(Stroke. 1997;28:2230-2237.)
© 1997 American Heart Association, Inc.
Articles |
Lamotrigine Protects Hippocampal CA1 Neurons From Ischemic Damage After Cardiac Arrest
From the Department of Molecular Pharmacology, Glaxo Wellcome Inc, Research Triangle Park, NC.
Correspondence to R. Christian Crumrine, PhD, Department of Molecular Pharmacology, Glaxo Wellcome Inc, PO Box 13398, Research Triangle Park, NC 27709-3398. E-mail rcc41549{at}glaxo.com
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Abstract |
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Background and Purpose Lamotrigine (LTG) is an anticonvulsant drug whose mechanism of action may involve the inhibition of glutamate release by blocking voltage-dependent sodium channels. Glutamate neurotoxicity may contribute to cerebral ischemic damage after recovery from cardiac arrest. Thus, LTG may prevent the brain damage associated with global cerebral ischemia by reducing the release of glutamate from presynaptic vesicles during the ischemic insult or the early recovery period.
Methods LTG was studied in cardiac arrest–induced global cerebral ischemia with reperfusion in rats. In the first set of experiments, LTG (100 mg/kg, PO) was administered before induction of ischemia; and in the second experiment, LTG (10 mg/kg, IV) was given 15 minutes after ischemia and a second dose (10 mg/kg,IV) was given 5 hours later.
Results In both experiments LTG reduced the damage to the hippocampal CA1 cell population by greater than 50%. Neuroprotection was not associated with changes in brain temperature or plasma glucose concentration. Plasma concentrations of LTG ranged between 8 and 13 µg/mL. Patients taking LTG as a monotherapy for epilepsy typically have plasma levels of LTG in the 10 to 15 µg/mL range.
Conclusions These data suggest that LTG may be effective in preventing brain damage after recovery from cardiac arrest. Patients on LTG monotherapy for epilepsy have plasma concentrations very similar to those found to be neuroprotective in this study. Although difficult to extrapolate, our data suggest that LTG at neuroprotective doses may be well tolerated by humans.
Key Words: rats • heart arrest • cerebral ischemia, global • neuroprotection • sodium channels • anticonvulsant • antidepressant agents
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Introduction |
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Glutamate excitotoxicity has been demonstrated in vitro1 2 and in vivo3 4 and may participate in the ischemic brain damage6 7 8 described in models of global stroke9 10 11 12 and in human patients recovering from cardiac arrest.13 Consequently, much effort has gone into targeting glutamate receptor subtypes in an attempt to limit ischemic brain damage. Indeed, there are many reports of the beneficial effects of N-methyl-D-aspartate receptor antagonists in models of focal stroke (for a review see Scatton et al14 ), although the efficacy of these compounds in GCI is less convincing15 16 17 18 (however, see Gill and Woodruff19 ). It appears that antagonism of the AMPA glutamate receptor may be more appropriate in models of global stroke.20 However, the adverse side effect profile of many glutamate receptor antagonists may limit their usefulness in the clinic.14 21
An alternative approach to ameliorate ischemic damage may be to inhibit the presynaptic release of glutamate. LTG is an antiepileptic drug. The proposed mechanism of action of LTG is to inhibit the presynaptic release of glutamate22 by blockade of voltage-sensitive sodium channels in a use-dependent manner.23 24 25 Thus, LTG may reduce ischemic damage by limiting the presynaptic release of glutamate during or after an ischemic event. Two analogues of this compound, 1003C87 and 619C89, as well as LTG have demonstrated anti-ischemic properties in focal cerebral ischemia models.26 27 28 29 30 31 The protective effect of 1003C87 was associated with reduced extracellular glutamate concentration in the ischemic penumbra as measured by microdialysis.26 27 1003C87 also reduced hippocampal CA1 cell degeneration after GCI in the rat,26 32 which again was associated with reduced extracellular glutamate concentration during the ischemic insult.32 Recently, Wiard et al33 and Shuaib et al34 demonstrated the benefit of LTG treatment in a gerbil model of GCI. In the report by Shuaib et al,34 a reduction in extracellular glutamate concentration was observed in animals pretreated with LTG. Bacher and Zornow35 observed a nearly complete inhibition of glutamate release during ischemia with LTG (50 mg/kg, IV) pre-treatment in a model of GCI in rabbits. The reduced extracellular concentration of glutamate was similar to that caused by hypothermia.35 In this report, we studied the effects of LTG in a cardiac arrest model of GCI in rats that more closely approximates human cardiac arrest with resuscitation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LTG was supplied by Burroughs Wellcome Co. The enzymes for the lactate assay were purchased from Bohringer Mannheim. All other compounds were purchased from Sigma.
