(Stroke. 1995;26:1107-1113.)
© 1995 American Heart Association, Inc.
Articles |
Chronic Depression of Glucose Metabolism in Postischemic Rat Brains
From the Institut für Anatomie der Universität Rostock (Germany).
Correspondence to Thomas Beck, PhD, Institut für Anatomie der Universität Rostock, Gertrudenstr 9, PO Box 10-08-88, D-18055 Rostock, Germany. E-mail beck@medizin.uni-rostock.d400.de.
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Abstract |
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Background and Purpose The present investigation aimed to quantify functional activity in rat brains after long-term recovery from transient forebrain ischemia.
Methods With the use of the [14C]2-deoxyglucose method, local cerebral glucose utilization was measured in 62 cortical and subcortical brain regions in postischemic rat brains. Transient forebrain ischemia of 10 minutes' duration was induced by clamping the common carotid arteries and simultaneously lowering blood pressure to 40 mm Hg. Rats survived the insults for 1 week, 2 weeks, 3 weeks, or 3 months.
Results Reductions predominated in the majority of gray matter structures at all time points investigated (P<.05). Except for a few areas, recoveries of local cerebral glucose utilization to preischemic levels did not occur.
Conclusions The data illustrate that widespread alterations of functional activity prevail in postischemic brains beyond the selectively vulnerable regions. The present functional data are in line with previous stereological results of reduced fresh volumes in the majority of postischemic brain structures. The data suggest that chronic alterations of ischemic brains are not confined to the selectively vulnerable regions.
Key Words: cerebral ischemia • glucose • rats
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Introduction |
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Although rather comprehensive information is available on the short-term consequences of cerebral ischemia, data on chronic brain alterations are scarce. This applies not only to morphological studies but is even more evident regarding investigations of functional parameters such as glucose utilization, blood flow, or neurotransmitter analysis. Since the evaluation of long-term outcome is of ultimate importance for estimating the protective potential of any drug regimen, the determination of pathophysiological baseline values in models of experimental cerebral ischemia remains a key prerequisite.
Clinically, recent positron emission tomography studies have drawn attention to time-dependent metabolic derangements in brain tissue after infarction. Progressive deterioration of the cerebral metabolic rate for oxygen in peri-infarct tissue but also decreases of the cerebral metabolic rate for glucose in noninfarcted remote areas such as the cerebellum weeks to months after the primary insult underscore the relevance of careful monitoring of such parameters in postischemic brains.1 2
In the rat, only a few studies extend beyond the acute postischemic period or focus on the primary affected areas only. Hippocampal glucose utilization has been measured from days up to 3 months after transient cerebral ischemia in the two-vessel occlusion model.3 4 5 A study that also includes the extrahippocampal regions was recently delivered by Kozuka et al,6 who revealed two patterns of altered local cerebral glucose utilization (LCGU) throughout the postischemic brain. Extending their measurements up to 14 days after ischemia, these authors could demonstrate transient increases of LCGU
that returned to normal or were permanently slightly reduced. Some aspects of this study were difficult to reconcile with data of significantly decreased fresh volumes 3 months after a transient insult.7 If area-specific volume reductions of brain structures occur consistently after long-term survival times because of loss of neurons or of neuropil, one would expect them to be linked to irreversible reductions in functional activity as measured by LCGU rather than associated with a recovery to preischemic levels. Moreover, since the alterations in volume were widespread throughout the brain, this would necessarily suggest that ischemic damage would manifest itself not only in the selectively vulnerable structures. The present investigation aimed to address this issue on the functional level. Using the identical experimental paradigm that we used previously with our stereological work, we sought to quantify functional activity in all major brain structures that could be delineated reliably up to 3 months after ischemia using a rigorous anatomic approach.
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Materials and Methods |
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Experimental procedures were carried out with 20 male Wistar rats (Winkelmann, Borchen, Germany) The rats were housed at 22±2°C under controlled environmental conditions and had free access to tap water and a standard diet (Altromin).
