamics of hippocampal ischemic injury.
energy metabolism both in neurons and glial cells is an
initiating factor. Temporal and spatial dynamics of ischemic injury are dictated by specific properties of neuronal
populations and suggest the action of multiple factors
including excitotoxicity, ion imbalance, oxidative stress,
inflammation, and so forth. Hippocampal tissue reacts
against ischemic injury using multiple compensatory
mechanisms, for example, synaptic plasticity, activation
of resident glial cells, neovascularization, and proliferation of stem cells in the dentate gyrus. The reaction of
hippocampal tissue depends on the type (global or focal)
and duration of cerebral ischemia. If the latter is relatively short, then cell death tends to be delayed and
selective for neurons, whereas longer episodes of ischemia cause broader and faster destructive changes. Neurons die by either necrotic, apoptotic, or autophagic
pathways or their death acquires hybrid features. Multiple lines of evidence point to the common nature of
neurodegeneration associated with a wide range of pathologies including cerebral ischemia and neurodegenerative disorders; however, it still remains a challenge to
study the mechanisms in detail. The investigation of
structural aspects of ischemic injury in the hippocampus
may provide insight into the pathogenetic mechanisms
and help to develop new therapeutic strategies.
To date, various agents including calcium and glutamate antagonists, sodium channel blockers, GABAA
receptors activators, free radical scavengers, and so
forth, have been studied in experimental settings in
terms of brain tissue protection against ischemic insults
(Kontos, 2001; Lo, 2008). Despite the fact that some
studies produced promising results most of them have
failed to translate the results into a viable therapy. At
the moment, there is no effective therapy to promote the
recovery of ischemic brain tissue except for the application of recombinant tissue plasminogen activator which
simply degrades the fibrin clot blocking blood flow (Lang
and McCullogh, 2008). Reasons for the mentioned therapeutic inefficiency are multiple. One could mention a
compromised blood flow making difficult on-time delivery of free radical scavengers to the affected region.
1920
NIKONENKO ET AL.
Another example deals with a biphasic (injury versus
repair) role of some molecular targets in the ischemiaaffected brain tissue (Lo, 2008).
However, there are more general aspects limiting the
development of effective anti-ischemic therapy. The most
important is that successful therapeutic strategy should
take into account multiple factors which are in play in
the ischemic brain tissue and be targeted at various
mechanisms (Fig. 4). For example, our experimental
data indicate that in the hippocampus ischemia-related
synaptic plasticity occurs well before the degeneration of
pyramidal neurons. Thus, from a clinical perspective it
would be interesting to investigate the therapeutic
potential of agents promoting synaptic plasticity (e.g.,
estrogens) and evaluate their role in the remodeling of
brain tissue injured by ischemia.
LITERATURE CITED
Akundi RS, Candelario-Jalil E, Hess S, Hull M, Lieb K, GebickeHaerter PJ, Fiebich BL. 2005. Signal transduction pathways regulating cyclooxygenase-2 in lipopolysaccharide-activated primary
rat microglia. Glia 51:199–208.
Arundine M, Tymianski M. 2003. Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium
34:325–337.
Avignone E, Frenguelli BG, Irving AJ. 2005. Differential responses
to NMDA receptor activation in rat hippocampal interneurons
and pyramidal cells may underlie enhanced pyramidal cell vulnerability. Eur J Neurosci 22:3077–3090.
Benveniste H, Drejer J, Schousboe A, Diemer NH. 1984. Elevation
of the extracellular concentrations of glutamate and aspartate in
rat hippocampus during transient cerebral ischemia monitored by
intracerebral microdialysis. J Neurochem 43:1369–1374.
Bonanni L, Chachar M, Jover-Mengual T, Li H, Jones A, Yokota H,
Ofengeim D, Flannery RJ, Miyawaki T, Cho CH, Polster BM,
Pypaert M, Hardwick JM, Sensi SL, Zukin RS, Jonas EA. 2006.
Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain. J Neurosci 26:6851–6862.
Brown ST, Scragg JL, Boyle JP, Hudasek K, Peers C, Fearon IM.
