(Stroke. 1995;26:1423-1430.)
© 1995 American Heart Association, Inc.
Articles |
Cerebral Protection Against Ischemia by Locomotor Activity in Gerbils
Underlying Mechanisms
From the Institute for Surgical Research (W.S., A.B., L.S.) and Institute for Anesthesiology (R.M.), Ludwig-Maximilians-University Munich, and Institute for Neurosurgical Pathophysiology, Johannes Gutenberg-University Mainz (O.S.K.) (Germany).
Correspondence to Oliver S. Kempski, MD, Institute for Neurosurgical Pathophysiology, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55101 Mainz, FRG.
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Abstract |
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Background and Purpose A previous communication of this laboratory demonstrated reduced mortality and neuronal damage by spontaneous locomotor activity preceding forebrain ischemia in Mongolian gerbils. The present experiments seek to elucidate potential mechanisms of protection by measurement of cerebral blood flow, cerebral tissue conductance as an indicator of ischemic cell swelling, and the cerebral release of eicosanoids.
Methods Gerbils were maintained either in conventional cages
(nonrunners) or with free access to running wheels (runners) for 2
weeks preceding 15 minutes of forebrain ischemia. During
ischemia and 2.5 hours of reperfusion, cerebral tissue
conductance was determined with a two-electrode system.
Simultaneously, prostaglandin
D2, prostaglandin
F2
, and thromboxane B2 were
measured in ventriculocisternal perfusate. In additional animals
cerebral blood flow was assessed by hydrogen clearance.
Results Decreases in tissue conductance during ischemia
were similar in nonrunners (56±3%) and runners (62±3%) but
normalized more rapidly in runners during reperfusion. In both groups
reperfusion was accompanied by marked increases of perfusate
prostaglandin D2,
prostaglandin F2, and
thromboxane B2. In nonrunners, however,
thromboxane B2 was already elevated during
ischemia (147±9%, P<.01) and remained elevated
longer during recirculation (P<.05).
Postischemic perfusion maxima were higher in runners
(70.8±7.4 versus 47.0±5.0 mL/100 g per minute, P<.05) and
were observed sooner (27.4±6.9 versus 62.2±12.3 minutes,
P<.05). Both groups displayed delayed hypoperfusion of a
similar magnitude (runners, 29.0±2.4 mL/100 g per minute; nonrunners,
30.1±2.4 mL/100 g per minute).
Conclusions Protection by preischemic locomotor activity may involve enhanced postischemic reperfusion, leading to more rapid normalization of conductance and thus of cell volume. Enhanced reperfusion may be the consequence of attenuated thromboxane liberation during and after ischemia.
Key Words: cerebral blood flow • cerebral ischemia • eicosanoids • locomotion • gerbils
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Introduction |
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Previous investigations of this laboratory1 revealed impressive protection from the sequelae of 15 minutes of forebrain ischemia by spontaneous preischemic locomotor activity in Mongolian gerbils maintained with free access to treadmills for 2 weeks preceding the insult. Postischemic survival was 91% at 2 weeks compared with only 37% in controls kept in conventional cages. Furthermore, neuronal death was reduced in selectively vulnerable areas of the brain, such as hippocampus, striatum, and certain laminae of the cortex. The incidence and extent of accompanying thalamic infarction was also reduced. However, these observations did not offer any obvious explanation as to the underlying mechanisms or whether protection was related to the ischemic episode itself or to early or late reperfusion, for example, inhibiting delayed neuronal death evolving days after ischemia.2
In the present experiments we investigated the period of
ischemia and subsequent 2 hours of reperfusion. During this
period we studied electrical tissue conductance of the brain to assess
the extent and reversibility of the extracellular to intracellular fluid shifts indicative of
ischemic cell swelling. It is generally accepted that changes
in the size of extracellular fluid volume are reflected by changes in
tissue conductance or its reciprocal, tissue impedance.3 4 5 6
Accordingly, a complete interruption of cerebral blood flow is
associated with a decline in tissue conductance of approximately 50%,
corresponding to a decrease of extracellular volume from approximately
20% to 10%.7 On the other hand, the normalization of
conductance or impedance indicates a restoration of energy
metabolism and ionic pump function, with recovery of cell
and extracellular volumes.8 Measurements of cerebral blood
flow (CBF) were included for evaluation of a major determinant of brain
function recovery and thus survival.9 10 11 12 13 14 CBF was studied
by the H2 clearance method,15 16 17 allowing
repetitive measurements in the same animal. Furthermore, the release of
important degradation products of arachidonic acid
were investigated, ie, prostaglandin D2
(PGD2), PGF2, and thromboxane
B2 (TXB2), the stable metabolite of
TXA2.18 Various laboratories have demonstrated
a rise in eicosanoids after ischemia19 20 21 caused
by the liberation of unesterified fatty acids, including
arachidonic acid, during
ischemia22 23 and their metabolism by
cyclooxygenase and lipoxygenase.
