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Research report
Intracerebroventricular propofol is neuroprotective against transient
global ischemia in rats: extracellular glutamate level is not a major
determinant
*
Toshiyuki Yano , Ryosuke Nakayama, Kazuo Ushijima
Surgical Center, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan Accepted 22 August 2000
Abstract
Excessive glutamate accumulation in extracellular space due to ischemia in the central nervous system (CNS) is believed to initiate the cascade toward irreversible neuronal damage. An intravenous general anesthetic, propofol (2,6-diisopropylphenol) has been implicated to be neuroprotective against cerebral ischemia. The purpose of this study was to test the hypothesis that intracerebroventricular propofol produced a reduction in extracellular glutamate level during global ischemia and the resultant neuroprotection. Adult male Wistar rats
were anesthetized with halothane in nitrous oxide / oxygen and mechanically ventilated. Propofol (3 or 10 mg / kg), Intralipid as a vehicle for propofol, or artificial cerebrospinal fluid (aCSF) was administered into the cerebral ventricles 15 min prior to a 10-min forebrain ischemia elicited by the four-vessel occlusion. Extracellular glutamate concentration in the hippocampal CA1 was continuously monitored during the peri-ischemic period with a microdialysis biosensor. Neuronal cell loss in the hippocampal CA1 was evaluated by cresyl-violet staining of sections 7 days later. Propofol (3 and 10 mg / kg) and Intralipid, compared with aCSF, similarly reduced the extracellular glutamate accumulation during the peri-ischemic period (P,0.05), indicating that the extracellular glutamate reduction that was seen primarily reflects the effect of Intralipid. The number of intact neurons in the hippocampal CA1 in propofol 10 mg / kg-treated rats was significantly higher than that in rats treated with propofol 3 mg / kg, Intralipid, or aCSF (P,0.05). We conclude that intracerebroventricu-lar propofol exhibits neuroprotection against transient global forebrain ischemia; however, the extracelluintracerebroventricu-lar glutamate level during ischemia is not a major determinant of this neuroprotection. 2000 Elsevier Science B.V. All rights reserved.
Theme: Disorders of the nervous system
Topic: Ischemia
Keywords: Delayed neuronal death; Hippocampus; Dialysis electrode; Neurotoxicity
1. Introduction of intravenous or intraperitoneal propofol on global and focal cerebral ischemia in animal models is still contro-Propofol (2,6-diisopropylphenol) in a lipid emulsion is versial [2,45,19,43,30,38,42].
used clinically as an intravenous general anesthetic and as Glutamate, the major excitatory neurotransmitter in the a sedative for critically ill patients. Propofol depresses mammalian CNS, activates post-synaptic receptors when electroencephalographic activity [14] and decreases the released from the pre-synapse. Excessive activation of cerebral metabolic rate for oxygen (CMRO ) [39,21] and2 post-synaptic glutamate receptors has been implicated in the cerebral blood flow [21,41]. Propofol also has anti- initiating the cascade that leads to neuronal cell death oxidant effects [24]. These features of propofol may [31,10]. Extracellular glutamate concentrations in the CNS provide protection against ischemia of the central nervous are normally low, but increase during ischemia [18,3]. The system (CNS). To date, however, a neuroprotective effect extracellular glutamate level depends on glutamate release into the extracellular space and its uptake into cells [5,4]. For this reason, regulation of glutamate release and of its *Corresponding author. Tel.: 181-96-373-5720; fax: 1
81-96-373-re-uptake during the peri-ischemic period could be a 5721.
E-mail address: [email protected] (T. Yano). promising strategy for alleviating neuronal injury. The 0006-8993 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved.
