(Stroke. 1995;26:1072-1078.)
© 1995 American Heart Association, Inc.
Articles |
Experimental Stroke and Neuroprotection in the Aging Rat Brain
From the Departments of Medicine (Geriatrics) (M.D., O.F.W.J.) and Surgery (Neurosurgery) (D.M.), University of Newcastle upon Tyne; and the Departments of Pathology (Neuropathology) (R.H.P.) and Medical Physics (I.R.C.), Newcastle General Hospital, Newcastle upon Tyne, England.
Correspondence to Dr M. Davis, c/o Professor A.D. Mendelow, The Regional Neurosciences Centre, Newcastle General Hospital, Westgate Rd, Newcastle upon Tyne, NE4 6BE England.
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Background and Purpose Experimental stroke research has for the most part incorporated the use of young animals despite the importance of aging in cerebrovascular disease in humans. We hypothesized that age-related reductions in the density and function of cortical N-methyl-D-aspartate (NMDA) receptors might limit neuroprotective potential in the elderly. In this study, a model of occlusive stroke in the aging rat brain has been developed and used to establish the effects of age on cerebral infarction and to evaluate the scope for protecting the aging brain during ischemia.
Methods Focal cerebral ischemia was produced by thermocoagulation of the left middle cerebral artery in adult (11 to 17 months) and aged (28 to 36 months) male Wistar rats. Infarcts were assessed histologically with volumetric analysis of infarct size, hemodynamically by serial cerebral blood flow measurement using the hydrogen clearance technique, and by analysis of specific gravity as an index of brain edema. Neuroprotective potential was assessed using the competitive NMDA receptor antagonist 3-(2-carboxy piperazin-4-yl)propyl-1-phosphonate (D-CPPene).
Results Aging was associated with a significant increase in infarct size, with a mean infarct volume of 40.5±2.6% of the hemisphere volume in aged rats compared with 30.9±0.7% in adult rats (P<.01). D-CPPene reduced the mean infarct volume to 33±1.8% and 20.7±3.2% in aged and adult rats, respectively (P<.05). Cerebral blood flow fell markedly after infarction, but thereafter D-CPPene–pretreated rats maintained higher cerebral blood flow than untreated animals throughout the duration of the experiment (22.8±3.2 and 30.1±5.5 mL · 100 g-1 · min-1 in treated aged and adult rats, respectively, compared with 11.3±2.7 and 16.5±3.2 mL · 100 g-1 · min-1 in untreated aged and adult groups, 90 minutes after infarction [P<.05]). Pretreatment also reduced cortical edema; mean cortical specific gravity 4 hours after infarction was 1.0381±0.0013 in untreated aged rats and 1.0391±0.0014 in untreated adults compared with 1.0458±0.0031 in treated aged rats and 1.0442±0.0014 in treated adult rats (P<.05).
Conclusions Under similar experimental conditions, there was an age-related increase in cerebral infarct size. However, NMDA receptor antagonism was neuroprotective in the aging brain and resulted in a significant reduction in cerebral ischemic damage, less cortical edema, and preservation of cerebral blood flow.
Key Words: aging • rats • N-methyl-D-aspartate • neuroprotection
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Introduction |
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Stroke is a major cause of death and disability in the elderly. However, in vivo experimental studies, including the evaluation of neuroprotective strategies, have almost universally relied on models of focal cerebral ischemia in young brains. This might reflect in part the considerable difficulties encountered in previous attempts to establish a reproducible stroke model in animals of a relevant age.1 2 The NMDA receptor antagonists have been reported to yield large reductions in focal ischemic damage in young animal models of stroke.3 Competitive antagonists of the NMDA receptor, including the highly specific antagonist 3-(2-carboxy piperazin-4-yl)propyl-1-phosphonate (D-CPPene), are thought to limit glutamate-mediated neurotoxicity by competing with the excitotoxin at the neurotransmitter recognition site, thereby blocking the calcium influx that is thought to be associated with cell death.4 However, there are well-documented age-related changes in the central nervous systems of humans and laboratory animals, and these include a significant decline in the density, sensitivity, and function of cortical NMDA receptors with age.5 6 This suggests that the scope of neuroprotection in ischemic brain tissue may diminish significantly with advancing age, which may have important implications for future therapeutic intervention in elderly stroke patients. This study has addressed the problem by developing a model of occlusive stroke in the aging brain and using it to evaluate the effects of age on cerebral infarction and neuroprotective potential.