Eicosanoids have been investigated extensively in connection with
cerebral ischemia because some of their
physiological effects, such as alterations of
platelet function or vascular tone and permeability,24
may modulate ischemic injury. We examined the release of these
substances using ventriculocisternal perfusion of the brain. The
technique permits studies of the temporal dynamics of mediator
liberation during and after circulatory arrest of the brain, as opposed
to the one-time assay of brain tissue homogenates at the
end of the experiment.19 25 26 27 28
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Materials and Methods |
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Male Mongolian gerbils (60 to 90 g body weight) raised from a stock of animals obtained from Hoechst (Frankfurt, Germany) were divided into two groups. Before ischemia one group was placed in cages with free access to running wheels with a diameter of 34 cm for 14 days (runners). The control group was kept in conventional cages (nonrunners). All gerbils were anesthetized with halothane (1.5% in room air) and maintained at 37°C by a feedback-controlled heating pad. The femoral artery of all gerbils was cannulated for monitoring of systemic blood pressure. Both common carotid arteries were carefully isolated from surrounding tissue and loosely encircled by a 5-0 monofilament ligature with the use of an operating microscope. Care was taken to avoid damage of adjacent vagal nerve fibers. The gerbils were then placed in a stereotactic holder in the prone position for combined ventriculocisternal perfusion and measurement of cerebral impedance (runners, n=7; nonrunners, n=9) or assessment of CBF (runners, n=7; nonrunners, n=8). Ischemia was induced by straining the ligature encircling both common carotid arteries with a weight of 15 g at both ends, leading to simultaneous occlusion of both vessels. After 15 minutes ischemia was terminated by cutting the ligature.
For ventriculocisternal perfusion the right lateral ventricle was punctured 2 mm lateral and 1 mm dorsal to the bregma at a depth of 3 mm below the skull surface. For this purpose a stainless steel cannula (0.4-mm diameter) connected to a Statham transducer and perfused by mock cerebrospinal fluid at a rate of 33 µL/min was lowered stereotactically through a burr hole into the brain. The intrusion of the cannula tip into the ventricle was confirmed by a drop in perfusion pressure. Subsequently, a polytetrafluoroethylene catheter (0.7-mm diameter) was stereotactically introduced into the cisterna magna. The correct position of the catheter was verified by an ascending, pulsating column of cerebrospinal fluid. All gerbils in which perfusate was macroscopically contaminated by blood were excluded from the study. If patent ventricular perfusion was not achieved at the first attempt, only impedance curves were registered (n=4 in both groups).
Perfusate was collected continuously through the cisternal cannula in
preweighed Eppendorf vials cooled to 1°C by a copper coil perfused
with ice water. The vials were pretreated with 20 µL
indomethacin (1%) per 200 µL perfusate. Two samples
of 200 µL each were collected before ischemia, two during
ischemia (at 6 and 13 minutes), and nine during 120 minutes of
reperfusion. Perfusate samples were immediately frozen in liquid
nitrogen. Concentrations of PGE2,
PGF2, and TXB2 were determined by
radioimmunoassay with antisera obtained from Pasteur
Diagnostics.
Cerebral conductance, which is the reciprocal of impedance, Z, was calculated from tissue resistance, R; capacity, C; and frequency, f as
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Resistance and capacity were determined with a two-electrode system with the use of a resistance-capacitance bridge and an alternating current of 1000 Hz at an effective voltage of 10 mVeff.29 Measurements were obtained at 30-second intervals during ischemia and every minute during reperfusion. The perfusion cannula in the lateral ventricle of the brain was simultaneously used as an impedance electrode. A second electrode was implanted stereotactically in the temporal cortex 4 mm above the right external acoustic meatus to a depth of 4 mm beneath the skull surface. Both electrodes were insulated with epoxy except for 1 mm at the tip.
