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Pathophysiology of Cerebral Ischemia
® 1991 S. Karger AG. Basel
1015—9770/91/0017—0002S2.75/O
Cerebrovasc Dis 1991:1(suppl 1):2—15
Animal Models of Cerebral Ischemia. 1. Review of Literature
Konstantin-A. Hossmann
Max-Planck-Institul für neurologische Forschung, Abteilung für experimentelle Neurologie, Köln, FRG
Key Words. Animal models of ischemia • Brain resuscitation • Stroke • Treatment of cerebral ischemia
The investigation of the pathophysiology and therapy
of cerebral ischemia requires animal experimental mod­
els in which an ischemic impact can be produced under
controlled conditions. The ideal animal model should be
relevant to the clinical situation, it should be highly
reproducible, it should avoid extracerebral complicatory
side effects, and it should be technically easy to perform.
This goal is not easy to achieve in view of the diversity of
scientific issues related to brain ischemia research. The
most important problems currently under investigation
are the prolongation of the survival time of the brain after
global ischemia; the selective vulnerability of certain
nerve cell populations within the central nervous system
after a brief cerebrocirculatory arrest; and the focal vul­
nerability of the brain to regional reduction or cessation
of blood flow.
Obviously, the strategy of animal experimentation
differs considerably for each of these issues. In order to
investigate the upper limits of reversibility of ischemic
lesions, all systemic effects should be excluded which
might complicate or prevent the recovery of the brain
after prolonged cerebro-circulatory, arrest [1], The ex­
ploration of selective vulnerability, in contrast, intends
to define the lower threshold of ischemic cel! damage, i.e.
the shortest duration of ischemia which may result in
irreversible injury [2]. The study of regional ischemia,
finally, intends to explore the capacitance of the cerebro­
vascular system to provide the minimum amount of
blood flow necessary to prevent ischemic cell damage [3]
and/or the possibility to temporarily protect nerve cell
survival until this minimum of blood flow has been
restored [4],
It is obvious that the different designs of animal
experiments must lead to different results, and that gener­
alizations of the observations are not possible without
precise knowledge of the experimental condition. A few
examples may illustrate this notion. The central nervous
system does not suffer any permanent damage if the
duration of ischemia is so short that energy reserves of the
cell are not used up. By increasing glucose stores of the
tissue or decreasing metabolic rate of the brain with
hypothermia or barbiturates, survival of the central ner­
vous system during ischemia can be prolonged [5, 6],
However, if ischemia is long enough to cause breakdown
of energy metabolism, ontoward side effects of these
interventions supervene: hyperglycemia results in more
pronounced tissue acidosis, and the suppression of meta­
bolic activity delays postischemic recovery, both of which
tend to enhance rather than to reduce ischemic brain
damage [7, 8].
Another example is the determination of the revival
time of the nerve cell after cerebrocirculatory arrest.
Pyramidal cells of cerebral cortex will resume electrophysiological and biochemical function after 1 h of com­
plete ischemia in normothermia if blood flow of the brain
is selectively interrupted [9], The same cells, however,
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Abstract. A summary of animal experimental models for the production and treatment of global and regional
cerebral ischemia is presented. The methodological peculiarities of the various procedures arc reviewed and discussed
with respect to the theoretical and clinical relevance.
suffer irreversible damage after only 5 min ischemia if
blood flow slops due to heart arrest [10]. Similarly, the
demonstration of loss of pyramidal neurons in CA1 sub­
field of hippocampus after 5 min bilateral carotid occlu­
sion in gerbils [11] is as little representative for the
resistance of the central nervous system to ischemia in
general, as is the demonstration of survival of cortical
neurons after 1 h ischemia [9] for the understanding of
selective vulnerability.
The interpretation of ischemia experiments, the com­
parison of data obtained in different laboratories and the
evaluation of therapeutic interventions, therefore, re­
quire the intimate knowledge of the particularities of the
animal models used. For this purpose, the most relevant
animal models for the study of brain ischemia, as well as
their applicability for therapeutical procedures will be
reviewed.