Permission for these animal experiments was obtained from the public veterinarian service certifying that they were within the guidelines set by the Animal Protection Act of the Federal Republic of Germany. Transient forebrain ischemia was induced as described by Smith et al.8 Male Wistar rats (weight, 300 to 350 g) were subjected to overnight fasting. Briefly, in the artificially ventilated animals (30% N2O, 70% O2) a silicon catheter for withdrawal of blood was inserted in the jugular vein and advanced into the inferior caval vein. Muscle paralysis was maintained with suxamethonium chloride (kindly provided by Dr B. Kutscher, Asta Pharma AG, Frankfurt, Germany) and blood clotting prevented by injection of heparin (200 IU/kg). Needle electrodes were placed in the temporalis muscle for electroencephalographic recording. Five milligrams per kilogram of the ganglionic blocker trimethaphan (a gift from Hoffmann–LaRoche) was injected, the carotid arteries were clamped, and blood pressure was lowered to 40 mm Hg by withdrawal of blood. The onset of isoelectric electroencephalography was taken as an indicator of ischemia. Blood pressure was recorded continuously until the animals were disconnected from the pump by means of a pressure transducer connected to the cannulated tail artery. Blood gases and blood pH were monitored routinely (AVL 950). Physiological variables were determined immediately before induction of ischemia and after reinstitution of normal blood pressure. After 10 minutes of ischemia, blood flow to the brain was reinstituted by release of the clamps and reinfusion of the shed blood. Rats received 1 mmol/kg NaHCO3 to counteract systemic acidosis. Temperature was closely maintained at 37°C throughout the experiment and early recovery. Artificial ventilation was continued until the animals regained spontaneous respiration. The animals were then disconnected from the pump and transferred to cages. The animals survived for either 1 week, 2 weeks, 3 weeks, or 3 months. The different groups then underwent the [14C]2-deoxyglucose procedure. Controls were treated in a similar way except for induction of ischemia. Since no developmental change of LCGU has been reported in young adult rats, LCGU of control rats was measured 1 week after the sham operation.
After 1-week, 2-week, 3-week, or 3-month recovery, the animals were subjected to the standard procedures for measuring LCGU as described by Sokoloff et al.9 In brief, the rats were anesthetized with 1% halothane in a 70:30 mixture of nitrous oxide and oxygen. The femoral artery and vein were cannulated, and lidocaine gel was applied to the wound before it was closed. Then the animals were lightly restrained with plaster casts covering the hind limbs and lower abdomen, leaving forelimbs and thorax free. They were then fixed on a preparation desk, with body temperature closely maintained at 37°C with a heating lamp. The rats were allowed to recover from anesthesia for 2 hours. After physiological variables were checked, 80 µCi/kg [14C]2-deoxyglucose (specific activity, 52.5 to 57.3 mCi/mmol; Biotrend) dissolved in physiological saline was injected via the femoral vein within 20 seconds. During the ensuing 45 minutes, 16 timed arterial blood samples were drawn from the arterial catheter. They were immediately centrifuged and assayed for radioactivity and plasma glucose. After 45 minutes the rats received a lethal dose of pentobarbital and were decapitated. The brains were rapidly dissected out and frozen in isopentane chilled to -50°C. Until they were sectioned, the brains were stored at -70°C. Sections of 20-µm thickness were cut in a cryostat (plane of sectioning according to the frontal plane given in the atlases of Paxinos and Watson10 and Zilles11 ), thaw-mounted on coverslips, glued to cardboard, and exposed to Osray M3 film (Agfa-Gevaert) together with precalibrated [14C]methylmethacrylate standards for 14 days.
Image analysis was performed with a VIDAS image analyzer (Kontron).