The experimental protocol was approved by our institutional animal care and use committee before implementation. All the rats were fasted 12 to 18 hours before experimentation.
Cardiac Arrest Model
The model of cardiac arrest has been described
elsewhere.12 Briefly, for the pretreatment study, the
ventral tail artery and the right atrium of the heart of Wistar rats
were cannulated under halothane anesthesia. The wounds were
infiltrated with Marcaine before closure. The rats were recovered from
anesthesia in plastic restraints for at least 1.5 hours.
The blood pressure was constantly monitored on a
physiological recorder (model RS3600; Gould
Inc). Cardiac arrest was induced by the rapid sequential intra-atrial
injection of d-tubocurarine (0.3 mg) and ice-cold KCl (0.5
mol/L; 0.15 mL/100 g body wt). CPR, consisting of artificial
ventilation and chest compression, was initiated 8.5 minutes after
arrest (see Reference 1212 ). Epinephrine (3 µg/mL) was
infused when spontaneous heart contractions were observed, and was
titrated to maintain a mean arterial blood pressure above
85 mm Hg. Recovery from ischemia was defined as a return
of mean arterial blood pressure to greater than 80
mm Hg (ischemic duration was approximately 14 minutes, Table 1
). The rats were weaned from the
ventilator, which required approximately 3 hours, and returned to
individual cages. The effects of d-tubocurare lasts about 30 minutes in
the normal rat; therefore, it is unlikely that this drug was a major
contributor to the time needed to wean the rats from the
ventilator.
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For the posttreatment studies, Fischer 344 rats were cannulated as
described above. However, after local anesthetic infiltration and wound
closure, they were paralyzed with d-tubocurare and the halothane was
discontinued. Sedation was continued with
N2O:O2 (70:30). Ischemia was induced 20
minutes later as described above except CPR was begun after 7 minutes
and recovery occurred about 3 minutes later (ischemic duration
of approximately 10 minutes, Table 2).
The extracranial temperature was monitored and maintained close to
37°C during ischemia and for approximately 3 hours
postischemia.
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The body temperature of all of the rats for both studies was monitored and maintained near 37°C for 18 to 20 hours after recovery from arrest.
Brain Temperature Measurement
Rats were obtained from the vendor (Zivic-Miller Laboratories,
Inc) with cannulas implanted into the left lateral ventricle. A
microthermistor probe (23 gauge; Physitemp Instruments, Inc) was placed
through the cannula into the lateral ventricle.
EEG Recordings
Bone screws were placed over the frontal and occipital cortexes
with the midline acting as the common ground. The EEG was displayed on
a physiological recorder (model RS3600, Gould
Inc). The filters of the amplifier were set from 0.1 to 30 Hz.
Cerebral Perfusion Measurement
The cortical cerebral blood flow was estimated with a laser
Doppler perfusion indicator (Periflex PF3, Perimed). The flow probe
was placed against thinned bone over the parietal lobe, taking care not
to position the probe directly over a pial vessel. The
recordings were in arbitrary perfusion units, and the
recorder channel was calibrated from 0 to 600 units full scale.
Plasma Lactate Concentration
Plasma samples were obtained from rats at baseline and after 1,
5, 10, 15, 20, and 30 minutes of recovery from cardiac arrest.
Twenty-microliter samples were extracted in 200 µL of 0.3
mol/L perchloric acid in 1 mmol/L EGTA, neutralized
with 20 µL 3N KHCO3, and stored at -80° C until
assayed. The extracts were assayed for lactate concentration by the
method described by Lowry and Passonneau.36
Histology and Hippocampal CA1 Cell Counts
Three weeks after recovery from ischemia, the rats were
anesthetized with pentobarbital and perfused for 15 seconds
with PBS followed by 10% buffered formalin. The brains were removed,
postfixed in formaldehyde for 5 to 7 days, and processed for paraffin
sectioning. Ten-micrometer sections were obtained from each
brain at the level of the anterior hippocampus and stained with cresyl
violet, and an adjacent section was stained with hematoxylin and eosin.
The hippocampal CA1 pyramidal cells within a 250-µm
length of the CA1 sector were counted. Four counts (two from each
hemisphere) were averaged from each animal.