2005. Hypoxic augmentation of Ca2þ channel currents requires a
functional electron transport chain. J Biol Chem 280:21706–21712.
Buddle M, Eberhardt E, Ciminello LH, Levin T, Wing R, DiPasquale K, Raley-Susman KM. 2003. Microtubule-associated protein
2 (MAP2) associates with the NMDA receptor and is spatially
redistributed within rat hippocampal neurons after oxygen-glucose deprivation. Brain Res 978:38–50.
Calabrese V, Boyd-Kimball D, Scapagnini G, Butterfield DA. 2004.
Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes. In Vivo 18:245–267.
Candelario-Jalil E, Gonzalez-Falcon A, Garcia-Cabrera M, Alvarez D,
Al Dalain S, Martinez G, Leon OS, Springer JE. 2003. Assessment
of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following
transient global cerebral ischemia. J Neurochem 86:545–555.
Chen J, Nagayama T, Jin K, Stetler RA, Zhu RL, Graham SH,
Simon RP. 1998. Induction of caspase-3-like protease may mediate
delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 18:4914–4928.
Choi DW, Rothman SM. 1990. The role of glutamate neurotoxicity in
hypoxic-ischemic neuronal death. Annu Rev Neurosci 13:171–182.
Chu X, Fu X, Zou L, Qi C, Li Z, Rao Y, Ma K. 2007. Oncosis, the
possible cell death pathway in astrocytes after focal cerebral ischemia. Brain Res 1149:157–164.
Colbourne F, Sutherland GR, Auer RN. 1999. Electron microscopic
evidence against apoptosis as the mechanism of neuronal death
in global ischemia. J Neurosci 19:4200–4210.
Dietrich WD, Ginsberg MD, Busto R, Watson BD, Yoshida S. 1986.
Vascular aspects and hemodynamic consequences of central nervous system injury. Cent Nerv Syst Trauma 3:265–280.
Gubellini P, Bisso GM, Ciofi-Luzzatto A, Fortuna S, Lorenzini P, Michalek H, Scarsella G. 1997. Ubiquitin-mediated stress response in a rat
model of brain transient ischemia/hypoxia. Neurochem Res 22:93–100.
Hammond C, Crépel V, Gozlan H, Ben-Ari Y. 1994. Anoxic LTP
sheds light on the multiple facets of NMDA receptors. Trends
Neurosci 17:497–503.
Harry GJ, Lefebvre d’Hellencourt C. 2003. Dentate gyrus: alterations
that occur with hippocampal injury. Neurotoxicology 24:343–356.
Higuchi M, Tomioka M, Takano J, Shirotani K, Iwata N, Masumoto
H, Maki M, Itohara S, Saido TC. 2005. Distinct mechanistic roles
of calpain and caspase activation in neurodegeneration as
revealed in mice overexpressing their specific inhibitors. J Biol
Chem 280:15229–15237.
Hill JW, Hu JJ, Evans MK. 2008. OGG1 is degraded by calpain following oxidative stress and cisplatin exposure. DNA Repair
(Amst) 7:648–654.
Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y,
Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y,
Tohyama M. 2004. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death.
J Cell Biol 165:347–356.
Hoffmann MC, Nitsch C, Scotti AL, Reinhard E, Monard D. 1992.
The prolonged presence of glia-derived nexin, an endogenous protease inhibitor, in the hippocampus after ischemia-induced
delayed neuronal death. Neuroscience 49:397–408.
Hsu M, Sik A, Gallyas F, Horváth Z, Buzsáki G. 1994. Short-term
and long-term changes in the postischemic hippocampus. Ann N
Y Acad Sci 743:121–139.
Hu BR, Martone ME, Jones YZ, Liu CL. 2000. Protein aggregation
after transient cerebral ischemia. J Neurosci 20:3191–3199.
Hu BR, Park M, Martone ME, Fischer WH, Ellisman MH, Zivin JA.
1998. Assembly of proteins to postsynaptic densities after transient cerebral ischemia. J Neurosci 18:625–633.
Ishimaru H, Casamenti F, Uéda K, Maruyama Y, Pepeu G. 2001.