CBF was measured by hydrogen clearance.15 16 For each measurement hydrogen gas was added to the inspiration gas mixture for a final concentration of 12% and maintained for 2 minutes. Tissue hydrogen was detected by four platinum electrodes implanted in frontoparietal and parietal cortices. The 2-mm-long electrodes were made of 75-µm-diameter platinum wire insulated by polytetrafluoroethylene with the insulation removed at the tip (0.75 mm). With these dimensions the exposed platinum surface of the electrodes penetrated the cortex of the gerbils but not the underlying white matter, as verified histologically in foregoing experiments. An electrode bias of +300 mV was produced by a modified circuitry for current-to-voltage conversion constructed by one of the authors (R.M.) according to Prazma et al.30 The circuitry generated and applied a constant bias voltage to the platinum electrodes. A built-in differential amplifier subtracted bias voltage from the electrode signal, yielding an output voltage proportional to the current generated by oxidation of H2 at the electrode. A low-pass filter with a cutoff frequency of 0.1 Hz was used to diminish current noise. Calculation of blood flow based on the Fick principle and simplifying assumptions15 was performed with the aid of a personal computer and software developed by one of the authors (R.M.). The H2 clearance curves had a large monoexponential contour allowing unequivocal calculation of a first-order time constant. Measurements were performed before and after ischemia at 15-minute intervals but not during ischemia because of distortions from a fluctuating baseline, probably secondary to spreading depression.31
Differences between nonrunners and runners were analyzed by the
Mann-Whitney U test. For intraindividual comparisons the
Wilcoxon-Wilcox test was used. All data are given as mean±SEM.
Differences were considered significant with an error probability
of less than 5% (two-tailed).
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Results |
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No differences were registered in the courses of systemic blood pressure of gerbils kept in conventional cages (nonrunners) and those with free access to running wheels (runners). Fig 1
displays the mean arterial blood pressure
recorded in both groups. On occlusion of the common carotid
arteries, mean arterial blood pressure rose sharply in both
groups from a control value of approximately 85 mm Hg to more than 110
mm Hg. After release of occlusion, blood pressure returned to
preischemic values and remained close to 80 mm Hg in both
groups until the end of the experiment 160 minutes after
ischemia.
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On induction of ischemia, conductance declined slowly at first.
With a delay of approximately 150 seconds, however, a large conductance
drop was observed, so that conductance was only approximately 60% at
the end of ischemia. No statistical differences in conductance
were registered between runners and nonrunners during ischemia.
After reestablishment of perfusion, conductance in nonrunners remained
low and slowly began to normalize after 100 minutes of reperfusion.
After 160 minutes of reperfusion, values were still reduced to
approximately 80% of control. In runners, however, decreased
conductance resolved rapidly after release of the ligature, reaching
90% of normal after only 80 minutes of reperfusion (Fig 2).
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The individual conductance courses were evaluated with respect to the
following values: latency, the time period between vessel occlusion and
a conductance drop to less than 90% of control; min, the minimal
conductance measured during ischemia and reperfusion; and
tmin, the time span between vessel occlusion
and the time point at which minimal conductance was observed. These
data are summarized in Table 1. As demonstrated, latency
did not differ significantly between runners and nonrunners. However,
minimal conductance was significantly higher in runners and was
measured approximately 30 seconds after discontinuation of
ischemia in this group, suggesting prompt reversal of
ischemic cell volume perturbations. This observation stood in
sharp contrast to gerbils without prior locomotor activity. In these
animals, the minimum in conductance did not coincide with the end of
ischemia but occurred approximately 30 minutes after the
vascular occlusion was reopened.
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Table 2 presents the mean baseline levels of
PGD2, PGF2, and
TXB2 in runners and nonrunners obtained immediately before
ischemia. No differences were noted between nonrunners and
runners. Fig 3 demonstrates the mean levels relative to
their respective baseline values in the 13 perfusate samples collected
from each gerbil. During ischemia no changes were seen for
PGD2 or PGF2. However, nonrunners
displayed a significant increase in TXB2 in the sample
collected between minutes 6 and 12 of ischemia to 147±9% of
baseline. This increase was not observed in runners. After
ischemia PGD2 and PGF2
concentrations increased approximately threefold compared with baseline
in both groups. Maximal concentrations were encountered in the samples
collected between 13 and 27 minutes after ischemia, returning
to baseline toward the end of the experiment (120 minutes of
reperfusion). No statistical differences were noted between runners and
nonrunners for these two prostanoids. The same holds for the course of
TXB2 during the first 30 minutes of reperfusion.