Global Ischemia (table 1)
Global ischemia of the brain is the reduction or cessa­
tion of total cerebral blood flow. The clinical interest of
global ischemia is the study of the vulnerability of the
brain to cardiocirculatory failure, and the réanimation of
the centra! nervous system following such an incident.
The clinically most relevant model is induced cardiac
arrest (fig. 1). However, cardiocirculatory failure affects
3
not only the brain but all organs of the body which, in
turn, may interfere with the réanimation of the brain in
various ways. For this reason, a number of models have
been developed which induce reduction or cessation of
cerebral blood flow without or with little interference of
peripheral organs.
Examples of complete global ischemia are compression
of the blood vessels in the neck by strangulation or
inflation of a pneumatic cuff, the intrathoracic occlusion
of the innominate and left subclavian arteries which
results in the interruption of blood supply to both carotid
and vertebral arteries (fig. 2), or the increase of intracra­
nial pressure above blood pressure by infusing fluids
under high pressure into the cisterna magna (fig. 3). In all
models of selective cerebrocirculatory arrest, care has to
be taken to avoid a collateral supply of blood to the
ischemic brain. This has been done by occluding, in
addition to the main arterial supply, the internal mam­
mary arteries [9], the pterygopalatine arteries [56]. or by
retrograde drainage of the occluded vessels [61. 62. 66].
Collateral flow can also be efficiently reduced by lowering
the blood pressure to hypotensive levels during ischemia,
cither by bleeding or application of ganglion-blocking
agents [66. 85]. For certain purposes, isolated head or
brain preparations are used for the production of com­
plete ischemia. In these preparations, blood flow can be
varied over a wide range simply by adjusting the pump
speed of the extracorporeal circulation system.
Fig. 1. Global cerebral ischemia during induced cardiocirculatory arrest. Cardiac arrest was produced by electrical fibrillation of the
left ventricle (arrow). Recording of the EEG. the ECG. central venous pressure (CVP) and systemic arterial pressure (SAP): 30 min after
ventricular fibrillation, heart was resuscitated by intrathoracic cardiac massage (horizontal bar) [from ref. 13J.
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Animal Models of Cerebral Ischemia
Hossmann
4
Table 1. Reversible global ischemia
Cardiac arrest
With KCI
Bv ventricular fibrillation
By exsanguination
By drowning
Induced hypotension
Animals
References
monkey
rat
cat
dog
dog
monkey
dog
dog
dog
Myers and Yamaguchi [7]
Blomqvist and Wieloch [12]
Hossmann and Hossmann [13]
Lin and Kormado [14]
Gurvitch et al. [15]
Bacalzo and Wolfson [16]
Heymans and Bouckaert [10]
Kirimli et al. [ 17]
Makarenko [18]
cat
cat
monkey
Gygax et al. [ 19]
Pasztor et al. [20]
Brierley et al. [21]
rat
cat
rabbit
dog
dog
dog
dog
dog
monkey
dog
dog
cat
rabbit
Wadc et al. [22]
Ten Cate and Horsten [23]
Cantu et al. [24]
Arai et al. [25]
Pontius et al. [26]
Marshall et al. [27]
Brockmann and Jude [28]
Jackson et al. [29]
Miller and Myers [30]
Zimmermann and Spencer [31]
Goldstein et al. [32]
Gânshirt and Zylka [33]
Lâwen and Sievers [34]
cat
Weinberger et al. [35]
dog
dog
groundhog
Cohen et al. [36]
Read et al. [37]
Bigelow and McBirnie [38]
cat
rabbit
dog
rat
rat
cat
monkey
Hart et al. [39]
Hirsch [40]
Kabat and Dennis [41 ]
Nemoto and Frinak [42]
Siemkowicz and Hansen [43]
Nemoto et al. [44]
Nemoto et al. [45]
hypertensive rat
gerbil
awake gerbil
gerbil
sheep
monkey
rat
cat
cat
rat
rat
rat
Fujishima et al. [46]
Kobayashi et al. [47]