Changes in presynaptic proteins, SNAP-25 and synaptophysin, in the
hippocampal CA1 area in ischemic gerbils. Brain Res 903:94–101.
Ito U, Kuroiwa T, Nagasao J, Kawakami E, Oyanagi K. 2006. Temporal profiles of axon terminals, synapses and spines in the ischemic penumbra of the cerebral cortex: ultrastructure of neuronal
remodeling. Stroke 37:2134–2139.
Johansen FF. 1993. Interneurons in rat hippocampus after cerebral
ischemia. Morphometric, functional, and therapeutic investigations. Acta Neurol Scand Suppl 150:1–32.
Jourdain P, Nikonenko I, Alberi S, Muller D. 2002. Remodeling of
hippocampal synaptic networks by a brief anoxia-hypoglycemia.
J Neurosci 22:3108–3116.
Kajihara H, Tsutsumi E, Kinoshita A, Nakano J, Takagi K, Takeo S.
2001. Activated astrocytes with glycogen accumulation in ischemic
penumbra during the early stage of brain infarction: immunohistochemical and electron microscopic studies. Brain Res 909:92–101.
Kayali F, Montie HL, Rafols JA, DeGracia DJ. 2005. Prolonged
translation arrest in reperfused hippocampal cornu Ammonis 1 is
mediated by stress granules. Neuroscience 134:1223–1245.
Kim WT, Chang S, Daniell L, Cremona O, Di Paolo G, De Camilli P.
2002. Delayed reentry of recycling vesicles into the fusion-competent synaptic vesicle pool in synaptojanin 1 knockout mice. Proc
Natl Acad Sci USA 99:17143–17148.
Koistinaho M, Koistinaho J. 2005. Interactions between Alzheimer’s
disease and cerebral ischemia – focus on inflammation. Brain Res
Rev 48:240–250.
Kontos HA. 2001. Oxygen radicals in cerebral ischemia: the 2001
Willis lecture. Stroke 32:2712–2716.
Kovalenko T, Osadchenko I, Nikonenko A, Lushnikova I, Voronin K,
Nikonenko I, Muller D, Skibo G. 2006. Ischemia-induced modifications in hippocampal CA1 stratum radiatum excitatory synapses. Hippocampus 16:814–825.
Lang JT, McCullogh LD. 2008. Pathways to ischemic neuronal cell
death: are sex differences relevant? J Transl Med 6:33–42.
Larsson E, Lindvall O, Kokaia Z. 2001. Stereological assessment of
vulnerability of immunocytochemically identified striatal and hippocampal neurons after global cerebral ischemia in rats. Brain
Res 913:117–132.
ISCHEMIC DAMAGE IN THE HIPPOCAMPUS
Lee SR, Tsuji K, Lee SR, Lo EH. 2004. Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral
ischemia. J Neurosci 24:671–678.
Li WE, Ochalski PA, Hertzberg EL, Nagy JI. 1998. Immunorecognition, ultrastructure and phosphorylation status of astrocytic gap
junctions and connexin43 in rat brain after cerebral focal ischaemia. Eur J Neurosci 10:2444–2463.
Liu KF, Li F, Tatlisumak T, Garcia JH, Sotak CH, Fisher M, Fenstermacher JD. 2001. Regional variations in the apparent diffusion coefficient and the intracellular distribution of water in rat
brain during acute focal ischemia. Stroke 32:1897–1905.
Lo EH. 2008. A new penumbra: transitioning from injury into
repair after stroke. Nat Med 14:497–500.
Mäkinen S, van Groen T, Clarke J, Thornell A, Corbett D, Hiltunen
M, Soininen H, Jolkkonen J. 2008. Coaccumulation of calcium and
beta-amyloid in the thalamus after transient middle cerebral artery
occlusion in rats. J Cereb Blood Flow Metab 28:263–268.
Martin LJ, Al-Abdulla NA, Brambrink AM, Kirsch JR, Sieber FE, Portera-Cailliau C. 1998. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the
contributions of apoptosis and necrosis. Brain Res Bull 46:281–309.