Thereafter, however, TXB2 remained elevated in nonrunners,
whereas TXB2 concentrations in the cerebrospinal fluid of
runners normalized within 45 minutes of reperfusion, eventually
descending below baseline level (P<.01 versus
baseline).
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, n=9)
and runners (
, n=7). In nonrunners, however, thromboxane
B2 (TXB2) release was more pronounced
compared with runners during ischemia and remained elevated far
longer during reperfusion. +P<.05, *P<.02,
**P<.01.
We performed a regression analysis to determine whether there
was a relationship between TXB2 release during
ischemia and the minimum of conductance (min). As demonstrated
in Fig 4 an inverse relationship was observed between
both parameters taken from nonrunning gerbils
(r=-.81, P<.01). A significant relationship was
also found when the data of runners and nonrunners were pooled
(r=-.70, P<.01), whereas no correlation was
obtained when regression analysis was restricted only to the
data of the runners.
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The findings on regional CBF are given in Fig 5. Since
no differences were observed between the parietal and frontoparietal
recordings of each gerbil, the flow data obtained at these
sites were averaged for final evaluation. Resting blood flow did not
differ between nonrunners (45.61±1.7 mL/100 g per minute) and runners
(44.5±1.4 mL/100 g per minute). During ischemia blood flow
measurements were severely disturbed by baseline instability so that no
data could be obtained during this period. After ischemia was
terminated, accustomed changes in CBF were observed. These changes
encompassed a period of impaired reperfusion followed by a transient
phase in which CBF returned to and generally exceeded the resting value
(postischemic hyperperfusion). Subsequently, blood flow
dropped below the control value in a phase of delayed hypoperfusion,
returning to normal toward the end of the experiment. However, as shown
in the bottom panel of Fig 5, there was a broad variation with respect
to the time at which postischemic hyperperfusion was
observed. Because hyperperfusion was generally a short-lived
phenomenon, calculation of an average of blood flow between different
gerbils at a fixed point of time would have mitigated the amplitudes
encountered in the single animals. Therefore, the individual curves
were analyzed for the value of postischemic
perfusion maxima and the point of time at which these occurred. The
same analysis was performed with respect to the value of
minimal perfusion after the initial perfusion maximum. Fig 5
presents the means of these data, including also values for control
blood flow, CBF 5 minutes after ischemia (early reflow), and
CBF at the end of the experiment (160 minutes of recirculation). As
demonstrated, CBF during early reflow was reduced in both nonrunners
(15.9±1.9 mL/100 g per minute) and runners (31.2±6.7 mL/100 g per
minute, P=NS). Maximal postischemic perfusion
did not always surpass resting values in nonrunners and occurred rather
late (62.2±12.3 minutes of recirculation). Mean values for CBF in this
phase exceeded baseline slightly (47±5 mL/100 g per minute). However,
in runners hyperperfusion evolved much earlier (27.4±6.9 minutes) and
was far more pronounced (70.8±7.4 mL/100 g per minute). Conversely,
minimal blood flow during delayed hypoperfusion was identical for both
groups, just as the point of time at which minimal blood flow was
measured (nonrunners, 30.1±2.4 mL/100 g per minute after 82.3±9.8
minutes; runners, 29.0±2.4 mL/100 g per minute at 80.2±11
minutes).
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Discussion |
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In a previous communication1 we reported unanticipated and impressive protection against ischemic brain damage by spontaneous locomotor activity in the Mongolian gerbil. Subsequent experiments reported in the present article demonstrate that ameliorated survival may be related to pathophysiological mechanisms operative during ischemia and early reperfusion. This conclusion is based on differences between runners and nonrunners with regard to measurements of cerebral tissue conductance, CBF, and thromboxane liberation.
Electrical tissue impedance, which is the reciprocal of tissue conductance, has frequently been measured for assessment of the shift of extracellular electrolytes and fluid into the intracellular space accompanying cell swelling during experimental ischemia.3 5 6 32 33 34 35 36 This approach is based on the close relationship between the extracellular to intracellular fluid distribution and electrical tissue impedance under normal and pathophysiological conditions. As a consequence of the high electrical resistance of cell membranes compared with extracellular fluid, a low-frequency alternating current passing through biological tissues is mainly conducted by the extracellular compartment.37 Nevertheless, quantitative estimates of extracellular volume by measurements of tissue impedance37 have been criticized because of the structural complexity of brain tissue and inherent methodological difficulties.4 Therefore, the current assessment of cerebral impedance was limited to a comparison of relative changes.