Chandler et al. [48]
Tomida et al. [49]
Terlecki et al. [50]
Sengupta et al. [51]
Smith et al. [52]
Welsh et al. [53]
Ginsberg et al. [54]
Kameyama et al. [55]
Gumerlock et al. [56]
Aragno and Doni [57]
Occlusion o f aorta
With vent into blood reservoir
With aorto-atrial bypass
Distally of left subclavian artery
And vena cava
And vena azygos
And arteria pulmonalis
Occlusion o f arteria pulmonalis
Occlusion o f vena cava
And vena azygos
Pneumatic cuff around neck
And hypotension
And hypotension
And basilary artery
And pterygopalatine artery'
And jugular veins
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Occlusion o f carotid arteries
Animal Models of Cerebral Ischemia
5
Table 1 (continued)
Animals
References
rat
cat
monkey
dog
monkey
rabbit
Pulsinelli and Brierley [58]
Sugar and Gerard [59]
Teraura et al. [60]
Fujishima [61 ]
Wolin et al. [62]
Kolata [63]
cat
dog
cat
monkey
Gildea and Cobb [64]
Pikc et al. [65]
Hossmann and Sato [9]
Hossmann and Zimmermann [66]
rat
cat
rabbit
dog
monkey
Siesjô and Zwetnow [67]
van Harreveld [68]
Marshall et al. (69)
Neely and Youmans [70]
Hcyrch and Edwards [71]
rat
dog
dog
rat
cai
monkey
Ljunggren et al. [72]
Kramer and Tuynman [73]
Hallenbcck and Bradley [74]
Kawakami and Hossmann [75]
Hekmatpanah [76]
Langfitt et al. [77]
rat
cat
dog
monkey
Kriegelstein et al. [78]
Hirsch et al. [74]
Hinzcn et al. [80]
While et al. [81 ]
guinea pig
Okada [82]
rat
guinea pig
Dong et al. (83)
Whittingham et al. [84]
Occlusion o f carotid and vertebral arteries
And retrograde drainage
And hypotension
Occlusion of innominate and subclavian arteries
And hypotension
Intracranial hypertension
By fluid infusion
And hypotension
And peritoneal dialysis
By balloon
Isolated head
In vitro ischemia
Hippocampal slice
Although the common pathogenic factor in all these
ischemia models is interruption of blood flow and hence
cessation of substrate exchange with the brain, consider­
able differences exist. When arterial blood supply is inter­
rupted without simultaneous blockade of venous outflow,
most of the blood escapes from the brain during ischemia
(anemic ischemia). The additional interruption of venous
outflow, e.g. during strangulation ischemia, causes mas­
sive congestion of the cerebral vasculature with blood
(hyperemic ischemia). This difference is of importance
for the recirculation after ischemia because the increased
viscosity of stagnant blood requires a higher reperfusion
pressure than following anemic ischemia.
Another difference is the intracranial fluid reservoir
during ischemia. In anemic ischemia this reservoir is
smaller than in hyperemic ischemia or compression isch­
emia with cisternal infusion of artificial cerebrospinal
fluid (CSF). Ischemic brain swelling, in consequence, is
less pronounced during anemic ischemia and, therefore,
interferes less with postischemic recirculation.
Incomplete global ischemia (oligemia) is produced by
reducing cerebral perfusion pressure, i.e. by lowering
arterial blood pressure, by extracranial ligation of the
carotid and vertebral arteries or by increasing intracranial
pressure slightly below blood pressure. In gerbils severe
oligemia can be produced by ligation of both common
carotid arteries without additional occlusion of the verte­
bral arteries, because in this species the circle of Willis is
incomplete, and there is no connection between the basi­
lary and the internal carotid artery. By implantation of
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In situ revival after decapitation
6
Hossmann
Fig. 2. Global cerebral ischemia following intrathoracic occlusion of ihe innominate and left subclavian arteries (upward arrow).