Compound Preparation and Administration
Pretreatment Study
LTG was suspended in methyl cellulose (10 mg/mL). The
rats were dosed (100 mg/kg, PO) 1 hour before cardiac arrest.
Posttreatment Study
LTG was solubilized in DMSO (30 mg/mL) and then diluted
1:2 with Poloxamer 188 (RheoThrx) to yield a 10 mg/mL solution.
The rats were dosed (10 mg/kg, IV) 15 minutes after recovery
from arrest and a second dose (10 mg/kg, IV) was given 5 hours
later.
The rats were dosed orally in the pretreatment study because of the lack of an intravenous formulation for LTG at the time. An intravenous formulation for LTG was developed for the posttreatment study as described above. Results from a pharmacokinetic study in rats receiving the oral and intravenous doses described here found that the plasma and brain concentrations of LTG of the two groups were nearly identical. Data from these studies indicated that the half-life of LTG is 12 to 18 hours in the rat. In the pretreatment study LTG was administered 1 hour before ischemia in order to achieve a stable plasma concentration before cardiac arrest.
A saline group was included in the posttreatment study as a control for the vehicle that was composed of DMSO and RheoThrx, both of which may have anti-ischemic properties.
Plasma and Brain Concentrations of LTG
In a parallel study, LTG (10 mg/kg, IV) was given to 30
rats mimicking the posttreatment-dosing paradigm (see above). Nine rats
were sacrificed 5 minutes after the first dose. Nine rats was killed 5
hours after the first LTG dose, and these animals did not receive a
second dose. Eight rats received two doses of LTG (10 mg/kg
each) 5 hours apart. These rats were killed 5 minutes after the second
dose. Plasma and brain samples were obtained from each rat and
analyzed for LTG concentration by high-performance
liquid chromatography.
To determine the effects of ischemia on LTG metabolism, 4 rats were treated with LTG 15 minutes after recovery from cardiac arrest. Plasma samples were obtained 5 minutes and 5 hours after treatment. The brains from 3 rats were obtained at the 5 hour mark while the fourth rat received a second dose of LTG. Plasma and brain samples from this rat were obtained 5 minutes after the second dose.
Statistical Analysis
The physiological variables, brain
temperature, cell counts, and the plasma and brain concentrations of
LTG for the nonischemic groups were analyzed by ANOVA
(Crunch statistical program) followed by Tukey's multiple comparison
test. Comparisons of LTG concentrations between the nonischemic
and ischemic animals were performed by t tests.
Power analysis for the cell counts in the posttreatment study
was performed using GB-Stat (New England Software, Inc). The pooled
standard deviation was used in the calculation.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Characteristics of the Model
The blood pressure and cerebral perfusion drop to near zero within seconds after the intra-atrial injection of ice-cold KCl. The electrocardiogram indicated no detectable heart beat within 3 seconds of the injection of the cardioplegic solution. The amplitude of the EEG progressively decreased until it became flatline by 15 seconds after injection of the KCl.
The initiation of CPR did not result in significant blood pressure nor was there an increase in cerebral perfusion until the heart began to beat spontaneously. Noticeable cerebral perfusion was observed only after the blood pressure had recovered to 70 to 80 mm Hg. Thus, even though CPR was initiated at 8.5 and 7 minutes as described for the pre- and posttreatment studies, respectively, the rats were not considered recovered from arrest until spontaneous blood pressure reached at least 80 mm Hg.
The plasma lactate concentration was dramatically elevated after 1 minute of recovery from 10 minutes of cardiac arrest (preischemia, 3.47±0.792 mmol/L; 1 minute recovery, 10.38±0.28 mmol/L, P<.01). The plasma lactate concentration declined to near preischemia values (3.35±0.67 mmol/L) over the next 30 minutes of re-flow. The t1/2 for lactate disappearance was approximately 15 minutes.
Because of the importance of brain temperature during ischemia,
we documented the changes in brain and body temperatures from 6 rats
following the pretreatment paradigm (Fig 1; these rats were not part of the
efficacy study). Initially, the brain temperature was higher than the
body temperature (37.7±0.2 and 37.5±0.2, respectively). After
initiation of cardiac arrest, the brain and body temperatures both
began to decline. By the third minute of arrest, the rate of decline of
the body and brain temperatures diverged, with the brain losing
temperature at a faster rate than the body. At the initiation of CPR,
there was a significant gap between the temperature of the brain and
body. The temperature of the brain stabilized after the initiation of
CPR; however, the temperature of the body continued to decline. It was
not until recovery from cardiac arrest that a noticeable increase of
both brain and body temperatures was observed.
