(Stroke. 1995;26:444-450.)
© 1995 American Heart Association, Inc.
Articles |
A Photothrombotic `Ring' Model of Rat Stroke-in-Evolution Displaying Putative Penumbral Inversion
From the Cerebral Vascular Disease Research Center, Department of Neurology, and the Departments of Biomedical Engineering (B.D.W.) and Anatomy and Cell Biology (W.D.D.), University of Miami (Fla).
Correspondence to Brant D. Watson, PhD, Neurology D4-5, University of Miami, PO Box 016960, Miami, FL 33101.
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Abstract |
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Background and Purpose To facilitate reproducible and rigorous study of a tissue zone at risk of encroaching ischemic damage, we propose a new model in which the potentially compromised tissue lies within rather than perifocal to an ischemic locus. The perimeter of the "zone at risk" is defined by a photothrombotically produced cortical lesion in the shape of a toroid (or "ring").
Methods The exposed crania of erythrosin B–injected rats were irradiated with a 514.5-nm laser beam, configured as a 5-mm-diameter ring, to yield a ring-shaped lesion caused by photochemically induced platelet occlusion of cortical vasculature. Developing perfusion deficits in the interior region were revealed by carbon black infusion. Tissue damage and infarct volumes were assessed by light and electron microscopy, and blood-brain barrier integrity was assessed with Evans blue dye and horseradish peroxidase as tracers.
Results For rats injected with 17 mg/kg erythrosin B and irradiated for 2 minutes with a ring beam intensity of 0.92 W/cm2 (beam power of 65 mW), carbon black infusion at times up to 4 hours demonstrated a shallow cortical ring lesion encircling a fully patent zone at risk, which by 24 hours evinced an essentially complete perfusion deficit. At times up to 24 hours, the ring lesion was penetrated at the pial surface by distal branches of the middle cerebral and anterior cerebral arteries. Stereotaxically based histopathological assessment showed that by 24 hours the lesion spanned the cortical thickness. Lesion volume increased from 14.5±8.0 mm3 (mean±SD) (n=8) to 46.2±15.6 mm3 (n=8) between 4 and 24 hours after irradiation (P<.01), but the anteroposterior lesion diameter did not change significantly between 4 hours (6.00±1.03 mm; n=9) and 24 hours (6.75±1.15 mm; n=9).
Conclusions The present model of slowly developing but inevitable cortical tissue death in a sequestered area should facilitate more precise observations of the evolution of tissue metabolic responses, from the impending onset of ischemia to the threshold of irreversible damage. This system may prove efficient for evaluating treatments intended to salvage a penumbral region.
Key Words: cerebral ischemia, focal • neuronal damage • photothrombosis • rats
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Introduction |
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Brain tissue in the territory of a thromboembolically obstructed feeder artery experiences an evolving perfusion deficit that will engender necrosis if allowed to persist.1 2 3 4 The ultimately infarcted tissue region is believed to have incorporated perifocal zones in which infarction could have been prevented by application of appropriate therapeutic efforts.5 6 Tissue zones in transition from reversible to irreversible states of damage constitute the ischemic penumbra. Originally the penumbral state was defined by an upper flow threshold in which spontaneous or evoked electric and synaptic transmission disappears and a lower flow limit at which loss of neuronal membrane potential and accumulation of extracellular potassium occur.3 7 8 9 10 The penumbral zone may also be characterized as potentially salvageable by either pharmacological treatment or relatively prompt reperfusion,11 but because its extent has not been determinable for a particular subject11 the original definition of penumbra is essentially impractical.3 Accordingly, the details of penumbral evolution and their effects on tissue survival have been difficult to obtain.
In 1985 we presented a method that was intended to model thrombotic stroke reproducibly in the context of photochemically mediated small-vessel occlusion.12 The model also generates vasogenic edema, which rapidly propagates the developing lesion beyond the irradiated cortical area,13 thereby compromising the development of an observable penumbra.14 The potentially salvageable region in this model is thus anatomically small and not predictable, which makes the lesion resistant to therapies.15 16 In stroke or focal ischemia models based on cerebral arterial occlusion, the fact that perifocal tissue can be salvaged pharmacologically in a study group indicates that an amenable penumbra exists, but its precise characterization is improbable owing to individual variation.9 10 11 17 18 19 To remedy this situation we have induced ischemia to develop reproducibly in a predesignated cortical region but over a greatly extended time period compared with the original12 method. This time dilation feature is achieved by initially circumscribing the predesignated "zone at risk" with a photothrombotically induced thin rim of ischemic tissue configured as a toroid or, colloquially, a ring. From this initial state, ischemia proceeds toward the ring center as a concentric annulus. The enclosed tissue, while being perfused by pial vasculature that penetrates the ring, thus undergoes time-sequenced metabolic and electrophysiological changes presumed to be involved in the development of a penumbra.