effect of propofol on the extracellular glutamate level Sycopel International, Ltd., Boldon, Tyne and Wear, UK) during cerebral ischemia remains to be elucidated. In this for continuous measurement of extracellular glutamate study, we tested the hypothesis that propofol delivered concentration as described previously in detail [3,26]. In directly to the CNS produced a reduction in extracellular brief, the microdialysis biosensor was made up of a glutamate level during global ischemia and the resultant platinum working electrode, a silver / silver chloride coun-neuroprotection in the hippocampal CA1 region of the rat. ter electrode, a silver reference electrode, and two vitreous silica tubes for changing the solution inside the biosensor, all of which were set inside a hollow semi-permeable
2. Materials and methods membrane, 230mm in outside diameter. The biosensor was filled and perfused with phosphate buffered saline (PBS)
2.1. Reagents pH 7.4 (mM: NaCl, 146; KCl, 2.7; Na HPO E H O, 4.3;2 4 7 2
KH PO , 1.4; CaCl , 2.4) by a perfusion pump (EP60;2 4 2
Glutamate oxidase, propofol, and Intralipid were ob- Eicom, Kyoto, Japan). O-phenylenediamine was elec-tained from Yamasa (Chiba, Japan), Aldrich (Milwaukee, tropolymerized onto the platinum electrode in PBS bub-WI, USA), and Pharmacia AB (Stockholm, Sweden), bled with 100% nitrogen and stirred to avoid interference respectively. All other reagents were purchased from from electroactive molecules such as ascorbate. The cur-Nacalai Tesque (Kyoto, Japan). rent from hydrogen peroxide produced by glutamate oxidation was detected amperometrically on the platinum 2.2. Subjects, preparation, and ischemia electrode at1650 mV by an electrochemical detector (EPS 800, Eicom) and recorded on a polygraph in real time. All animal care procedures in this study were performed After stabilization of the current at1650 mV, the biosensor according to the Guidelines for Animal Experiments of the was perfused with glutamate oxidase (0.05 U /ml) dis-Kumamoto University School of Medicine. The animal solved in PBS at a rate of 0.2ml / min. The calibration in care and use committee for our institute approved the study vitro was performed by placing the tips in the PBS protocol. We used adult male Wistar rats weighing between containing cumulated concentrations of L-glutamate. The
230 and 290 g. The animals were given free access to food current that developed on the platinum electrode increased and water. At the time of the experiment, they were linearly withL-glutamate concentrations up to at least 300
anesthetized with 4% halothane in nitrous oxide / oxygen mM. The sensitivity and response time of the microdialysis (F O ; 0.33), after which their tracheas were intubated andI 2 biosensors used were around 0.15 nA /mM and within 20 s they were connected to a rodent ventilator (7025; Ugo for a 90% steady state response, respectively. The micro-Basile, Camerio, Italy). They were mechanically ventilated dialysis biosensors were also calibrated forL-glutamate in
(tidal volume, 10 ml / kg; frequency, 60 / min) with 1% different concentrations (10 and 30%) of Intralipid, which halothane in nitrous oxide / oxygen. The pericranial tem- was a vehicle for propofol in this study (see Experimental perature was continuously monitored with a tissue implant- design), to see whether Intralipid influenced on the cali-able thermocouple microprobe (IT-14; Physitemp Instru- bration curve. The biosensor was implanted stereotaxically ments Inc., Clifton, NJ, USA) and maintained at on the left side of the hippocampal CA1 area 75 min 37.060.28C during surgery, brain ischemia, and recovery before the initiation of ischemia, and perfused with PBS from anesthesia with the use of a temperature controller containing glutamate oxidase at a rate of 0.2 ml / min to (TCAT-1A; Physitemp Instruments Inc.) and a radiant initiate in vivo real-time measurement of glutamate. The heating lamp. Electroencephalogram (EEG) from bilateral area under the curve defined as integrated increments of needle electrodes was continuously monitored and re- glutamate concentration from the pre-ischemic baseline corded. The tail artery was cannulated for monitoring of value between the beginning and 20 min after the end of arterial pressure and analysis of arterial blood gases, ischemia was calculated from the actual trace using NIH glucose, and hematocrit. Global forebrain ischemia was Image version 1.61 software.
achieved by the four-vessel occlusion method originally
described by Pulsinelli and Brierley [27]. In brief, vertebral 2.4. Experimental design arteries were coagulated at the alar foramina of the first
stereotaxically infused for 1 min into the bilateral cerebral ventricles (10ml into each ventricle) through burr holes 15 min prior to the initiation of ischemia. The glutamate analysis and anesthesia were terminated 30 min after the initiation of reperfusion. Animals were directly monitored until they fully woke from the anesthesia, then their tracheas were extubated.