Recording of the EEG, conical steady potential (DC), electrical impedance of the conex (Imp), and the pyramidal response following
electrical stimulation of the sensorimotor conex (PR). Recirculation after 30 min of ischemia in normothermia was achieved by removing
the vessel clamps (downward arrow) and by raising blood pressure to hypenensive levels. Note the suppression and recovery of EEG and
evoked potentials during and after ischemia, and the close relationship between impedance and neuronal excitability [from ref. 152].
carotid artery occluders, this intervention can also be
carried out in awake gerbils [60], This is of particular
interest for the investigation of repetitive ischemia be­
cause animals do not have to be reanesthetized for each
ischemic episode [49].
The main pathophysiological pecularity of incomplete
global ischemia is the fact that the critical perfusion
pressure necessary for the maintenance of blood flow in
the brain is compromised at first in the peripheral regions
of the supplying territories of the cerebral arteries. Since
these regions are located in the border zones between
these territories, the resulting decrease in blood flow is
referred to as ‘border line’ or ‘border zone’ ischemia [21].
Under clinical conditions, the temporoparietal region is
mostly endangered because it is the common border zone
between the territories of all three cerebral arteries [86].
Lowering of cerebral perfusion pressure, moreover,
does not result in homogeneous reduction of flow at the
microcirculatory level. On the contrary, an extremely
irregular distribution of blood flow may ensue with low
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Fig. 3. Global cerebral ischemia produced
by induced intracranial hypertension. Record­
ing of the EEG, intracranial pressure (ICP)
and systemic arterial pressure (SAP). Intra­
cranial pressure was raised by infusing artificial
CSF into the cistcrna magna. During ischemia
blood pressure was controlled by bleeding and
infusion of the ganglion-blocking agent Arfonad®. Recirculation after 30 min ischemia
was achieved by discontinuing infusion of
CSF, and raising blood pressure to hyperten­
sive levels with Novadral® [from ref. 75).
7
Animal Models of Cerebral Ischemia
Table 2. Regional ischemia and microembolism
Animals
References
gerbil
hypertensive rat
sheep
gerbil
Levine and Payan [88]
Choki el al. [89]
Terlecki et al. [50]
Bosma et al. [90]
rat
Dougherty et al. [91]
rat
rat
rat
rat
Bannister and Chapman [92]
Busto and Ginsberg [93]
Levine [94]
MacMillan [95]
rat
rat
rat
hypertensive rat
cat
dog
monkey
rat
rat
rat
cat
dog
monkey
rat
cat
dog
cat
gerbil
rat
dog
monkey
monkey
rabbit
rat
rabbit
monkey
rat
dog
Robinson [96]
Tamura et al. [97]
Albanese et al. [98]
Coyle et al. [99]
Sundt and Waltz [100]
Anthony et al. [101]
Meyer and Dennv-Brown [102]
Chen et al. [103]
Rubino and Young [104]
Shiino et al. [105]
O’Brien and Waltz [106]
Fisk et al. [107]
Hudgins and Garcia [108]
Brint et al. [109]
Bose et al. [110]
Diaz et al. [Ill]
Berkelbach v.d. Sprenkel and Bulleken [112
Yoshimine and Yanagihara [113]
Turner [114]
Molinari [115]
Molinari et al. [116]
Brassel et al. [ 117]
Hegedüs et al. [118]
Nagasawa and Kogure [119]
Molnar et al. [120]
Bremer et al. [121]
Kudo et al. [122]
Hill et al. [123]
gerbil
dog
dog _
Yamada et al. [ 124]
Oki et al. [125]
Fujishima et al. [126]
monkey
Vajda et al. [127]
goat
Miletich et al. [128]
rat
dog
Watson et al. [129]
Penry and Netsky [130]
Occlusion o f common carotid artery
And contralateral external carotid artery
After previous ligation of contralateral
carotid and both vertebral arteries
And contralateral anastomoses between
carotid artery and jugular vein
And intracranial hypertension
And asphyxia
And CO-poisoning
Occlusion of middle cerebral artery
Retroorbital ligation
And both carotid arteries
MCA branches
And olfactory branch
Transorbita! ligation
And internal carotid artery
Postorbital ligation
And posterior cerebral artery ligation
By embolization with silicon rubber
With cyanoacrylate-monomers
With silver/gold balls
With retractable embolus
With autologous blood clot
Occlusion o f basilary artery
By clip
By macroembolism
By magnetic localization of iron filings
Occlusion of posterior choroidal artery
Occlusion of pial arteries
By illumination of photosensitizer
By embolization with steel balls
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Internal maxillary artery occlusion
Hossmann
8
Tabic 2 (continued)
Animals
References
dog
monkey
Suzuki ei al. [131]
West and Matsen [132]
rat
eat
rat
rabbit
rat
cat
dog
monkey
Kogure et al. [133]
Vise et al. [ 134]
Furlow and Bass [135]
Fieschi et al. [136]
Johansson [137]
Fritz and Hossmann [138]
Simms et al. [139]
Meldrum et al. [140]
hypertensive rat
Okamoto et al. [141]
Occlusion o f the circle o f Willis
Microembolism
With microsphercs
With arachidonate-induced platelet aggregates
With ADP-induced platelet aggregates
With air bubbles
Spontaneous infarcts
obtained in such models have, therefore, little - if anything in common with the in vivo situation of brain ischemia and
should be interpreted with great caution.