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Materials and Methods |
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Food-deprived male Wistar rats (n=57 for carbon black, n=6 for blood-brain barrier experiments, n=18 for histopathology) weighing 280 to 330 g were initially anesthetized with 3.5% halothane, intubated with polyethylene tubing (PE-240), and then mechanically ventilated with 0.5% halothane and catheterized for arterial blood pressure and blood gas measurement and drug administration essentially as described previously.17
Respiratory adjustments were made as needed to ensure normal arterial blood gases. Pancuronium bromide 0.6 mg/kg was injected intravenously, and additional doses of 0.2 mg/kg were administered to immobilize the animals. Rectal temperature was maintained at 37.5°C with a rectal thermistor probe and a thermostatically regulated heating pad (CMA/150, CMA/Microdialysis). Head temperature was kept at 37.0°C to 37.5°C with a thermistor probe in the temporal muscle and a thermostatically controlled heating lamp (50-W halogen bulb with a 72-mm-diameter Tiffen Red filter) placed 15 cm from the skull at an angle of 45°. These studies were approved by the Animal Care and Use Committee of the University of Miami in conformation with the National Institutes of Health guidelines for care and use of research animals.
Rats were mounted on a stereotaxic frame (David Kopf), and the skull was exposed. An argon ion laser (Innova 70-4, Coherent, Inc) prism tuned to the 514.5-nm transition was used to irradiate the exposed skull. The output beam was focused with a 3-cm focal length spherical lens into a 400-µm-diameter optical fiber (model SL-ST-400E, Diaguide, Inc) at a 10.8° angle of incidence. The laser power, measured by a Scientech model 3600 power meter, must be optimally tuned before aligning the optical fiber to quench the formation of multiple beam modes. Under this condition the beam emerged at this same angle but with radial symmetry, thereby describing a ring when projected at vertical incidence onto the exposed skull. Vertical incidence was necessary for uniform lesion formation and was achieved by aligning the retroflected ring beam (from a flexible aluminized sheet placed on the skull) concentrically with the incident beam. The ring beam was placed symmetrically within the coronal, sagittal, and lambdoid sutures and the parietal bone crest and was 5 mm in outside diameter with a thickness of 0.5 mm. After application of a thin film of mineral oil, the right parietal skull bone was irradiated for 2 to 5 minutes at powers of 25 to 80 mW. The average irradiation intensity in the ring annulus, obtained by dividing the ring beam power by the annular ring area, thus ranged from 0.354 to 1.13 W/cm2, whereas the laser intensity in the central region was unmeasurable (minimum sensitivity was 2 mW/cm2). The photosensitizing dye erythrosin B20 (ErB, 12.96 mg/mL in 0.9% saline) or the saline vehicle was injected intravenously to a body dose of 8.5 to 34 mg/kg over 30 seconds simultaneously with the start of the irradiation. Rats were temperature-controlled and kept on a respirator for 1 hour after irradiation, except in the case of acute blood-brain barrier experiments.
To acquire a rapid determination of the temporal and spatial profiles of flow deficit, rats were transcardially perfused with carbon black. After an initial washout with saline for 2 minutes, 60 mL of filtered Higgins carbon black ink (Faber-Castell Corp) was injected. These perfusions were performed at 1, 2, 4, and 24 hours for several combinations of irradiation intensities, durations, and ErB concentrations. The goal was to find a parameter combination that would initiate the development of a complete perfusion deficit in 24 hours.
Blood-brain barrier studies were conducted with Evans blue dye or horseradish peroxidase (HRP) as permeability tracers at 15 minutes after lesion formation. Brains were perfusion fixed and sectioned with a Vibratome (100 µm) in the coronal plane, and sections were reacted for light and electron microscopic visualization of HRP by methods previously described.13 Rats were prepared for histopathological analysis at 4 and 24 hours by perfusion fixation.17 Paraffin-embedded brain sections (10 µm) were then prepared at 220-µm intervals, stained with hematoxylin and eosin, and quantitated for infarct area and summed for volume determination by computer with the aid of a camera lucida attachment.17 The lesion diameter at 4 and 24 hours after irradiation was determined by correlation of coronal sections at the anteroposterior limits of the lesion with corresponding sections from a stereotaxic atlas.21 This was done to facilitate accurate comparison of lesion dimensions with the 5-mm irradiating ring beam diameter, which capability would otherwise be lost owing to tissue contraction during fixation procedures. The tissue was found to shrink by 15.2±2.5% in the anteroposterior direction, from which a correction factor of 1.18±0.03 was deduced. The 4- and 24-hour coronal sections were also compared with the closest corresponding atlas sections to derive an area correction factor. This amounted to an average of 1.28±0.04, which accounted for an areal contraction of 21.9±0.9%. Lesion volumes at 4 and 24 hours were statistically compared by a one-way ANOVA to detect and assess changes in size.