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Materials and Methods |
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The investigations were performed in accordance with the Animals (Scientific Procedures) Act 1986 in adult (11 to 17 months) and aged (28 to 36 months) male Wistar rats weighing between 341 and 529 g. The age ranges were selected following reference to survival curves for this strain.7 Anesthesia was induced by inhalation of 4% halothane in a nitrous oxide and oxygen (70%-30%) mixture and, after intubation, was maintained by ventilation with 1% halothane, with a further reduction to 0.4% after infarction. The femoral vessels were cannulated to allow sampling for levels of glucose, hematocrit, and arterial gases, administration of drugs and fluids, and continuous monitoring of arterial blood pressure. Core temperature was controlled using a rectal thermistor probe and a heating pad. A microcraniectomy was performed using the left subtemporal approach, after partial resection of the temporalis muscle, but with preservation of the zygomatic arch. After the dura was incised, the left middle cerebral artery was permanently occluded proximal to the lenticulostriate branch by thermocoagulation, using microbipolar diathermy. This yields a focal ischemic lesion involving the cortex and caudate nucleus.8
The ischemic damage was assessed histologically after perfusion fixation of the animals 6 hours after left middle cerebral artery occlusion (LMCAO), using 40% formaldehyde/glacial acetic acid/methanol (FAM 1:1:8). The brains were removed, embedded in paraffin wax, sectioned at 20-µm intervals, stained alternately with hematoxylin and eosin and cresyl fast violet, and analyzed by light microscopy by a consultant neuropathologist (R.H.P.) who was unaware of the age or treatment protocol of the animals. Those sections corresponding to eight predetermined stereotactic levels were used to map the infarction on line diagrams. The ischemic areas were measured by a video plan image analyzer. The infarct volume was calculated by integrating the ischemic areas at each coronal section over their anteroposterior coordinates.9 Cerebral blood flow (CBF) was measured using the hydrogen clearance technique.10 This involved the insertion of platinum electrodes 1 mm into the frontal and parietal cortex of each hemisphere through four burr holes, each sited 3 mm anterior or posterior to the bregma and 2.5 mm lateral to the midline. A reference electrode of silver/silver chloride was inserted subcutaneously, overlying the spine. Hydrogen was delivered through the inspiratory branch of the ventilator circuit at a concentration of 5% to 10% until the electrodes were saturated. The hydrogen was discontinued, and the changes in electrical impedance evoked by the hydrogen ion current were recorded as desaturation curves on a Rikadenki chart recorder. Values were plotted against time on semilog graph paper to reveal t1/2, and blood flows were calculated using the method described by Haining et al.11 Recordings were made as a baseline and at half-hour intervals for 4 hours after LMCAO. Specific gravity (SG) was measured as an index of cerebral edema using calibrated gravimetric columns.12 A coronal slice (from an identical site corresponding to the bregma in each brain) was used to cut paired 1-mm3 cubes of tissue from the cerebral cortex, caudate nucleus, and white matter of each hemisphere. Samples taken from the cerebellar cortex acted as a control. Specimens were cut and analyzed in the same sequence and were allowed to fall in graduated bromobenzene/kerosene columns. The descent level of the samples in the gravimetric columns was recorded at 1 minute. The SG of the specimen was calculated using a linear regression analysis derived from calibration of the column with potassium sulphate droplets of known SG. Measurements were made at 4 and 24 hours after LMCAO.