Regional Ischemia (table 2)
Extracranial occlusion of a carotid or vertebral artery
without further surgical intervention does not produce
cerebral ischemia because the circle of Willis provides
sufficient collateral blood supply via the nonaffected ves­
sels. The only exceptions are the Mongolian gerbil in which
the circle of Willis is incomplete, the sheep in which the
vertebral arteries do not unite to form a basilary artery',
and the stroke-prone spontaneously hypertensive rat in
which the collateral system is compromised. However,
even in these species, infarcts do not develop in all
animals. Extracranial ligation of a carotid artery' in the
gerbil produces infarcts in only about 30% of the animals.
This incidence can be raised to 70% by additional coagula­
tion of the contralateral external carotid artery, in order to
reduce collateral blood supply from the opposite side [90],
In other species, more complicated surgical interventions
have to be carried out in order to produce focal brain
ischemia by manipulation of extracranial arteries. In rats,
carotid artery occlusion has been combined with intra­
cranial hypertension [93] or by anastomosing the contra­
lateral carotid artery with the jugular vein, in order to
reduce collateral blood perfusion pressure [92],
In monkeys and dogs, interruption of the circle of
Willis has been carried out by clipping the anterior com-
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flow rates in some and relatively high flow rates in other
parts. Without appropriate measuring techniques, there­
fore, the actual flow rate in a particular region is difficult
to assess. Another complicating factor of incomplete
ischemia is the fact that the vasculature is slowly perfused
with blood during the ischemic period. The resulting
supply of fluid causes ischemic brain swelling and a
compression of the microcirculation which may compro­
mise the recirculation of the brain following ischemia.
This factor is presumably one of the reasons why severe
incomplete ischemia causes more pronounced damage
than complete ischemia [66, 87],
Recently in vitro models have found increasing appli­
cation for ischemia research. In these models, brain tissue
slices are incubated in oxygen and glucose-free medium
in order to mimic the interruption of the supply of
nutrients to brain parenchyma [83, 84], These models
have several major disadvantages. First, the preparation
of the slice is associated not only with substantial tissue
trauma but also with a period of ischemia before it is
brought into the incubation medium. Control recordings,
in consequence, refer to a post-traumatic, postischemic
situation which may be basically different from the nor­
mal situation. This is particularly disturbing, when
studies are carried out in the hippocampus where brain
trauma or a few minutes of ischemia are known to cause
irreversible injury. Furthermore, brain slices require in­
cubation media which differ substantially from the nor­
mal extracellular environment and which, in contrast to
the in vivo situation, provide an unlimited supply of
extracellular solutes, such as sodium and calcium. Results
municaling and posterior communicating arteries [131.
132], Subsequent extracranial ligation of the arteria carotis communicans produces a regional reduction of blood
flow in the ipsilateral hemisphere.