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) and body (
) temperatures of
rats before, during, and after recovery from cardiac arrest. The rats
were conscious and in plastic restraints before ischemia
(pretreatment protocol). The 0 time point indicates the onset of
cardiac arrest. The first dashed line indicates the initiation of CPR.
The second dashed line indicates recovery from cardiac arrest. Values
are mean±SEM (n=4-6). *P<.05 brain temperature compared
with body temperature (t test).The neurological consequences of this model have been described in a previous report.12 The rats in all of the groups were quadriplegic for the first 12 to 24 hours after recovery from arrest. The quadriplegia resolved over the next 5 days so that the rats were able to eat, drink, and groom normally. Some of the Fischer 344 rats developed neurogenic urine retention that was treated by catheterization and expression of the bladder. This condition also resolved by 5 days. Interestingly, urine retention was not a problem in the Wistar rats.
During the period of quadriplegia, the rats received 5 mL of 0.5N saline and 5 mL of 5% dextrose in water subcutaneously (one injection under the lateral thoracic skin on each side of the rat) two times each day. In addition to the injections, the rats also received 5 mL of nutrient supplement by gavage two times a day. This treatment was continued until the rats were observed eating and drinking.
LTG Pretreatment
Table 1
shows the physiological variables
for the experimental groups before cardiac arrest while the rats were
conscious and in plastic restraints. No significant differences were
found between the experimental groups.
There was significant protection of the hippocampal CA1 cells from
ischemic damage with LTG treatment (Table 2). However, the number of remaining
cells in the LTG-treated group was significantly less than the
nonischemic control group (Table 3).
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LTG Posttreatment
Table 3 shows the physiological variables
for the LTG-, saline-, and vehicle-treated groups before cardiac arrest
and after 15 and 30 minutes of recovery from arrest. The body weight of
the saline-treated group was significantly less than the rats in the
LTG group. Besides this, all other variables were similar between
the experimental groups.
Ischemic durations of 10 minutes resulted in nearly
complete destruction of the hippocampal CA1 pyramidal cell
region in the saline and vehicle control groups, whereas LTG (10
mg/kg, IV) treatment resulted in significant protection of these
cells (Table 2 and Fig 2B, 2C, and 2D,
respectively). However, as in the pretreatment study, the LTG-treated
group had significantly less CA1 cells than the nonischemic
control animals (Table 2).
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The dispersion of the cell counts for the individual animals are
presented in Fig 3. The
nonischemic control, saline-, and vehicle-treated groups had
little variability between animals. The LTG-treated group had 3 rats
that demonstrated nearly complete protection from ischemic
damage and 2 animals with moderate protection. However, LTG appeared to
be totally ineffective in one rat (Fig 3).
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) displayed are mean±SEM.
*P<.01 compared with the nonischemic (Non-isch) and
LTG-treated groups. +P<.05 compared with the
nonischemic control group. Power of these tests was
>90%.
Fig 4 shows the external cranial
temperature of the three experimental groups during the cardiac arrest
and the early reperfusion period. There was no significant differences
in the extracranial temperature between the three groups either during
the ischemic event or the early reperfusion period.
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; dose volume, IV) 15 minutes after recovery from
ischemia. A second dose was given 5 hours later. Values are
mean±SEM. No significant differences were observed.
The recovery of EEG activity in the LTG-treated group after reperfusion
was delayed as compared with untreated animals (Fig 5). After 2 hours of re-flow, the
untreated rats showed marked improvement of EEG activity, whereas the
LTG group showed only intermittent spike activity (Fig 5B and 5C,
respectively), reminiscent of untreated rats at 30 minutes of re-flow
(data not shown). Even by 5 hours, the EEG waveform of the LTG rat was
markedly depressed compared with the untreated rats at 2 hours (compare
Fig 5D and 5B).
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Plasma and Brain Concentrations of LTG
Table 4 shows the plasma and brain
concentrations of LTG in nonischemic and ischemic rats
when the dosing protocol of the posttreatment study was used. In the
nonischemic rats, an intravenous dose of 10
mg/kg was correlated with a plasma concentration of 7.87±0.26
µg/mL after a 5-minute circulation time. By 5 hours the plasma
levels of LTG had declined to approximately 60% of the original dose
(Table 4). A second dose of LTG (10 mg/kg, IV) resulted in a
nearly identical boost in plasma concentration as seen 5 minutes after
the first dose (ie, a 7 to 8 µg/mL increase in plasma levels;
Table 4). The brain concentrations of LTG after the first dose was 9.6
µg/g and remained there for the next 5 hours. Similar to the
plasma levels, a second dose of LTG (10 mg/kg, IV) resulted in a
comparable change in brain levels as after the first dose (an increase
of 8.65 µg/g; Table 4).