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Results |
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Physiological Parameters
Physiological parameters are presented in Table 1
. The data demonstrate that pH,
PO2, and
PCO2 before and 1 hour after irradiation were
within normal limits. Continuous mean arterial blood pressure
monitoring before, during, and after the photothrombotic procedure
revealed no significant changes during the experiment.
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Carbon Black Perfusion
Initial screening experiments (n=17) were conducted to obtain an
approximate idea of the parameters necessary to obtain a lesion. We
then attempted to produce a robust ring-shaped cortical perfusion
deficit that extended down to cortical layers V to VI, with a
well-perfused interior perifocal zone at 1 hour after irradiation.
However, with 80-mW irradiation for 5 minutes at an ErB body dose of 34
mg/kg, the ring interior zone displayed a complete perfusion deficit
within 2 hours after irradiation (n=4), which was maintained for
perfusion times between 4 hours and 7 days (n=5) (data not shown). By
decreasing the irradiation period to 2 minutes, the interior perifocal
zone was well perfused at 2 hours after irradiation but showed a
complete perfusion deficit at 4 hours after irradiation (n=12, data not
shown). To additionally delay the perfusion deficit in the interior
perifocal zone, rats (n=4) were irradiated with the lower power of 50
mW for 2 minutes after injection with 17 mg/kg ErB, but no perfusion
deficit was observed at 4 hours after irradiation. In effect, these
rats served as ipsilateral tissue controls for ErB injection. In no
case was a contralateral perfusion deficit observed for any combination
of ErB dose, irradiation intensity, and time of irradiation.
Finally, a new group (n=15) was irradiated at the intermediate power of
65 mW for 2 minutes with an ErB dose of 17 mg/kg. With these
parameters, inspection of the brain surface at 1, 2, and 4 hours (n=10)
after irradiation revealed a ring-shaped cortical perfusion deficit
that progressively increased in thickness while surrounding a perfused
ring interior; a 4-hour perfusion result (n=3) is shown in Fig 1A. Patent distal branches of the middle cerebral artery
(MCA) were commonly observed to penetrate the ring at this time. At 24
hours after irradiation, the perfusion deficits had enveloped the
central zone (n=3, Fig 1B). However, distal branches of the MCA and a
few scattered penetrating MCA branches in the most superficial part of
the interior zone still appeared patent. With the attainment of a
24-hour delayed but apparently complete microvascular perfusion
deficit, histological characterization was done with this parameter set
(65-mW irradiation for 2 minutes with ErB at 17 mg/kg) using the carbon
black experiments as a qualitative guide of lesion development.
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Early Changes in Blood-Brain Barrier Integrity and
Morphology
At 15 minutes after irradiation, animals given Evans blue dye
intravenously demonstrated a ring-shaped enhancement of permeability
(Fig 1C
). In HRP-injected rats (n=2), sections taken tangential to the
irradiated pial surface also demonstrated a well-demarcated ring of
leaky blood vessels (Fig 1D). Microscopic examination of leaky blood
vessels subtended by the ring identified multiple foci of HRP leakage.
In brains that were sectioned coronally, HRP leakage was primarily
restricted to the walls of the irradiated ring (Fig 1E). Sites of
leakage extended from layer I to the subcortical white matter. In
contrast, the nonirradiated interior appeared relatively normal except
for an occasional focus of extravasated HRP. In a few specimens, a
penetrating vessel displaying HRP within its wall was observed in the
nonirradiated core (also compare Fig 1E). Toluidine blue–stained
plastic sections through the irradiated wall indicated early signs of
tissue necrosis in two animals (Fig 1F). This included blood vessels
containing thrombotic material as well as dark, shrunken neurons. The
evacuolated neuropil also contained swollen astrocytes and static red
blood cells. No changes were seen in control animals injected with HRP
or toluidine blue and irradiated (n=2).