Adult and aged rats were randomly allocated into treated and untreated groups. Treated animals received D-CPPene (15 mg · kg-1) 15 minutes before LMCAO followed by an infusion (0.17 mg · kg-1 · min-1) for the duration of the experiment, according to the high-dose treatment schedule previously evaluated in young animals.3 Untreated animals received a similar regimen using the vehicle (0.9% saline). In the 24-hour experiments, the pretreatment D-CPPene (4.5 mg · kg-1 · min-1 IV) was followed by intraperitoneal injections of 4.5 mg · kg-1 every 3 hours after LMCAO. Untreated animals received similar volumes of saline. Procedures were performed aseptically; a topical antibiotic and 2% bupivacaine hydrochloride were applied to incisions with suturing before recovery. Animals were placed in an incubator after surgery with free access to food and water and regular monitoring of core temperature and oxygen saturation. Cerebral infarct size was analyzed 6 hours after LMCAO in treated and untreated adult and aged rats to allow time for the pathological changes of infarction to develop. CBF was analyzed for 4 hours in an additional set of treated and untreated animals from both age groups, with analysis of SG at the end of the experiments. SG was also analyzed after 24 hours of survival in a third set of treated and untreated adult and aged rats.
Data is presented as mean±SEM; comparisons were made with nonparametric Mann-Whitney tests.
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Results |
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Neuropathology
Aging was associated with a significant increase in cerebral infarct size. The mean infarct volume (expressed as a percentage of the total volume of the left hemisphere) was 40.5±2.6% in aged untreated rats (n=9) compared with 30.9±0.7% in untreated adult rats (n=10, P<.01; Fig 1
). This age-related increase in
infarct size was predominantly a reflection of more extensive cortical
infarction in the older animals. At each of the eight predetermined
stereotactic levels, there was more ischemic cortical damage in the
aged group than in adults, with the difference achieving significance
at levels 2, 3, 4, 6, 7, and 8 (P<.05; Fig 2). The area of infarction in the basal ganglia did not
increase significantly with age. Pretreatment with
D-CPPene reduced the volume of cerebral infarction
in the aged animals from a mean of 40.5±2.6% to 33.0±1.8% (n=10,
P<.05). This was largely attributable to a neuroprotective
effect in the cerebral cortex, with treated aged animals having less
ischemic cortical damage than their untreated counterparts at all of
the eight stereotactic levels that were analyzed (levels 3 and 4,
P<.05; Fig 3, top). The volume of basal
ganglia infarction was unaffected. D-CPPene had a more
marked neuroprotective effect in the adult animals: the mean infarct
volume was reduced from 30.9±0.7% (n=10) to 20.7±3.2% (n=8,
P<.05; Fig 1), representing a 33% reduction in
infarct size compared with an 18.5% reduction in the aged brains. In
addition, D-CPPene pretreatment reduced the area of
cortical infarction measured from each coronal section in adult brains
(levels 1 and 5, P<.05; Fig 3, bottom). The differences in
infarct volume were not a reflection of significant changes in
physiological variables, since these parameters were similar in all
groups (Table). All brains were well perfusion-fixed.
Classic ischemic changes were seen in all infarcted areas, and the
pattern of ischemic damage corresponded to the typical distribution of
the left MCA.
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Cerebral Blood Flow
Left Parietal Electrode
Baseline CBF values were similar in the aged and adult rats
(44.5±6.3 mL · 100 g-1 · min-1 in
untreated aged animals [n=7] compared with 51.4±5.7 mL · 100
g-1 · min-1 in untreated adults [n=9,
not significant]). CBF fell markedly within the first 30 minutes of
the occlusion, and although cerebral perfusion was maintained at a
lower level in the aged animals than in adults (n=8 in each group)
throughout the experiment, this difference did not achieve
significance. Pretreatment with D-CPPene moderated the
postocclusion fall in CBF, allowing aged rats to maintain perfusion at
or just above the critical threshold of 20 mL · 100
g-1 · min-1, below which ischemia
and infarction are likely to occur. CBF was significantly higher in the
treated aged group (22.8±3.2 mL · 100
g-1 · min-1, n=8) than in their
untreated counterparts (11.3±2.7 mL · 100
g-1 · min-1, n=7,
P<.05; Fig 4, top) from 60 minutes after
LMCAO. D-CPPene had a more marked influence in adult
rats, maintaining significantly higher flow from 90 minutes to 240
minutes after LMCAO in the treated group (untreated adults, 16.5±3.2
mL · 100 g-1 · min-1; treated adults,
30.1±5.5 mL · 100 g-1 · min-1; 90
minutes after infarction, n=8 in each group, P<.05; Fig 4,
bottom).