In the goat the following approach has been used to
produce cerebral ischemia by extracranial vascular oc­
clusion. In this species blood flow to the brain is via a
rete mirabile which is supplied with blood from the
carotid and the internal maxillary artery. After ligation
of the internal maxillary artery and thrombosis of the
extracerebral branches, blood supply to the brain is con­
fined to the carotid artery, and subsequent ligation of
this vessel causes ischemia of the ipsilateral side of the
brain [142],
Intracranial occlusion o f a major cerebral artery, most
commonly the middle cerebral artery (MCA), is the fre­
quently used method for experimental production of
stroke (fig. 4). This vessel can be exposed by retroorbital.
postorbital or transorbital approach, and can be clipped
or ligated under the operating microscope. The transor­
bital approach requires removal of the eyeball but is
otherwise considered to be atraumatic because it is not
necessary to retract the brain for exposure of the vessel.
Surgical procedures have been described for the cat, dog
and monkey. Following implantation of an occluding
device, vascular occlusion can be performed even in
unanesthetized, unrestrained animals [143, 144],
Intracranial vessels have also been occluded by injec­
tion of macroemboli. Such emboli arc usually made from
aged clots, silicon rubber or metal balls and have been
injected into the internal carotid or vertebral artery for
embolization of the middle cerebral or basilar artery,
respectively. The advantage of this procedure is that
craniotomy is not required for exposure of the arteries.
On the other hand, precise localization of the embolus is
not possible and infarcts, in consequence, cannot be
standardized.
Recently, retractable emboli have been developed
which can be removed by the use of a fine thread attached
to the embolus [120, 121], These emboli provide the
opportunity to study reversible focal ischemia as an
experimental model of therapeutical recanalization of
macroembolic occlusion.
Following occlusion of a major intracerebral artery,
ischemia is most dense in the center of the territory of
supply. This is basically different from incomplete global
ischemia in which, quite contrary, ischemia is most pro­
nounced in the peripheral border zone. The size of the
ischemic region depends on the efficacy of collateral
blood supply. The territories supplied by the three major
9
Fig. 4. Regional cerebral ischemia produced by transorbiial
occlusion of the MCA in the cal (marked by the arrow). Recording
of the electrocoriicogram (ECoG). cortical steady potential (DC),
pial arterial pressure (PAP), cortical blood flow, systemic arterial
pressure (SAP), and tidal CO,. PAP was measured in the territory
of the occluded MCA using a servo-nulling micropressure record­
ing system, and cortical blood flow was measured in the same
region using a heated thermocouple (from ref. 153).
brain vessels - the anterior, middle and posterior cerebral
arteries - are interconnected by the pial network of
Heubner’s anastomoses. Blood supply by this system
depends on the anatomical configuration of the network,
vascular tone, viscosity of the blood and the blood pres­
sure. Under unfavorable conditions, ischemia may devel­
op in the total distribution of the occluded vessel
(maximal infarct), but the ischemic region may also be
very small when collateral supply is optimal (minimal
infarct) [145],
For this reason, a great variety of modifications of the
MCA occlusion model have been described for improving
reproducibility of the lesion. As a general rule, infarcts
become more uniform the lower the animal species and
the more proximal to the internal carotid artery the MCA
is occluded. This is the reason for the increasing use of
proximal MCA occlusion in rats which results in large,
uniform infarcts [97], However, it has to be realized that
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Animal Models of Cerebral Ischemia
Hossmann
10
age presumably is the consequence of an ‘irritation’ of the
vascular wall and not an ischemic event because, under
pure ischemic conditions, the barrier breaks down only
after several hours [147].
Another particularity of microembolism is the devel­
opment of multifocal reactive hyperemia in the surround­
ing of occluded microvessels. This leads to the sudden
swelling of the brain, and an extremely inhomogeneous
distribution of microcirculation with very low flow rates
in embolized and high flow rates in nonembolized vessels
(fig. 5). The net blood flow of the total brain, therefore,
may remain in the normal range although a substantial
number of brain vessels has been occluded.