Martone ME, Jones YZ, Young SJ, Ellisman MH, Zivin JA, Hu BR.
1999. Modification of postsynaptic densities after transient cerebral ischemia: a quantitative and three-dimensional ultrastructural study. J Neurosci 19:1988–1997.
Matsuda S, Wen TC, Morita F, Otsuka H, Igase K, Yoshimura H,
Sakanaka M. 1996. Interleukin-6 prevents ischemia-induced
learning disability and neuronal and synaptic loss in gerbils. Neurosci Lett 204:109–112.
Mizushima H, Zhou CJ, Dohi K, Horai R, Asano M, Iwakura Y, Hirabayashi T, Arata S, Nakajo S, Takaki A, Ohtaki H, Shioda S.
2002. Reduced postischemic apoptosis in the hippocampus of mice
deficient in interleukin-1. J Comp Neurol 448:203–216.
Müller GJ, Stadelmann C, Bastholm L, Elling F, Lassmann H,
Johansen FF. 2004. Ischemia leads to apoptosis–and necrosis-like
neuron death in the ischemic rat hippocampus. Brain Pathol
14:415–424.
Naganuma Y. 1990. Changes of the cerebral microvascular structure and endothelium during the course of permanent ischemia.
Keio J Med 39:26–31.
Nagy Z, Vastag M, Kolev K, Bori Z, Karáidi I, Skopál J. 2005.
Human cerebral microvessel endothelial cell culture as a model
system to study the blood-brain interface in ischemic/hypoxic conditions. Cell Mol Neurobiol 25:201–210.
Neumar RW, Meng FH, Mills AM, Xu YA, Zhang C, Welsh FA,
Siman R. 2001. Calpain activity in the rat brain after transient
forebrain ischemia. Exp Neurol 170:27–35.
Nicholson Ch, Sykova E. 1998. Extracellular space structure
revealed by diffusion analysis. Trends Neurosci 21:207–215.
Nikonenko AG, Skibo GG. 2004. Technique to quantify local clustering of synaptic vesicles using single section data. Microsc Res
Tech 65:287–291.
Nikonenko I, Bancila M, Bloc A, Muller D, Bijlenga P. 2005. Inhibition of T-type calcium channels protects neurons from delayed ischemia-induced damage. Mol Pharmacol 68:84–89.
Petito CK. 1986. Transformation of postischemic perineuronal glial
cells. I. Electron microscopic studies. J Cereb Blood Flow Metab
6:616–624.
Petito CK, Pulsinelli WA. 1984. Delayed neuronal recovery and neuronal death in rat hippocampus following severe cerebral ischemia: possible relationship to abnormalities in neuronal processes.
J Cereb Blood Flow Metab 4:194–205.
Pivneva TA, Tsupikov OM, Pilipenko MN, Vasilenko DA, Skibo GG.
2005. Structural changes in astrocytes in gerbil’s hippocampus after experimental cerebral ischemia. Neurophysiology 37:410–415.
Rami A. 2003. Ischemic neuronal death in the rat hippocampus: the
calpain-calpastatin-caspase hypothesis. Neurobiol Dis 13:75–88.
Rami A, Kögel D. 2008. Apoptosis meets autophagy-like cell death
in the ischemic penumbra: two sides of the same coin? Autophagy
4:422–426.
Rodriguez-Yanez M, Castillo J. 2008. Role of inflammatory markers
in brain ischemia. Curr Opin Neurol 21:353–357.
1921
Rosenblum WI. 1997. Histopathologic clues to the pathways of neuronal death following ischemia/hypoxia. J Neurotrauma 14:313–326.
Rossi DJ, Brady JD, Mohr C. 2007. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci 10:1377–1386.
Schild L, Huppelsberg J, Kahlert S, Keilhoff G, Reiser G. 2003.
Brain mitochondria are primed by moderate Ca2þ rise upon hypoxia/reoxygenation for functional breakdown and morphological
disintegration. J Biol Chem 278:25454–25460.