Autoradiograms were digitized with a resolution of 14x14 µm per
pixel. LCGU was calculated in two steps. First, images were printed as
hard copies. In these prints anatomic structures were outlined by
superimposing the prints with adjacent Nissl- or
acetylcholinesterase-stained sections by means of a drawing tube
attached to a microscope. Nissl sections were also used for
determination of ischemic cell damage by cell counts in the CA1 sector.
Gray values of the autoradiograms were transformed to LCGU values by
using the operational equation for changing arterial plasma
levels.12 Region-specific LCGU was measured by
superimposing the prints with the topographical data array of LCGU
values stored in the computer and by selecting the region of interest
according to the anatomic boundaries marked previously
(Figure
). In each rat, 10 to 12 autoradiograms were
measured.
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Results |
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Physiological variables shown in Table 1
were in a
range similar to those recorded in previous
investigations.3 4 8 13 The rats exhibited no obviously
altered motor behavior except for deficits during the initial 30
minutes of the recovery period, consisting primarily of an impaired
righting reflex and dragging of the hind limbs.
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Cell counts revealed significantly (P<.05, Kruskal-Wallis H test, Mann-Whitney U test) reduced numbers of pyramidal cells in all ischemic groups investigated. Sham-operated controls had 210±35 pyramidal cells per millimeter. The values for the postischemic groups were as follows (cells per millimeter): 1 week, 48±30; 2 weeks, 42±25; 3 weeks, 37±17; and 3 months, 39±10. Counts were obtained from 10 sections per animal.
At all time points measured, most areas showed a significant reduction of LCGU. The reductions persisted as long as 3 months after the insult and thus seemed irreversible within the time span under investigation.
According to the temporal profile of the changes in LCGU, brain areas
could be assigned to five different groups (Table 2): (1) The first group consisted of
brain structures that showed significant decreases in LCGU at all time
points investigated, such as the forelimb and hind limb areas, the
occipital cortex, area 2 of the parietal and temporal cortices, parts
of the peripalaeocortex and the periarchicortex, the dorsal subiculum,
regions of the dentate gyrus, the medial and lateral geniculate, the
globus pallidus, and the caudate. (2) Structures of the second group
exhibited a variable time course characterized by reductions of LCGU 1
week after the insult (except for the medial habenula), return to
normal levels at 2 or 3 weeks after ischemia, and significant
reductions at 3 months after the infarct. This pattern could be
ascribed to areas 1 and 2 of the frontal cortex, area 1 of the parietal
and temporal cortices, the whole orbital cortex, a number of
periarchicortical areas, the ventral subiculum, presubiculum, the CA2
and CA3, the majority of the thalamic nuclei, the amygdala, the
mamillary body, the nuclei of the vertical and horizontal diagonal
band, and the nuclei of the rhombencephalon. (3) This group consisted
of the CA1 only and showed a continuous increase of LCGU peaking at 3
weeks after ischemia and a significant decline below normal at 3 months
after the ischemic episode. (4) This group, which showed either no
reductions at all or transient reductions after 1 week only, consisted
of the olfactory tubercle, the lateral septal nucleus, the prepiriform
cortex, the anterior nucleus of the thalamus, and the accumbens
nucleus. (5) This group, which showed significant reductions of LCGU 3
weeks after ischemia but returned to normal levels at 3 months after
the ictus, primarily included the isocortical areas, such as the entire
cingulate cortex and area 3 of the frontal cortex, as well as one
peripaleocortical area, the ventral agranular insular cortex.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study we investigated the time course of LCGU in rats that were long-term survivors of an episode of transient forebrain ischemia. The intriguing point of the data seems to be the irreversibility of the metabolic alterations and their wide distribution in many brain structures after the insult. With the exception of a few structures, most areas showed significantly reduced LCGU 3 months after ischemia.