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Left Frontal Electrode
CBF fell within 30 minutes of LMCAO in both treated and untreated
aged rats, and a similar pattern of CBF change was seen in the adult
animals (Fig 5, top).
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Right Frontal and Parietal Electrodes
There were no significant differences in CBF in treated or
untreated aged or adult rats (Fig 5
, middle and bottom).
Cerebral Edema
SG of samples from the cerebral cortex, caudate nucleus, and white
matter of the left hemisphere was significantly lower than that of
corresponding samples from the right nonlesioned hemisphere in all rats
(P<.05, Fig 6). Pretreatment with
D-CPPene resulted in significantly less cortical edema in
the lesioned hemispheres of both adult and aged animals at 4 hours
after LMCAO. Treated aged rats (n=7) had a mean cortical SG of
1.0458±0.0031 compared with 1.0381±0.0013 in untreated aged rats
(n=9, P<.05). Treated adults (n=8) had a mean value of
1.0442±0.0014 compared with 1.0391±0.0014 in untreated adults (n=8,
P<.05; Fig 7). D-CPPene
pretreatment did not have a significant effect on edema in the basal
ganglia or white matter (Fig 8). The
neuroprotective effect in the cerebral cortex was still evident at 24
hours, with a mean cortical SG of 1.0403±0.0006 in treated aged rats
compared with 1.0361±0.0014 in untreated aged animals (n=6 in each
group, P<.05; Fig 9).
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Discussion |
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A physiologically stable model of occlusive stroke has been developed in the aging brain, and to our knowledge, this is the first study in which this reproducible focal ischemic lesion has been used to evaluate the influence of advancing age on cerebral infarct size and neuroprotective potential. Apart from the reliability of the model, there is further compelling evidence to suggest that its use in experimental stroke research is appropriate, since there are well-documented fundamental similarities in the age-related changes in rat and human brains. These include altered catecholamine levels,13 fewer and less sensitive dopamine receptors,14 15 a reduction in neurotrophic factors,16 a decrease in the neuron to glial cell ratio,17 18 and, most relevant to neuroprotective potential, a decline in NMDA receptor density6 and function.5 The age-related increase in cerebral infarct size is not explained by factors such as differences in arterial carbon dioxide or blood pressure levels because, although they may influence CBF, they were similar in the two age groups. The explanation may lie in a relative deficiency in the collateral circulation with age. This could account for the more extensive cortical infarction in the aged groups and the lack of a similar age-related effect in the basal ganglia, which has an end-artery vascular supply without collateral support. Documented morphological changes in the cerebral vasculature of aging rats include thinning of the endothelium,19 20 thickening of the basal lamina in hippocampal vessels,21 increases in collagen and elastin within vessel walls with arteriosclerosis,22 and impaired reactivity to vasodilator stimuli, which is thought to result from declining endothelial function.23 24 These factors may contribute to a reduced capacity in aged cerebral vessels to respond to ischemia and hypoxia. Red blood cell deformability has also been reported to decline with age in stroke patients and may contribute to reduced blood filterability in the elderly.25 Alternatively, aged neurons may have an inherent susceptibility to stress,26 27 with evidence to suggest reduced blood-brain barrier transport of glucose28 and amino acids,29 decreased metabolic rates for glucose30 and oxygen,31 and declining oxidative metabolism in aged brain mitochondria.32 33 34 35 Furthermore, using an embolic stroke model, it has been suggested that the immunologic response may decline with age, with older rats having less macrophage infiltration within cerebral infarcts than young animals.36 Higher basal glutamate release37 and reduced affinity of the high energy reuptake mechanism38 39 have been thought to be responsible for the higher glutamate levels recorded in aging brains.40 According to the excitotoxic theory of neuronal injury,41 42 there is a massive rise in extracellular glutamate levels after an ischemic insult.43 44 The aging brain might have an exaggerated response and, with a less efficient means of glutamate disposal, may be susceptible to more excitotoxic damage. However, the age-related decline in NMDA receptor density and sensitivity would tend to limit the effects of enhanced