2.5. Histology
The rats surviving for 7 days were sacrificed under pentobarbital anesthesia, then perfused transcardially with heparinized normal saline followed by 10% neutral buf-fered formalin. The brains were removed and fixed in 10% neutral buffered formalin, processed and embedded in paraffin. Five-micrometer-thick coronal sections were taken from the dorsal hippocampus and stained with cresyl violet acetate. The number of histologically intact pyrami-dal cells with a distinct nucleus and nucleolus in a 1-mm length of the middle portion of the CA1 subfield was counted on the right hippocampus by an inspector blinded
Fig. 1. A calibration curve of the microdialysis biosensor for glutamate in to intervention using a microscope at3400 magnification.
different concentrations of Intralipid. A linear regression line is shown The location of the microdialysis electrode was ascertained only for the plots from the calibration in Intralipid-free PBS.
in each 5 mm-thick coronal section stained with hemato-xylin and eosin. If the track of the electrode was outside
the CA1 region, the glutamate data was excluded. chemia was higher than those were at the baseline and after the intracerebroventricular administration in all
treat-2.6. Statistics ment groups (P,0.05).
Neither aCSF nor Intralipid administration into the Values were expressed as the mean6S.D. and data were cerebral ventricles influenced the EEG before ischemia. A analyzed by a one-way analysis of variance or repeated- pattern of burst suppression with an interval reaching measures analysis of variance. The Student–Newman– approximately 10 s appeared within a few minutes after the Keuls multiple comparison procedure was then used to intracerebroventricular injection in all rats given 3 or 10 determine which pairs of means differed. A chi-square test mg / kg of propofol. Thereafter, the EEG was gradually was used to identify differences in the survival rates. restored to the same pattern as that seen before propofol Statistical significance was defined as a P value,0.05. administration, and the pattern of burst suppression was no longer observed in any of the propofol-treated rats by 15 min after the injection (just prior to initiation of ischemia)
3. Results (Fig. 2).
ob-Table 1 a Physiologic data
Treatment aCSF Intralipid Propofol Propofol
3 mg / kg 10 mg / kg
n 9 10 9 10
Body weight (g) 256620 266619 257616 271618
Hematocrit (%) 3964 3963 3963 4162
Blood glucose (mg / dl) 127620 114620 117613 120615
Mean arterial pressure(mmHg)
baseline 7468 7669 74613 7968
15 min after treatment 76613 7665 69611 7568
†§ †§ †§ †§
5 min before reperfusion 108618* 115615* 102617* 119615*
†
30 min after reperfusion 87616 88616* 88615* 84612
Arterial pH
baseline 7.4360.04 7.4460.04 7.4360.02 7.4560.03
5 min before reperfusion 7.4360.06 7.4260.09 7.3860.05 7.4360.04
30 min after reperfusion 7.4360.04 7.4560.05 7.4060.06 7.4260.03
PaCO2(mmHg)
baseline 3763 3964 3863 3764
5 min before reperfusion 3766 41610 4467 3865
30 min after reperfusion 3769 3664 4368 3763
PaO2(mmHg)
baseline 135613 140629 129618 145614
5 min before reperfusion 147614 137633 131627 148620
30 min after reperfusion 152615 151631 140625 152615
Pericranial temperature(8C)
baseline 37.060.1 37.060.1 36.960.1 37.060.1
15 min after treatment 37.060.1 37.060.1 37.060.1 37.060.1
5 min before reperfusion 37.060.1 37.060.1 37.060.0 37.060.1
30 min after reperfusion 37.060.1 37.060.1 37.060.1 37.060.1
a † §
Values are expressed as the mean6S.D. * P,0.05 vs. baseline, P,0.05 vs. 15 min after treatment, P,0.05 vs. 30 min after reperfusion.
served in the time course of extracellular glutamate among animals (P,0.05). There were no significant differences in Intralipid and 3 and 10 mg / kg propofol treatments. the area under the curve among Intralipid and 3 and 10
The area under the curve in aCSF-treated animals was mg / kg propofol-treated animals (Fig. 4).
greater than those were in Intralipid and propofol-treated All aCSF-treated rats survived for the 7-day observation period. Two of 10, one of 9, and one of 10 rats died in the Intralipid, 3 and 10 mg / kg propofol treatment groups, respectively, during the 7-day reperfusion. No significant differences in mortality rate were observed among the treatment groups.