The nature of the acute vascular response to the photochemical insult
was further studied by transmission electron microscopic analysis
of tissue in the ring wall at 15 minutes after irradiation. Fig 2A depicts an occlusive thrombus containing mostly
degranulated platelets appearing in a small cortical venule. Edema
likely originating from photochemically induced endothelial defects is
also observed. A cortical venule (Fig 2B) is also shown to contain an
occlusive thrombus in conjunction with an amorphous perivascular
exudate. Fig 2C depicts a thrombus in apparently an early stage of
formation, wherein mostly granulated platelets are shown adhering to
damaged endothelium. Blood-brain barrier leakage is indicated in Fig 2D
via HRP transport into the basal lamina and the perivascular space.
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Paraffin Histopathology
At 4 hours after irradiation, coronal sections through the
epicenter of the irradiated zone revealed two wedge-shaped columns of
necrotic cortical tissue (Fig 3A). At this early
postirradiation period, necrotic areas routinely extended through layer
V of the cerebral cortex. Necrotic areas appeared pale-staining and
contained necrotic neurons (Fig 3B). Histopathological analysis of
the nonirradiated central zone revealed a relatively intact neuropil
with normal-appearing neurons (Fig 3C). The pial surface also appeared
unremarkable, with few vessels containing thrombotic material. However,
in some specimens the neuropil appeared vacuolated. At 24 hours after
irradiation, the area of cortical necrosis had increased to include the
ring core (Fig 3D). This early infarct appeared bowl-shaped and
extended down to the subcortical white matter. In contrast to earlier
periods, subcortical areas, including the hippocampus, appeared to be
slightly displaced downward because of infarct expansion. However,
histopathological damage was not seen in subcortical areas. In contrast
to experimental animals, sham-operated animals (n=3) that had been
irradiated but not given ErB appeared unremarkable by histopathology.
Neither vascular stasis nor neuronal changes were observed in these
animals.
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Stereotaxically corrected quantitations of lesion diameter (measured
between the anterior and posterior extents) and infarct volume at 4 and
24 hours are displayed in Table 2. At 4 hours the
infarcted tissue zones often appeared to be complex composites of
microfocal tubular infarcts, each apparently surrounding an occluded
penetrating artery. At 24 hours this characteristic had disappeared
near the cortical surface, as the infarct was continuous there.
However, variability in volume at 24 hours did occur, chiefly due to a
typically irregular subcortical perimeter again composed of
superimposed microtubular infarcts; this feature accounted for
variations in infarct depth.
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Discussion |
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The photothrombotic ring lesion model was conceived to facilitate reproducible study of a spatially defined region that experiences ischemic encroachment in a manner reminiscent of a penumbra. The ring infarct configuration, where the zone at risk of developing ischemic injury is surrounded by acutely ischemic territory, has no clinical or experimental precedent. However, this model still appears to exhibit several advantages for study. First, it produces an anatomically defined zone at risk in a region supplied by distal branches of the MCA and anterior cerebral artery (ACA).22 23 As shown by the carbon black experiments, the rate of development and the spatial extent of perfusion deficit may be altered reproducibly by changing the irradiation parameters, and the zone at risk may be placed in any desired location. Second, the pathomechanisms likely to be involved in the progress of the ring lesion to infarction are considered to be relevant to the evolution of clinical thromboembolic stroke with penumbra (see below). These same mechanisms may be important for the development of clinical progressive stroke (deteriorating stroke, "stroke-in-evolution"), defined as worsening of neurological symptoms and signs that occurs between 1 and 72 hours after stroke onset.24 Third, the zone at risk should be accessible to postlesioning therapeutic strategies since blood flow to this region is facilitated by patent distal branches of the MCA and ACA for an extended (and predetermined) time after the insult. A corollary feature is that the initial volume of the zone at risk is greater than the volume of ischemic tissue in the initial ring lesion, which is opposite to what is observed in most focal ischemia models. Fourth, the operation technique is minimally invasive, easily performed, and leads to good recovery with no premature short- or long-term mortality among the experimental animals, as well as reproducible lesions at time of death.
In the original model of photothrombotic cortical infarction, scattering of the arc lamp beam by the skull was minimal, inasmuch as the edges of the acute lesion were sharply demarcated. We thus anticipated that a ring beam would maintain its focality as it transited the skull, and it is clear that this conjecture has been justified. However, formation of a suitable ring lesion during the 2-minute irradiation period required higher beam intensity than that used previously to obtain the focal cortical lesion of the original model.12 This indicates that photothrombotic occlusion of any part of a vascular network is made easier by confluent reductions in flow among the network branches. This likely leads to sequestration of the photosensitive dye and hence enhancement of photothrombotic efficiency,25 but the vessels subtended by the ring beam are comparatively isolated from one another and therefore cannot sequester dye with the efficiency of a network whose elements are subjected to photothrombosis simultaneously. We note further that the ring beam itself may be made sharper merely by increasing the angle of laser beam incidence on the optical fiber, but at the cost of progressively decreasing fiber transmission efficiency. The ring intensity must also be increased to obtain an initial lesion depth comparable to that obtained with a thicker ring beam (data not shown), again demonstrating that the vessels subtended by the thin ring are less interconnected than those included in the thick ring.