Skibo GG, Lushnikova IV, Voronin KY, Dmitrieva O, Novikova T, Klementiev B, Vaudano E, Berezin VA, Bock E. 2005. A synthetic
NCAM-derived peptide, FGL, protects hippocampal neurons from ischemic insult both in vitro and in vivo. Eur J Neurosci 22:1589–1596.
Skibo GG, Nikonenko IR, Savchenko VL, McKanna JA. 2000.
Microglia in organotypic hippocampal slice culture and effects of
hypoxia: ultrastructure and lipocortin-1 immunoreactivity. Neuroscience 96:427–438.
Solenski NJ, diPierro CG, Trimmer PA, Kwan AL, Helm GA. 2002.
Ultrastructural changes of neuronal mitochondria after transient
and permanent cerebral ischemia. Stroke 33:816–824.
Sudhof TC. 2000. The synaptic vesicle cycle revisited. Neuron
28:317–320.
Sugawara T, Fujimura M, Morita-Fujimura Y, Kawase M, Chan
PH. 1999. Mitochondrial release of cytochrome c corresponds to
the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia. J Neurosci 19:RC39.
Sulkowski G, Struzynska L, Lenkiewicz A, Rafalowska U. 2006.
Changes of cytoskeletal proteins in ischaemic brain under cardiac
arrest and reperfusion conditions. Folia Neuropathol 44:133–139.
Taguchi Y, Takashima S, Sasahara E, Inoue H, Ohtani O. 2004.
Morphological changes in capillaries in the ischemic brain in Wistar rats. Arch Histol Cytol 67:253–261.
Tallent MK. 2007. Somatostatin in the dentate gyrus. Prog Brain
Res 163:265–284.
Tyler WJ, Pozzo-Miller LD. 2001. BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles
at active zones of hippocampal excitatory synapses. J Neurosci
21:4249–4258.
Vanlangenakker N, Berghe TV, Krysko DV, Festjens N, Vandenabeele P. 2008. Molecular mechanisms and pathophysiology of necrotic cell death. Curr Mol Med 8:207–220.
Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. 2009.
Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980.
Wei L, Ying DJ, Cui L, Langsdorf J, Yu SP. 2004. Necrosis, apoptosis and hybrid death in the cortex and thalamus after barrel cortex ischemia in rats. Brain Res 1022:54–61.
Wen Y, Yang S, Liu R, Simpkins JW. 2004. Transient cerebral ischemia induces site-specific hyperphosphorylation of tau protein.
Brain Res 1022:30–38.
Willis CL, Nolan CC, Reith SN, Lister T, Prior MJ, Guerin CJ, Mavroudis G, Ray DE. 2004. Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in
the apparent absence of direct astrocytic contact. Glia 45:325–337.
Yagita Y, Kitagawa K, Ohtsuki T, Takasawa K, Miyata T,
Okano H, Hori M, Matsumoto M. 2001. Neurogenesis by progenitor
cells in the ischemic adult rat hippocampus. Stroke 32:1890–1896.
Yokota M, Saido TC, Kamitani H, Tabuchi S, Satokata I, Watanabe
T. 2003. Calpain induces proteolysis of neuronal cytoskeleton in
ischemic gerbil forebrain. Brain Res 984:122–132.
Yu AC, Wong HK, Yung HW, Lau LT. 2001. Ischemia-induced apoptosis in primary cultures of astrocytes. Glia 35:121–130.
Zhan RZ, Nadler JV, Schwartz-Bloom RD. 2006. Depressed
responses to applied and synaptically-released GABA in CA1 pyramidal cells, but not in CA1 interneurons, after transient forebrain ischemia. J Cereb Blood Flow Metab 26:112–124.
Zhang F, Liu CL, Hu BR. 2006. Irreversible aggregation of protein
synthesis machinery after focal brain ischemia. J Neurochem
98:102–112.
Zhu DY, Liu SH, Sun HS, Lu YM. 2003. Expression of inducible nitric oxide synthase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci 23:223–229.
Документ
Категория
Без категории
Просмотров
5
Размер файла
332 Кб
Теги
features, structure, ischemia, hippocampus, damage
1/--страниц
Пожаловаться на содержимое документа