The number of intact pyramidal cells in the hippocampal CA1 was greater in the 10 mg / kg propofol group than in the aCSF, Intralipid, or 3 mg / kg propofol group (P,0.05, Fig. 5). However, no statistical differences were observed in the number of intact pyramidal cells among groups treated with aCSF, Intralipid, and 3 mg / kg propofol, respectively (Fig. 5B).
4. Discussion
Fig. 2. A burst-suppression pattern of electroencephalogram from rats given 3 mg / kg of propofol. Propofol was injected into the cerebral
This work demonstrates that propofol (10 mg / kg) ventricle. Similar changes were observed in rats treated with 10 mg / kg of
Fig. 3. The time course of extracellular glutamate concentration in artificial cerebrospinal fluid (aCSF), Intralipid, 3 mg / kg of propofol, and 10 mg / kg of propofol treatment groups (n58, 8, 9, and 7, respectively). The glutamate concentrations were plotted on the actual trace before the treatment and every 2 min between the beginning and 20 min after the end of ischemia. The intracerebroventricular treatment was performed 15 min prior to the initiation of 10-min four-vessel occlusion. Symbols indicate the mean and bars S.D. * P,0.05 vs. Intralipid. † P,0.05 vs. propofol 3 mg / kg. § P,0.05 vs. propofol 10 mg / kg.
Fig. 5. The effect of propofol on neuronal damage 7 days after ischemia. Rats were given artificial cerebrospinal fluid (aCSF), Intralipid, or 3 or 10 mg / kg of propofol into the cerebral ventricles 15 min prior to the initiation of 10-min four-vessel occlusion. (A) Representative photo-micrographs of the hippocampal CA1 subfield stained with cresyl violet, (a) aCSF, (b) Intralipid, (c) propofol 3 mg / kg, (d) propofol 10 mg / kg. Bar525mm. (B) The number of intact pyramidal cells in the hippocam-pal CA1 counted on the sections. Columns indicate the mean and bars S.D. * P,0.05 vs. other groups.
neuronal death when assessed at 7 days. Notably, propofol (3 and 10 mg / kg) and Intralipid similarly reduced the extracellular glutamate accumulation in the hippocampal CA1 region exposed to transient global forebrain ischemia. Although propofol is lipophilic and easily crosses the blood–brain barrier [32], we administered propofol into the cerebral ventricles to clarify its neuroprotective proper-ty, which remains controversial when administered in-travenously or intraperitoneally in the wake of several studies using different ischemic models and animals Fig. 4. The area under the curve of extracellular glutamate concentration [2,45,19,43,30,38,42]. The intracerebroventricular adminis-during peri-ischemic period. The area under the curve was measured on tration in the present study required a considerably lower the actual trace of glutamate between the beginning and 20 min after the dose of propofol to elicit electroencephalographic burst-end of ischemia. Rats were given artificial cerebrospinal fluid (aCSF),
suppression and neuroprotection against global ischemia as Intralipid, or 3 or 10 mg / kg of propofol into the cerebral ventricles 15
compared with the amount required via intravenous or min prior to the initiation of 10-min four-vessel occlusion. Columns
The administration of propofol used in this study also tration of Intralipid might have a clearer pharmacological prevented the systemic hypotension usually observed in effect, rather than the systemic administration, on brain both humans [13,12] and animals [22,17] by intravenous cells governing the glutamate release and its re-uptake. administration of propofol. Hypotension may influence the Intracerebroventricular Intralipid with and without prop-neuroprotective effects of propofol due to a reduction of ofol lowered the extracellular glutamate concentration cerebral blood flow. Thus, intracerebroventricular adminis- during ischemia to the similar level (¯100mM in Fig. 3).