1 min
Fig. 5. Transient incomplete ischemia of cat brain after air
embolism. Recording of the EEG, of brain volume using a volume
gauge, of intracranial pressure (ICP) and systemic arterial pressure
(SAP). Note the discrepancy between the transient slight reduction
of EEG amplitude and the massive brain swelling following air
embolism {from ref. 138],
there is minimal collateral flow to the ischemic territory
which is different from infarcts in higher species in which
collateral flow is a characteristic of the hemodynamic
situation and in which manipulation of collateral flow
provides a major therapeutical chance for improving the
pathological process.
A particular type of ischemia is that produced by
microembolism (fig. 5). Clinical examples are fat emboli,
platelet aggregates or air embolism, by means of which
arterioles or capillaries are reversibly or irreversibly oc­
cluded. Under experimental conditions, microembolism
is most commonly produced by intraarterial injection of
microspheres. Other experimental models are the intra­
carotid injection of air or infusion of adenosine diphos­
phate or arachidonic acid in order to induce platelet
aggregation. An important pathophysiological difference
between microembolism and other forms of ischemia is
the fact that following microembolism, the blood-brainbarrier instantaneously breaks down [146], Barrier dam­
The great number of experimental models developed
for the production of ischemia reflects the difficulty to
investigate the various aspects of ischemia - including
therapy - with the same experimental approach. It is,
therefore, difficult to provide recommendations which of
the numerous experimental models are most relevant for
testing new therapeutical approaches.
As a general rule, models used for therapeutical studies
should provide a high degree of reproducibility in order
to minimize statistical scatter, and they should apply to
the same category of lesions which the therapeutical
approach intends to ameliorate, e.g., stroke treatment
should be tested in animal models of stroke, or allevations
of hippocampal injury in models of selective vulnerabil­
ity. Although this requirement may appear to be trivial, it
is frequently violated. In fact, many drugs which are
currently considered for the treatment of stroke or other
forms of cerebrovascular disease, have been tested under
conditions of hypoxia or in models of selective hippocam­
pal injury.
In our laboratory the following models are used for
therapeutical purposes. Treatment of brain injury asso­
ciated with cerebral resuscitation after global cerebrocirculatory arrest is investigated in cats or monkeys by
intrathoracic occlusion of the innominate and subcla­
vian arteries [9, 66]. This model permits complete in­
terruption of total cerebral blood flow without
involvement of the heart or other peripheral organs
and thus minimizes the interference of general cardiocirculatory or other systemic complications. Modifica­
tions of this model are suited for in vivo nuclear
magnetic resonance spectroscopy and, in consequence,
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Selection of Animal Models for the Treatment of
Cerebral Ischemia
Animal Models of Cerebral Ischemia
References
1 Hossmann K-A. Kleihues P: Reversibiltv of ischemic brain
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can also be used for the investigation of drug effects on
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The gerbil model results in severe injury of hippocam­
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sions of the dorsolateral striatum. Both models arc
suited for use in chronic experiments. This is a re­
quirement for this kind of investigation because the
manifestation of selective injury of hippocampus is de­
layed for several days after the ischemic impact.
Treatment of stroke is studied in our laboratory us­
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the cat is the well-developed collateral system at the
cortical surface (Heubner’s anastomoses). However,
these collaterals introduce a variability factor which
makes it difficult to standardize the size of infarcts.
The use of this model, therefore, requires techniques
which allow the precise evaluation of the density of
ischemic flow reduction before treatment is started,
e.g. by using differentially labeled microspheres for
comparing pre- and postischemic blood flow. The size
of infarcts in rats is more reproducible; it is, therefore,
possible to compare mean group values of treated and
untreated animals. A convenient method to evaluate
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[151]. However, in contrast to higher species, collateral
flow is of lesser importance in this model, and generali­
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be done with caution.
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in different laboratories for pharmacological research in
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Prof. Konstantin-A. Hossmann
Max-Planck-lnstitul fur neurologische Forschung
Abteilung fur experimentelle Neurologie
Gleuclcr Strasse 50
D-W-500(1 Köln 41 (FRG)
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