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The plasma concentration 5 minutes after the administration of LTG to
the ischemic group was significantly higher than the plasma
levels of LTG at the same time point in the nonischemic animals
(Table 4, compare 5 min/GCI with 5 min). By 5 hours, the plasma
concentration of LTG in the ischemic group was not different
from the nonischemic group. Brain levels of LTG in the
ischemic animals were not different from the
nonischemic animals after a 5-hour circulation time (compare 5
hours with 5 h/GCI). In the one ischemic rat given a second
dose, the plasma concentration was found to be 10.39 µg/mL,
and the brain concentration was 18.85 µg/g, which was very
similar to that seen in the nonischemic animals (compare with
second dose plus 5-minute group in Table 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The first set of experiments was designed to better characterize the model of cardiac arrest–induced GCI with resuscitation in the rat. From these studies we found that the EEGs during ischemia and in the early reperfusion phase were similar to those seen in other models. We found that adequate cerebral perfusion was not achieved until the heart began to beat spontaneously and not until the blood pressure was at least 80 mm Hg. Plasma lactate concentration was very high immediately after re-flow in this model, unlike models of selective brain ischemia such as carotid occlusion in gerbils and the 4VO model in rats. Indeed, plasma lactate concentrations also increased in response to nearly total body ischemia in the dog,37 which was not observed in compression ischemia in the same species.38 These considerations suggest that this model may be a more accurate model of human cardiac arrest than selective brain ischemia models.
Wiard et al33 demonstrated the efficacy of LTG in the prevention of hippocampal cellular degeneration in a model of GCI in gerbils. LTG prevented CA1 cell death after the customary 5 minutes of GCI. In addition, Wiard et al33 demonstrated performance improvement in the Morris water maze corresponding to protection of the CA3 hippocampal neurons after 15 minutes of ischemia. Our study extended these results to a model of total body ischemia in rats. We found LTG to be equally effective in reducing CA1 hippocampal pyramidal cell loss in either a pre- or posttreatment paradigm. The degree of protection in our study was similar to that reported by Wiard et al33 except that we did not observe complete preservation of the hippocampal CA1 cells in the pretreatment study. The reason for the difference between their study and ours is unclear. However, in the study by Wiard et al33 the brain temperature of the gerbils in the pretreatment studies was not estimated and, thus, LTG treatment may have augmented the cooling effect of the anesthetic during ischemia. In addition, our animals were conscious or lightly sedated, whereas the gerbils were anesthetized before and during the ischemic event. Also, there was a species and ischemic duration difference between our two studies. It may, however, be possible to achieve complete protection of the brain from ischemic damage in this model if the initial dose of LTG was higher or if the duration of LTG treatment was extended. Further experiments are warranted for this compound in cardiac arrest–induced brain damage.
The mechanism by which LTG prevents brain damage in the pretreatment study may be largely attributed to its ability to inhibit the release of glutamate by blockade of presynaptic sodium channels. However, the mechanism of cerebral protection by LTG in the posttreatment study is less clear. Because treatment with LTG was initiated 15 minutes after reperfusion, a time point at which the extracellular glutamate concentration has been reported to be at or near control values,39 40 41 it would seem that the protective effect of LTG was not based solely on its ability to prevent glutamate release. It may be that blockade of voltage-sensitive sodium channels by LTG inhibits postischemic sodium influx, thereby facilitating membrane repolarization and helping cells maintain more stable and more negative membrane potentials. This may also explain the delay in the return of EEG activity. In addition, LTG may benefit ischemic tissue by reducing sodium flux and thereby ameliorating intracellular edema formation, preventing reversal of the sodium/glutamate and/or sodium/hydrogen transporter, reducing cerebral synaptic activity (see below), and possibly LTG may act as a free radical scavenger because of its unsaturated ring structure. Recently, in a model of cardiopulmonary bypass in pigs, LTG decreased systemic vascular resistance while having little effect on cerebral blood flow. LTG also decreased cerebral metabolic rate, which was suggested as another possible mechanism of protection for LTG (personal communication, William Johnston, MD, Department of Anesthesia, University of Texas Medical Branch, Galveston, Tex; 1997).