tration could minimize the hemodynamic effects of prop- However, Intralipid alone did not contribute to the neuro-ofol and still produce CNS effects such as that seen after nal survival. The extracellular glutamate level above 100
systemic administration. mM for more than a few minutes triggers neuronal cell
The basal levels of extracellular glutamate in the rat death [11]. The reduced glutamate level during ischemia hippocampal CA1 reported here are similar to those in the seen in the present study would have been still capable of rat striatum measured by using the microdialysis electrodes inducing neuronal death in the hippocampal CA1. in Zhao et al. [46]. The change in extracellular glutamate The mechanism by which the intracerebroventricular in the hippocampal CA1 region was qualitatively similar to Intralipid reduced extracellular glutamate accumulation that monitored in the same region subjected to transient due to cerebral ischemia is unclear as yet. As demonstrated ischemia by using the glutamate microdialysis electrode in in Fig. 1, 30% or less of Intralipid did not interfere with
Terada et al. [37]. the glutamate detection by the microdialysis biosensor. It
Glutamate is released from nerve endings (vesicular is unlikely that 20 ml of Intralipid administered into the release), and its post-synaptic action is terminated by its cerebral ventricles of adult rats reflected an extracellular uptake into neurons and glia by glutamate transporters Intralipid concentration higher than 30% in the hippocam-[35]. Therefore, the extracellular glutamate concentration pus. In addition, glutamate levels were unchanged after the depends on the glutamate release and its uptake (glutamate intracerebroventricular administration of Intralipid. Gluta-dynamics). In ischemic conditions, an accelerated gluta- mate concentrations determined in the animals given mate release by an increase of vesicular release and a Intralipid intracerebroventricularly would not have been reversed uptake of glutamate transporters causes extracel- underestimated. Amorim et al. reported that propofol and lular glutamate accumulation, which is a major cause of Intralipid similarly attenuated the decrease in ATP content neuronal cell death because glutamate receptor antagonists of rat hippocampal slices during anoxia, which, given that reduce the number of neurons killed [6]. Several com- Intralipid contains lipids, suggests that Intralipid is an pounds inhibiting glutamate release (e.g. lamotrigine) or energy source [1]. The glutamate gradient across the stimulating its uptake (e.g. (R)-(2)-5-methyl-1-nicotinoyl- plasma membrane of brain cells, which is markedly higher 2-pyrazoline) represent a cerebroprotective effect against within cells than in the extracellular space, is maintained ischemia [36,34]. Propofol may have a potential to modify by energy-dependent carrier-mediated glutamate uptake glutamate dynamics during cerebral ischemia. It has been into neurons and glia [25]. In the hippocampus under reported that propofol inhibits glutamate release by block- energy deprivation, net glutamate uptake was decreased ing current through sodium channels or activating GABAA within 2–3 min and later the reversed glutamate uptake receptors at clinically relevant concentrations [28,29,9]. was promoted [20]. One possible explanation is that Propofol also has been shown to prevent the inhibition of Intralipid reduced ATP depletion, resulting in the attenua-glutamate uptake in cultured astrocytes exposed to perox- tion of extracellular glutamate elevation during ischemia. ide in pharmacologic models of brain trauma and reperfu- Electroencephalographic burst suppression is regarded sion injury [35]. However, we could not clearly describe as a clinical endpoint for titration of CMRO reduction by2
that propofol itself modulated the glutamate dynamics anesthetics [40]. Yamasaki et al. reported that a dose because two concentrations of propofol plus Intralipid and sufficient to induce a pattern of burst suppression was Intralipid alone similarly reduced the extracellular gluta- required for neuroprotection against incomplete global mate concentration in the late phase of ischemic period in cerebral ischemia in rats undergoing intravenous propofol comparison with the aCSF-treated control. Moreover, the infusion [44]. In contrast, Warner et al. demonstrated that areas under the curve representing net glutamate amount pentobarbital, which has effects similar to those of prop-released into the extracellular space were also similar in ofol on brain electrical activity, CMRO , and cerebral2
burst-suppres-sion pattern before the initiation of ischemia. However, Resources and Development, Kumamoto University only 10 mg / kg propofol showed a neuroprotective effect. School of Medicine, and was supported in part by a These results suggest that CMRO2 suppression when Grant-in-Aid for Scientific Research (No. 09470332) from ischemia was induced was minimal for neuroprotection by the Ministry of Education, Science, Sports and Culture of intracerebroventricular propofol under the conditions used Japan.
here.
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