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(Stroke. 1996;27:1236-1240.)
© 1996 American Heart Association, Inc.
Articles |
Felbamate Protects CA1 Neurons From Apoptosis in a Gerbil Model of Global Ischemia
the Department of Neurology and Brain Research Institute, VA Medical Center at Sepulveda, University of California-Los Angeles School of Medicine (C.G.W., L.M.A.); and the Preclinical Research Department, Wallace Laboratories, Inc, Cranbury, NJ (J.K.W., R.D.S.).
Correspondence to Claude G. Wasterlain, MD, Neurology Service (127), VA Medical Center, Sepulveda, CA 91343-2099.
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Background and Purpose Felbamate, a novel anticonvulsant that binds to the glycine site of the N-methyl-D-aspartate receptor, has been shown to have neuroprotective properties in vitro and in vivo. In a rat pup model of hypoxia-ischemia, felbamate selectively reduced delayed death in hippocampal granule cells. The present study explores its neuroprotective potential in a gerbil model of global ischemia, in which good evidence exists that ischemia triggers apoptosis of CA1.
Methods Gerbils were subjected to bilateral carotid occlusion for 5 minutes and then treated with felbamate (100 or 200 mg/kg IV) or vehicle. They were killed 3 days later, and the numbers of live and dead neurons in the CA1 sector of the hippocampus were counted at stereotaxically defined levels.
Results Felbamate (200 mg/kg IV) administered after the release of carotid clamping did not change brain temperature but reduced neuronal death in CA1 from 332±60 cells per section of dorsal hippocampus in unmedicated gerbils to 62±12 cells in felbamate-treated animals (P<.001). A lower dose of felbamate (100 mg/kg post hoc) showed only a nonsignificant reduction of neuronal death. In the 200-mg/kg group, felbamate serum concentrations peaked at 162 µg/mL and were above 100 µg/mL for at least 3 hours, and brain levels reached 150 µg/mL at 1 hour. In the 100-mg/kg group, blood serum levels were well below 100 µg/mL.
Conclusions These results suggest that felbamate given post hoc is remarkably effective in preventing delayed apoptosis secondary to global ischemia but that effective neuroprotection requires doses higher than those used for anticonvulsant treatment.
Key Words: apoptosis • cerebral ischemia • neuroprotection • gerbils
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The novel anticonvulsant felbamate (2-phenyl-1, 3-propanediol dicarbamate) has been shown to have neuroprotective properties in vitro in hypoxic hippocampal slices1 and in vivo in a rat pup model of partial cerebral hypoxia-ischemia and an adult rat model of cardiac arrest.2 3 Felbamate is a dicarbamate with good anticonvulsant potency, which may act partially as a glutamate blocker and partially as a
-aminobutyric acid agonist4 and binds to the glycine site of the N-methyl-D-aspartate (NMDA) receptor.5 Felbamate is particularly effective against seizures induced by NMDA6 7 8 9 and kainatelike agents.7 8 In a rat pup model of partial cerebral hypoxia-ischemia,10 felbamate reduced the volume of cerebral infarction but was far more effective in blocking the death of hippocampal granule cells, which is delayed and characterized by early nuclear fragmentation. The purpose of the present study was to investigate (1) whether felbamate is neuroprotective in an established model of global ischemia and (2) whether it is effective against apoptosis triggered by ischemic insults. Recent evidence indicates that in the CA1 sector of the hippocampus, the mechanism of pyramidal cell death after transient bilateral carotid occlusion is indeed apoptotic.11 Our results indicate that at a high dose, felbamate given after the release of the occlusion is quite effective in preventing the death of CA1 pyramidal cells.
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Animals and Surgery
Adult male Mongolian gerbils weighing 45 to 60 g (Meriones unguiculatus, Tumblebrook Farms, Mass) were housed on a 12/12-hour light/dark cycle with food and water ad libitum. On the morning of the experiment, animals were anesthetized with methoxyflurane, and the femoral vein was cannulated with polyethylene tubing (PE10). After 4 hours of recovery, the animals were again anesthetized with methoxyflurane, and the skin of the neck was infiltrated with novocaine; both common carotid arteries were exposed through a ventral midline incision and carefully isolated with 4-0 silk suture, microaneurysm clips (Roboz) were simultaneously applied to both carotids, and anesthesia was stopped. Five minutes after the carotid arteries were clamped, the clips were removed, the skin was reinfiltrated with novocaine, and the incision was closed. A suspension of felbamate was administered (100 or 200 mg/kg IV). The infusion was continuous over a period of 5 minutes. Controls received the same volume of solvent intravenously. Injection of vehicle or 100 mg/kg felbamate had no visible behavioral effect on any group of gerbils. Felbamate 200 mg/kg caused a mild decrease in motor activity in both the control and ischemic groups, which lasted approximately 1 hour. Body temperature was maintained by a heat lamp with rectal probe (37±0.5°C) throughout the procedure, and animals were then placed in a warm cage (33°C to 34°C) for recovery. These procedures follow institutional guidelines and were approved by our Animal Research Committee. The protocol required elimination of any animals that displayed behavioral seizures, but none were seen. In a separate group of eight gerbils, a microthermocouple radio transmitter brain probe (Mini Mitter) was implanted into the parietal cortex under methoxyflurane anesthesia, after careful calibration with standard baths; transmission frequency temperature was recorded throughout the experiment and converted to degrees centigrade according to a standard curve established in our laboratory.