Busto et al42 demonstrated the neuroprotective effects of
reducing brain temperature in global ischemia with reperfusion.
Although not estimated in the pretreatment study, data from the rats
shown in Fig 1 suggest that the brain temperature declined dramatically
after induction of ischemia. However, because all of the rats
were conscious, in plastic restraints, and were similar in body
temperature before ischemia in this study, the loss in brain
temperature should also have been very similar in all of the groups
and, thus, would not be a factor in the final histopathology. In the
posttreatment study the brain temperature of all the rats was estimated
from the cranial temperature and kept close to
preischemic values. Indeed, this regulation of brain
temperature most likely accounts for the discrepancy between the two
studies in the ischemic duration necessary to achieve similar
pathology. In the posttreatment study, the extracranial temperature was
similar in all of the experimental groups, and, thus, the protective
effect of LTG cannot be attributed to fluctuations in brain
temperature. LTG, also, does not affect plasma glucose concentrations
(authors' unpublished observations).
LTG has been extensively characterized.22 23 24 43 It has little affinity for most receptor systems, although it will displace [3H]quipazine from the 5-HT receptor.43 LTG does not inhibit N-methyl-d-aspartate–, Kainate-, or AMPA-induced currents in hippocampal neurons but potentially inhibits sodium currents in both hippocampal neurons and N4TG1 mouse neuroblastoma cells24 (authors' unpublished observations, internal document). LTG inhibited veratrine (a potent sodium channel activator) but not potassium-induced glutamate release from cortical and hippocampal slices with an ED50 of 21 µmol/L.43 These data lend further support to the hypothesis that the ameliorating effect of LTG in GCI observed in this report was related to the blockade of voltage-sensitive sodium channels.
EEG activity was suppressed in LTG-treated rats as compared with untreated rats for at least 5 hours. Delayed recovery of EEG activity after ischemia has been observed with MK801 treatment following both focal ischemia and GCI.17 18 44 Since LTG, like MK-801, interferes with glutamate excitotoxicity and because LTG has antiepileptic properties, it is not surprising that LTG may alter EEG activity after ischemia. This property may contribute to the neuroprotective property of LTG by stabilizing neuronal membranes and thereby reducing the excitability of neuronal tissue, which may be metabolically compromised. This has been suggested as a component of the neuroprotective effect of MK-801.44
The plasma concentration of LTG after ischemia was elevated compared with that seen in the nonischemic rats 5 minutes after administration of the initial dose. This likely reflects a decreased metabolism of LTG by the liver, which is also recovering from ischemia. A reduction in metabolism of MK-801 after complete body ischemia has been observed and was largely attributed to ischemic injury to the liver.45 By 5 hours both the brain and plasma concentrations of LTG were not significantly different from those seen in nonischemic animals. Plasma concentrations of LTG from patients on LTG monotherapy for epilepsy are in the 12 to 14 µg/mL range,46 which is very similar to the plasma concentrations that afforded neuroprotection in this report (9 to 13 µg/mL). Although difficult to estimate from animal studies, our results indicate that the doses of LTG required for neuroprotection may be well tolerated by humans.
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Selected Abbreviations and Acronyms |
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Received January 29, 1997; revision received June 27, 1997; accepted July 2, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Choi DW, Maulucci-Gedde M, Kriegstein AR. Glutamate neurotoxicity in cortical cell culture. J Neurosci. 1987;7:357-368.[Abstract]
2. Rothman SM, Thurston JH, Hauhart RE. Delayed neurotoxicity of excitatory amino acids in vitro. Neuroscience. 1987;22:471-480.[Medline] [Order article via Infotrieve]
3. McDonald JW, Roeser NF, Silverstein FS, Johnston MV. Quantatine assessment of neuroprotection against NMDA-induced brain injury. Exp Neurol. 1989;106:289-296.[Medline] [Order article via Infotrieve]
4. Fujisawa H, Dawson D, Browne SE, Mackay KB, Bullock R, McCulloch J. Pharmacological modification of glutamate neurotoxicity in vivo. Brain Res. 1993;629:73-78.[Medline] [Order article via Infotrieve]
5. Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci. 1990;13:171-182.[Medline] [Order article via Infotrieve]
6. Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic—ischemic brain damage. Ann Neurol. 1986;19:105-111.[Medline] [Order article via Infotrieve]
7. McCulloch J. Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man. Br J Clin Pharmacol. 1992;34:106-114.[Medline] [Order article via Infotrieve]
8. Swan JH, Meldrum BS. Protection by NMDA antagonists against selective cell loss following transient ischaemia. J Cereb Blood Flow Metab. 1990;10:343-351.[Medline] [Order article via Infotrieve]
9. Ito U, Spatz M, Walker JT, Klatzo I. Experimental cerebral ischemia in Mongolian gerbils. Acta Neuropathol (Berl). 1975;32:209-223.[Medline] [Order article via Infotrieve]
10. Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res. 1982;239:57-69.[Medline] [Order article via Infotrieve]
11. Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol. 1982;11:491-498.[Medline] [Order article via Infotrieve]
12. Crumrine RC, LaManna JC. Regional cerebral metabolites, blood flow, plasma volume, and mean transit time in total cerebral ischemia in the rat. J Cereb Blood Flow Metab. 1991;11:272-282.[Medline] [Order article via Infotrieve]
13.