Perfusion of the zone enclosed by the ring, at all stages of lesion
development, is maintained by penetrating distal branches of the MCA
and ACA at the pial surface.22 There is no evidence as yet
of intracortical functional pathways or anastomoses between white
matter and the deeper cortical layers (P. Coyle, conversation, 1993). A
likely contribution to deterioration of tissue regions adjacent to the
ring is vasogenic edema emanating from the infarcted ring locus that
progressively compresses the adjacent tissue, inducing mechanical
occlusion of the vasculature within.13 The increase in
lesion diameter (Table 2) at 4 and 24 hours compared with the 5-mm
irradiating beam diameter is consistent with edematous expansion.
Interestingly, the area of the annulus contained within the 24-hour
lesion diameter (6.75 mm) and the irradiating beam diameter (5 mm) is
nearly equal to the area of the circle contained within the latter
(16.14 mm3 compared with 19.63 mm3,
respectively). This suggests that the perimetric expansion of the ring
lesion has been counterbalanced by edematous compression of the ring
interior, as would seem necessary if enlargement of the ring lesion can
be viewed subacutely as occurring essentially in two dimensions. The
fact that the outer limits of the lesion do not change significantly
between 4 and 24 hours is also consistent with a previous volume
analysis of infarcts induced photochemically by areal irradiation
of the cortex with a 5-mm-diameter beam.14 The influence
of edema is supported further by the observation of a disrupted
blood-brain barrier, as indicated by leakage of the tracers Evans blue
dye and HRP (Fig 1C through 1E, Fig 2D) as well as the slight downward
displacement of the hippocampus at 24 hours after irradiation (Fig 3D).
A source of focal ischemic change in the lesion interior may be emboli
released from irradiated arteries in the ring locus; these may obstruct
cerebral blood flow within the encircled region, with consequent
reduction in blood flow to this area. This possibility is supported by
observations of platelet embolus production in a model of nonocclusive
carotid artery photothrombosis.26 In addition, the
presence of focal sites of blood-brain barrier breakdown in the central
zone at risk (Fig 1E) also has been shown to be correlated with
platelet emboli.27 It is therefore conceivable that
nonocclusive thrombi forming in those branches of the MCA and ACA that
are intercepted by the ring beam but nonetheless remain patent for an
extended period after irradiation could be a source of emboli. In the
carbon black experiments, a complete perfusion deficit was seen in the
small arteries within the infarcted ring tissue, presumably because of
thrombotic occlusion. This is in agreement with the observation of
histopathologically visualizable thrombi forming in small arteries
within the infarcted ring locus (Fig 1F). In addition, vasoactive and
neurotoxic substances originating from the primary photochemical insult
and from acute thrombus formation could be released into the downstream
blood and transported into the zone at risk or released into the brain
extracellular space with diffusion to the zone at risk. Such factors
may include oxygen radicals and their peroxidation
products28 ; adenosine monophosphates, diphosphates, and
triphosphates; serotonin29 ; thromboxane A2;
platelet activating factor; and histamine.30
In summary, the ring method allows a predefined area at risk, a so-called penumbra, to be observed and its characteristics quantitated. Because infarction of the ring core tissue is so greatly delayed but inevitable in this experimental model, the core tissue is likely to exhibit the same response to ischemic encroachment as a penumbra, but one that can be uniformly and reproducibly simulated. We recognize that our present evidence of flow compromise must be abetted by suitable electrophysiological characterization. Nonetheless, owing to its simple geometric structure, reproducible pathology, and perimetric production of substances likely to induce tissue damage in the ring interior, the ring lesion offers a potentially very sensitive technique to assess the efficacies of relevant therapeutic interventions.
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Acknowledgments |
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This study was supported by grants NS-05820, NS-23244, NS-27127, and NS-26784 from the National Institutes of Health (National Institute of Neurological Disorders and Stroke [NINDS]). Dr Wester was supported by a US Public Health Service Fogarty International Research fellowship (1 FO5 TW04558) ICP [AHR-5], the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, King Gustaf's Anniversary Foundation, and the Malmborgs and Bergwalls Foundations. Dr Watson is a recipient of a Jacob Javits Neuroscience Investigator award from the NINDS.
Received August 30, 1994; revision received October 27, 1994; accepted November 3, 1994.
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