glutamate release; in addition, glutamate release in ischemic striatum is not significantly higher in aging brains.45 Moreover, the hippocampal release of the inhibitory amino acid taurine declines with age in spontaneously hypertensive rats subjected to transient global ischemia, whereas the rise in glutamate levels in ischemic hippocampus remains similar.46 These findings suggest that the documented age-related vulnerability of hippocampal neurons to a global ischemic insult47 is more likely to be attributable to impairment of an inherent protective inhibitory mechanism rather than to excessive excitotoxin release. In contrast, the levels of both excitatory and inhibitory neurotransmitters found in ischemic striatum do not alter with age,44 suggesting that, in global ischemia at least, an imbalance of excitotoxic and inhibitory amino acid release, and hence a presynaptic mechanism, is not responsible for the enhanced neuronal susceptibility of the aging striatum. However, the response in focal ischemia may be different, and the rise in glutamate in aging brains subjected to focal lesions has yet to be reported. Enhanced excitotoxicity may still play an important role in the pathogenesis of the age-related vulnerability of cortical neurons to a focal ischemic insult.
Although aging is associated with an increase in cerebral infarct size, NMDA receptor antagonism is neuroprotective in focal ischemic lesions of the aging brain, with D-CPPene pretreatment leading to significantly less edema and infarction of the cerebral cortex in the absence of any significant effect on physiological variables. Furthermore, the benefit is still apparent 24 hours after infarction, with persistent moderation of cerebral edema formation in the groups pretreated with D-CPPene. The prominence of the cortical protection reflects the distribution of NMDA receptors and has been noted previously in young brains.3 48 Similarly, the lack of a significant neuroprotective effect in the basal ganglia has been documented in young animals and has been attributed to the nature of the vascular supply in this region (ie, from an end artery without collateral support). The potential for benefit becomes less marked with age. This may be attributable to the reported decline in NMDA receptors with age, although with such a reduction in receptor function it is surprising that a significant benefit from D-CPPene was demonstrable. D-CPPene may have an alternative site of action (other than its role as a calcium channel blocker via the NMDA receptor) such as a direct effect on the cerebral vasculature and CBF. CBF values in this study are comparable with, albeit slightly lower than, those found in previous studies in which the hydrogen clearance technique has been used to assess blood flow in much younger animals.49 50 Physiological variables and the depth of anesthesia were similar in all animals and could not account for any differences in CBF among groups. The higher levels of CBF recorded in treated animals of all ages were an unexpected finding, and it is not clear whether the higher flows were responsible for, or merely resulted from, the reductions in infarct volume. However, D-CPPene did not increase CBF in the contralateral nonischemic hemisphere, suggesting that the relative preservation of perfusion in the ischemic brain may not be a primary effect, although further studies are warranted.
The use of this model of focal cerebral ischemia in the aged rat brain should permit more relevant experimental research into an illness that in humans is most prevalent in the elderly. The results of this study are encouraging in that there is scope for neuroprotection in the aging brain. Although the effect is less marked with age, the unprotected aged brain is liable to sustain a larger and potentially more disabling infarct, and modest degrees of neuronal salvage ultimately may be of clinical use in this age group. A potential role for NMDA receptor antagonists in ischemic aged brains has been identified, and a study of the value of a postinfarction treatment regimen in this age group would be useful, as it would be more representative of the clinical situation in stroke patients.
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Acknowledgments |
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This study was supported by the Northern Regional Research Committee, Eurage, the Sir James Knott Trust, and Sandoz Ltd (Berne, Switzerland). The technical assistance of Mr W. McMeekin and Mr A. Brown is much appreciated.
Received June 23, 1994; revision received January 25, 1995; accepted February 20, 1995.
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