The short-term course of cerebral tissue impedance (or conductance) on flow interruption is characterized by two different phases.4 5 6 Initially, tissue conductance remains relatively stable for 1 to 2 minutes, followed by a rapid fall until a plateau is reached that corresponds to approximately 50% of the preischemic level. The onset of the rapid decline of conductance has been attributed to a negative shift of the extracellular steady potential and to the disappearance of evoked potentials as a consequence of terminal cell depolarization.3 4 An interesting relationship has been observed for plasma glucose levels and the latency between flow interruption and the rapid decline of conductance.38 This may indicate a dependency of the initial delay of the impedance decrease on tissue energy reserves before occlusion. The ischemic threshold for the beginning impedance rise has been reported at 9.6 mL/100 g per minute in monkeys after middle cerebral artery occlusion.32 Accordingly, failure of normalization has been related to an absent recovery of neuronal function,4 to blood-brain barrier disruption, and to tissue damage assessed by elevated Na+-K+ ratios.6 Consequently, normalization of conductance and thus of cell volume implies that water and ions are transported across the cellular membrane, indicating functional recovery.8
In the present investigation we encountered no differences in the
initial delay or subsequent rapid conductance decrease during
ischemia in gerbils with or without prior spontaneous locomotor
activity (Table 1
). Moreover, the decreases in conductance registered
were of a magnitude observed by other researchers during cerebral
ischemia or cardiac arrest.3 5 6 34 36 39
Therefore, we conclude that ischemia was severe and similar in
gerbils with or without preischemic running. However,
recovery of conductance after reopening of the carotid arteries was
enhanced in runners, indicating early recuperation of membrane function
and a normalization of extracellular space and cell volume.
A factor conceivably contributing to enhanced recovery with regard to
cell volume was better and earlier reperfusion in gerbils with
preischemic wheel running. As demonstrated in Fig 4 the
dynamic profile of postischemic blood flow in runners
displayed characteristic features, namely, a brief impairment of
reperfusion followed by hyperperfusion and subsequent delayed
hypoperfusion.9 10 11 12 13 14 Five minutes after restoration of
perfusion, blood flow was still distinctly impaired in both nonrunners
and runners. Shortly thereafter, CBF in runners clearly exceeded that
of nonrunners in a period of hyperperfusion. These differences could
not be explained by changes in systemic arterial blood
pressure, which was identical for both groups.
Impaired reperfusion has been attributed to a variety of factors, such as increased blood viscosity, endothelial and perivascular glial swelling,40 endothelial blebs protruding into the capillary lumen,41 platelet aggregation,42 43 and vessel obstruction by leukocyte attachment to the endothelial surface.44 45 Perfusion deficits after ischemia may result in a prolongation of cerebral hypoxia, thus contributing to cerebral damage. Accordingly, adequate postischemic reperfusion has been associated with restoration of brain electrical activity.46 47 Other researchers have shown that even long periods of ischemia can be survived provided that impaired reflow is prevented.48 49 The present investigation corroborates these observations, because marked and early hyperperfusion was witnessed in the group of gerbils with superior survival and reduced neuronal damage in selectively vulnerable brain regions.1 Conceivably, the earlier recovery of brain tissue conductance in runners was similarly the consequence of enhanced reflow.
On the other hand, the magnitude and time course of a delayed decrease in perfusion appeared not to have been affected by preischemic locomotor activity. Generally considered to increase ischemic brain damage, the mechanisms underlying the phenomenon of delayed hypoperfusion are not yet fully understood.41 45 50 51 Our own data suggest that under the present experimental circumstances prompt and sufficient reperfusion may have been more crucial than delayed hypoperfusion for ameliorating the outcome.
Enhancement of postischemic reflow in runners may be
attributed to attenuated release of thromboxane during and
after ischemia, as determined by ventriculocisternal perfusion.
By this method, time-course determinations are possible in individual
animals in contrast to studies in which tissue levels of eicosanoids
have been determined in brain homogenates during and after
ischemia.19 25 26 27 28 In confirmation of these studies
and of others using microdialysis,52
cerebroventricular perfusion,21 or an ex vivo
analysis of eicosanoid levels in the supernatant of brain
slices,20 we found increased cerebral release of
TXB2, PGD2, and
PGF2 in the postischemic brain.
PGD2 and PGF2 peaked at 27 minutes of
reperfusion, and TXB2 was already elevated at 20 minutes.