Petito CK, Feldmann E, Pulsinelli WA, Plum F.
Delayed hippocampal damage in humans following cardiorespiratory
arrest. Neurology. 1987;37:1281-1286.
14. Scatton B, Frost J, George P, Carter C, Benavides J. Present developments in NMDA receptor antagonists against cerebral ischaemia. Current Patents Ltd. 1994;ISSN 0926-2594:523-545.
15. Buchan A, Li H, Pulsinelli WA. The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats. J Neurosci. 1991;11:1049-1056.[Abstract]
16. Buchan A, Pulsinelli WA. Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci. 1990;10:311-316.[Abstract]
17. Michenfelder JD, Lanier WL, Scheithauer BW, Perkins WJ, Shearman GT, Milde JH. Evaluation of the glutamate antagonist dizocilipine maleate (MK-801) on neurologic outcome in a canine model of complete cerebral ischemia: correlation with hippocampal histopathology. Brain Res. 1989;481:228-234.[Medline] [Order article via Infotrieve]
18. Lanier WL, Perkins WJ, Karlsson BR, Milde JH, Scheithauer BW, Shearman GT, Michenfelder JD. The effects of dizocilpine maleate (MK-801), an antagonist of the N-methyl-D-aspartate receptor, on neurologic recovery and histopathology following complete cerebral ischemia in primates. J Cereb Blood Flow Metab. 1990;10:252-261.[Medline] [Order article via Infotrieve]
19. Gill R, Woodruff GN. The neuroprotective actions of kynurenic acid and MK-801 in gerbils are synergistic and not related to hypothermia. Eur J Pharmacol. 1990;176:143-149.[Medline] [Order article via Infotrieve]
20. Nellgard B, Wieloch T. Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia. J Cereb Blood Flow Metab. 1992;12:2-11.[Medline] [Order article via Infotrieve]
21. Sharp FR, Jasper P, Hall J, Noble L, Sagar SM. MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex. Ann Neurol. 1991;30:801-809.[Medline] [Order article via Infotrieve]
22. Leach MJ, Marden CM, Miller AA. Pharmacological studies on LTG, a novel potential antiepileptic drug, II: neurochemical studies on the mechanism of action. Epilepsia. 1986;27:490-497.[Medline] [Order article via Infotrieve]
23. Lees G, Leach MJ. Studies on the mechanism of action of the novel anticonvulsant LTG (Lamictal) using primary neurological cultures from rat cortex. Brain Res. 1993;612:190-199.[Medline] [Order article via Infotrieve]
24.
Lang DG, Wang CM, Cooper BR. LTG, phenytoin and
carbamazepine interactions on the sodium current present in N4TG1
mouse neuroblastoma cells. J Pharmacol Exp
Ther. 1993;266:829-835.
25. Cheung H, Kamp D, Harris E. An in vitro investigation of the action of LTG on neuronal voltage-activated sodium channels. Epilepsy Res. 1992;13:107-112.[Medline] [Order article via Infotrieve]
26. Meldrum BS, Swan JH, Leach MJ, Millan MH, Gwinn R, Kadota K, Graham SH, Chen J, Simon RP. Reduction of glutamate release and protection against ischemic brain damage by BW 1003C87. Brain Res. 1992;593:1-6.[Medline] [Order article via Infotrieve]
27. Graham SH, Chen J, Sharp FR, Simon RP. Limiting ischemic injury by inhibition of excitatory amino acid release. J Cereb Blood Flow Metab. 1993;13:88-97.[Medline] [Order article via Infotrieve]
28.