For all measurements performed in this study we used the rate constants and lumped constant for normal rats as published by Sokoloff et al.9 This procedure seems justified by previous work performed in human and animal studies, showing that the lumped constant either rapidly returns to normal or is even unchanged in postischemic brains.14 15 16 Similarly, changes of rate constants are confined to the early recirculation period, and the error thus introduced is negligible provided that the standard procedure for measuring LCGU is used.15 16 17
As may be inferred from "Materials and Methods," we did not use age-matched controls for each of the time points investigated. This approach appears tenable, since previous work has demonstrated that LCGU does not change significantly during the first 3 to 5 months of life in the rat, although changes did occur in very old rats aged 24 to 27 months.18 19 20 For this reason, the alterations of LCGU measured in the present study cannot be reasonably attributed to the age of the animals but should result from the ischemic episode.
Surprisingly few data are available that define the time course of postischemic LCGU in postischemic rat brains. In previous work, quantification of LCGU in all major hippocampal subregions revealed increases in LCGU in severely damaged layers of the CA1, notably the pyramidal layer at 1 to 2 weeks after the insult.3 4 This result held true for shorter time points in the range of hours to days after ischemia as well.5 6 Some unresolved controversy existed as to whether this increase was of glial origin or could be traced back to neuronal sources due to persisting presynaptic terminals.21 However, this does not constitute an essential point, since regardless of a putative glial contribution to hippocampal hypermetabolism during the early postischemic period, it could be clearly demonstrated that all hippocampal compartments, whether severely damaged or not, still showed significantly reduced LCGU after long-term recovery 3 months after the ictus.4
To date, the most comprehensive analysis of postischemic LCGU in the whole rat brain was delivered by Kozuka et al,6 who defined two distinct patterns. Pattern 1 applied to the cortex and striatum and was characterized by a modest increase of LCGU 7 days after ischemia and a return to control levels or levels slightly below control levels. In contrast, pattern 2 consisted of considerable increases in LCGU at 7 days and a return to normal levels at 14 days after ischemia. Typical structures belonging to pattern 2 were the cerebellum, red nucleus, and raphe nuclei. A direct comparison of this study with the present one is doubtless hampered by differences in study design. Kozuka et al6 used the four-vessel occlusion model, and the duration of ischemia was 30 minutes compared with 10 minutes in the present investigation. However, some qualitative similarities do exist. In accordance with the data presented by Kozuka et al,6 LCGU increased in the CA1. The temporal profile of hippocampal LCGU as defined in the present report, however, differs from previous data in that significant increases occur not earlier than 3 weeks after the insult.3 4 5 6 Different procedures of image analysis of the hippocampus may be responsible for these varying data. For reasons of technical convenience, the present investigation contains no layer-specific data on the hippocampus, and the pronounced tendency to higher LCGU at 1 and 2 weeks indicates that small hypermetabolic areas of the hippocampus may have been averaged.
Our results on functional activity in the substantia nigra illustrate
that the severity of the ischemic episode exerts a direct influence on
the functional outcome after long-term survival times. Whereas the
present study clearly showed continuously decreased LCGU in the
substantia nigra up to 3 months after 10 minutes of ischemia, a
30-minute insult induced considerable increases of LCGU at 5 to 7 days
that normalized at 14 days after ischemia.6 Previous work
has clearly established a link between ischemic damage to the striatum
and subsequent degeneration of the substantia nigra 14 days to 3 months
after the primary lesion.6 22 Although histological data
were not provided, one may speculate that sufficiently long survival
would have revealed exactly the same histological end point in the
study of Kozuka et al,6 while the time course differs
depending on the severity of the initial insult. We agree that
disinhibition of the substantia nigra possibly due to loss of neurons
activated by 
-aminobutyric acid as a consequence of striatal
degeneration is a good candidate for the nigral damage, and the rapid
decline of striatal LCGU at 1 to 3 days after the insult reported by
Kozuka et al6 thus could be the harbinger of rapid
disinhibition and hypermetabolism in the substantia
nigra.23 24 25 Our data do not include such early
postischemic time points, but since we did not measure an increase in
LCGU in the substantia nigra, one may assume that the shorter duration
of ischemia in the present study may have generated a slower
progressive striatal degeneration so that the ensuing disinhibition
would not have reached levels sufficiently high to induce transient
hypermetabolism. This example emphasizes the dependence of the final
functional outcome on the duration of ischemia. Moreover, it
underscores the need for long-term survival studies and illustrates the
imponderabilities incurred by evaluating only a few time points.