No differences were observed between runners and nonrunners for
PGD2 and PGF2, and the
production of these two eicosanoids during ischemia was
not stimulated. On the other hand, TXB2 release was higher
in nonrunners compared with runners in perfusate collected during
ischemia. Furthermore, TXB2 levels remained
elevated longer in nonrunners during reperfusion. In view of the potent
vasoconstrictor and platelet aggregatory properties of
thromboxane,24 53 the poor and delayed reperfusion
in nonrunning gerbils might have been related to an increased
production of thromboxane in the brain during and after
ischemia. This conclusion is consistent with former
evidence suggesting that a suppression of thromboxane formation
by cyclooxygenase or thromboxane synthase
blockers enhances postischemic CBF12 26 54 and
reduces neuronal death in the CA1.55 This hypothesis is
underscored by the close relationship between TXB2 release
during ischemia and the severity of the conductance decrease
observed in the present experiments (see Fig 3).
We see no evident explanation for the differences in thromboxane liberation during and after ischemia. Possibly, residual blood flow in the brains of nonrunners during ischemia may have allowed for metabolism of arachidonic acid because of the availability of molecular oxygen,56 increasing thromboxane in the perfusate in this group. Unfortunately, CBF measurement by hydrogen clearance during ischemia was not possible because of an instability of the electrode current during this period. This instability correlated well with changes in cortical steady potentials (data not shown), which displayed a rapid negative shift approximately 1.5 seconds after onset of ischemia, followed by a slower negative shift throughout the period of occlusion.
However, forebrain ischemia in the gerbil is recognized as
being exceptionally dense,13 14 and the changes in
electrical conductance in both groups that were registered during
ischemia were similar and of a magnitude comparable to those in
other studies of global ischemia.3 5 6 34 36 38
Also, residual perfusion during ischemia in one or both groups
of gerbils would also have resulted in increased metabolism
of arachidonic acid by
cyclooxygenase to PGD2 and
PGF2.57 This was not the case, so
ischemia of equal density in both groups of gerbils can be
assumed.
An alternate explanation may be derived from observations by Eichner58 that physical exercise modifies the ratio of prostacyclin to thromboxane in an "antithrombotic" direction by increased endothelial liberation of tissue plasminogen activator and prostacyclin. Consequently, activation of platelets and hence aggregation during ischemia42 43 may be suppressed, attenuating thromboxane synthesis by platelets that are capable of thromboxane production.18 24 By this reasoning, however, higher perfusate levels of thromboxane in nonrunners may only be secondary to platelet activation, and platelet aggregation may be the explanation for reflow deficits observed in this group. Interestingly, thromboxane levels in runners dropped significantly below baseline levels in the course of reperfusion. This observation may indicate downregulation of synthesis or enhanced clearance of thromboxane by an intrinsic mechanism activated by ischemia. However, it is an open question by what basic mechanism preischemic, spontaneous locomotor activity affects the release of thromboxane and enhances reperfusion. Wheel running may influence a number of other pathophysiological processes that may potentially be involved in conferring the observed protection, for instance, the release of endogenous opioids and hormones.59 60 In addition, environmental changes, which were an intricate part of the present experiments, may themselves alter brain weight and metabolism61 and thus possibly influence outcome after ischemia. Nevertheless, the present experiments suggest that physical exercise is the factor offering protection against the sequelae of cerebral ischemia in the gerbil.
In conclusion, our data are consistent with the hypothesis that markedly improved survival and protection of the brain against ischemic damage by preischemic physical activity may be attributable to the better quality of early postischemic blood flow. Tentatively, we contend that thromboxane mediates reflow deficits because we observed significantly lower levels of thromboxane liberation in a group of gerbils with good reperfusion; rapid functional recovery, as indicated by conductance measurements; and better outcome, as demonstrated in a previous report.1 However, the basic mechanism by which preischemic, spontaneous locomotor activity affects the release of thromboxane and enhances reperfusion remains unknown. Because physical exercise offers unprecedented protection against the consequences of ischemia in the gerbil, we believe that further research into this intriguing phenomenon is warranted in the hope of establishing new treatment strategies for cerebral ischemia.
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Acknowledgments |
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This work was supported by grant DFG Ba 452/6-7. It contains substantial elements of the doctoral thesis of one of the authors (W. Stummer). We gratefully acknowledge the excellent technical assistance of Hilde Lainer and Ulrike Görke.
Received November 7, 1994; revision received February 1, 1995; accepted March 30, 1995.
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