Graham SH, Chen J, Lan J, Leach MJ, Simon RP.
Neuroprotective effects of a use-dependent blocker of voltage-dependent
sodium channels, BW619C89, in rat middle cerebral artery
occlusion. J Pharmacol Exp Ther. 1994;269:854-859.
29.
Leach MJ, Swan JH, Eisenthal D, Dopson M, Nobbs
M. BW619C89, a glutamate release inhibitor, protects
against focal cerebral ischemic damage.
Stroke. 1993;24:1063-1067.
30.
Smith SE, Meldrum BS. Cerebroprotective effect
of lamotrigine after focal ischemia in rats.
Stroke. 1995;26:117-121.
31. Lekieffre D, Meldrum BS. The pyrimidine-derivative, BW1003C87, protects CA1 and striatal neurons following transient severe forebrain ischaemia in rats: a microdialysis and histological study. Neuroscience. 1993;56:93-99.[Medline] [Order article via Infotrieve]
32. Rataud J, Debarnot F, Mary V, Pratt J, Stutzmann J-M. Comparative study of voltage-sensitive sodium channel blockers in focal ischemia and electric convulsions in rodents. Neurosci Lett. 1994;172:19-23.[Medline] [Order article via Infotrieve]
33.
Wiard RP, Dickerson MC, Beek O, Norton R, Cooper
BR. Neuroprotective properties of the novel antiepileptic LTG in
a gerbil model of global cerebral ischemia.
Stroke. 1995;26:466-472.
34. Shuaib A, Mahmood RH, Wishart T, Kanthan R, Murabit MA, Ijaz S, Miyashita H, Howlett W. Neuroprotective effects of lamotrigine in global ischemia in gerbils: a histological, in vivo microdialysis and behavioral study. Brain Res. 1995;702:199-206.[Medline] [Order article via Infotrieve]
35. Bacher A, Zornow MH. Lamotrigine inhibits extracellular glutamate accumulation during transient global cerebral ischemia in rabbits. Anesthesiology. 1997;86:459-463.[Medline] [Order article via Infotrieve]
36. Lowry OH, Passonneau JV. A Flexible System of Enzyme Analysis. New York, NY: Academic Press Inc; 1972.
37. LaManna JC, Romeo SA, Crumrine RC, McCracken KA. Decreased blood volume with hypoperfusion during recovery from total cerebral ischaemia in dogs. Neurol Res. 1985;7:161-165.[Medline] [Order article via Infotrieve]
38. Michenfelder JD, Milde JH. Postischemic canine cerebral blood flow appears to be determined by cerebral metabolic needs. J Cereb Blood Flow Metab. 1990;10:71-76.[Medline] [Order article via Infotrieve]
39. Benveniste H, Drejer J, Schousboe A, Diemer NH. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem. 1984;43:1369-1374.[Medline] [Order article via Infotrieve]
40. Globus MY, Busto R, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem. 1988;51:1455-1464.[Medline] [Order article via Infotrieve]
41. Hagberg H, Lehmann A, Sandberg M, Nystrom B, Jacobson I, Hamberger A. Ischemia-induced shift of inhibitory and excitatory amino acids from intra- to extracellular compartments. J Cereb Blood Flow Metab. 1985;5:413-419.[Medline] [Order article via Infotrieve]
42. Busto R, Dietrich WD, Globus MY-T, Valdes I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab. 1987;7:729-738.[Medline] [Order article via Infotrieve]
43. Leach MJ, Baxter MG, Critchley MA. Neurochemical and behavioral aspects of LTG. Epilepsia. 1991;32(suppl 2):S4-S8.
44. Iijima T, Mies G, Hossmann KA. Repeated negative DC deflections in rat cortex following middle cerebral artery occlusion are abolished by MK-801: effect on volume of ischemic injury. J Cereb Blood Flow Metab. 1992;12:727-733.[Medline] [Order article via Infotrieve]
45. Schwartz PH, Wasterlain CG. Cardiac arrest and resuscitation alters the pharmacokinetics of MK-801 in the rat. Res Comm Chem Pathol Pharmacol. 1991;73:181-195.[Medline] [Order article via Infotrieve]
46. Faught E, Leroy RF, Messenheimer JA, Matsuo F, Bergen D, Dren AT, Keaney PA. Clinical experience with LTG (Lamictal) monotherapy for partial seizures in adult outpatients. Presented at the Annual Meeting of the American Epilepsy Society, Dec 4-10 Seattle, Wash, 1992. Abstract.
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