As has been demonstrated in numerous pharmacological studies trying to relate receptor densities to altered LCGU, a structure-related interpretation of LCGU values is always hampered by the fact that glucose utilization as such is a very general parameter, thus necessarily opening up the possibility that an alteration of functional activity measured in a defined structure is subject to opposing or supporting effects in interconnected areas or may even be the indirect result of changes in those remote structures. A similar situation exists when the data on volume reductions 3 months after ischemia7 are compared with the coinciding changes in LCGU after the same experimental procedure. As mentioned above, quite a number of structures show significantly reduced levels of LCGU at all time points, eg, most cortical areas and the dentate gyrus. However, the volume of the dentate gyrus is not significantly different 3 months after the insult.7 The same holds true for the entorhinal cortex and the presubiculum. For example, no reductions in volume occurred, but reduced functional activity was observed. In contrast, the cingulate cortex showed reduced postischemic volume but unchanged functional activity. This latter example is particularly intriguing. It could mean that after removal of damaged cells from the cingulate cortex during the postischemic period, the remaining cell population depicts an intrinsically higher functional activity so that the overall metabolic level in the area remains apparently unaltered. In contrast, areas like the agranular insular cortex and the frontal areas show changes neither in volume nor in LCGU, so that on the whole a correlation between histological damage and functional activity is unlikely to exist.
Metabolic depression has been reported to occur after a variety of lesions such as concussive head injury,26 27 freezing lesions,28 and ischemia.1 2 29 30 31 In models of chronic bilateral carotid artery occlusion31 or fluid percussion injury,27 the metabolic depression days after the lesion could be induced irrespective of overt cell damage. This is in line with the present data showing that depressions of LCGU can be found in areas devoid of histologically verifiable chronic cell damage. In keeping with this fact, we also recorded reductions of LCGU in areas like the cerebellum where local cerebral blood flow is maintained well above the ischemic threshold during ischemia.8 32 33 It seems noteworthy that glycolysis is not the sole metabolic pathway affected after concussive head injury. Oxidative metabolism, as measured by cytochrome oxidase histochemistry and protein synthesis, may still be depressed 5 to 10 days after the head injury, with values still below control levels.26 34 The mechanism underlying these derangements remains to be clarified. However, one may presume that long-lasting perturbations of membrane potential due to shifts in ionic balance after the lesion lead to an altered metabolic state, a view that is corroborated by the finding that these alterations can be prevented at least in part by antagonists of excitatory amino acids.35 One may speculate that similar phenomena may also be determining the postischemic hypometabolism measured in the present study, and it would be useful to determine whether this metabolic alteration is accessible to therapeutic intervention.
One additional aspect of the present findings is that CA1 damage is apparently not the sole parameter for estimating the final functional outcome after cerebral ischemia. This concept has been advanced recently by Nunn et al,36 who tested behavioral deficits 13 to 18 days after four-vessel occlusion in the rat and failed to establish a link between histological damage in the CA1 and performance in a water maze. Thus, in our view quantification of the severity of ischemic damage urgently needs revision to keep it linked to functional deficits. It is within the scope of future work to determine whether and to what degree these deficits can be attenuated pharmacologically.
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Acknowledgments |
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This study was supported by a grant from the Deutsche Forschungsgemeinschaft. We gratefully acknowledge Günter Ritschel's assistance with the art work.
Received August 22, 1994; revision received January 18, 1995; accepted February 17, 1995.
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