Histology
Seventy-two hours after carotid occlusion, the animals were anesthetized with pentobarbital (200 mg/kg IP), the chest was opened, the right auricle was incised, and a needle (No. 18) was inserted into the left ventricle. Transcardiac perfusion began with heparinized saline for 30 seconds, followed by 10% buffered formaldehyde at pH 7. After perfusion of at least 50 mL, the heads were stored in the same fixative at 0°C overnight; then the brains were removed, processed through graded ethanols and xylene, and embedded in paraffin. Serial 8-µm sections were stained with hematoxylin and eosin. Sections at the level of the ventral and dorsal hippocampus (-3.8 and -5.3 mm to bregma, respectively)12 were used for CA1 cell counts. Dying neurons were identified under light microscopy at a magnification of x200 by their pyknotic nucleus and eosinophilic cytoplasm. Statistical significance was determined by nonpaired Student's t test with a value of P
.001.
Pharmacokinetics
Twenty-four gerbils were injected with felbamate (100 or 200 mg/kg IV over 5 minutes). Animals were killed, and serum and brain were collected 15 minutes and 1, 3, and 6 hours after injection. All serum and brain samples were analyzed at Wallace Laboratories with the use of a reverse-phase high-performance liquid chromatography internal standard method with ultraviolet detection.13
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No significant behavioral differences were seen between the three groups. Recovery may have been slightly faster in the 200-mg/kg felbamate group, since both the mild behavioral depression seen immediately after ischemia and the mild hyperactivity observed at 48 to 72 hours were less marked in that group. Felbamate did not alter brain temperature before, during, or after ischemia (Fig 1
). With intravenous administration, felbamate blood levels peaked very quickly, reaching a maximum after 15 minutes that was almost twice as high in the 200-mg/kg group as in the 100-mg/kg group (Fig 2). Brain levels were close to blood levels but peaked later. The 1-hour values in the 100-mg/kg group were clearly subtherapeutic for blood and brain compared with neuroprotective levels for rat brain or rat hippocampal slices.1 2 In the 200-mg/kg group, they were well above the 100-µg/mL level that is usually required for effective neuroprotection in the rat. These levels were maintained from 1 to 3 hours but fell by 6 hours after injection (Fig 1). Blood and brain levels of the 2-hydroxy metabolite (W2992) followed a curve similar to that of felbamate. However, since the potency of W2992 in vitro is similar to that of felbamate (R.A. Wallis, unpublished data, 1994) and blood levels were severalfold lower, it is unlikely that it played a significant role in the neuroprotective effects observed in this study, unless the relative potencies of the two compounds in the gerbil are different from those previously noted in the rat. Brain temperature decreased in both groups in association with carotid occlusion, but no difference was found between the felbamate and control groups (Fig 2). The small trend toward a higher temperature in the felbamate group would be expected to increase damage and cannot be responsible for the neuroprotection observed in that group.
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As expected, widespread delayed cell death was observed in CA1 in the ischemic controls, which received only intravenous vehicle (Fig 3). Many CA1 neurons showed fragmented nuclei, and only a modest amount of eosin fluorescence was seen in the cytoplasm. Severe cell loss was also observed in subiculum, with more moderate loss in CA3. A group of untreated controls was not included in the study, since no injured cells were observed in any animal. In the experimental group receiving 100 mg/kg felbamate, three of nine animals showed minimal CA1 damage (3, 16, or 68 injured cells per hippocampal section). This was not observed in any of the controls, since the three paired ischemic controls with the lowest number of injured neurons had 225, 321, and 335 dying cells per hippocampal section, respectively. However, in a comparison between ischemic controls and the 100-mg felbamate group, no significant protection was noted (Table). By contrast, with 200-mg/kg treatment, a striking preservation of morphology of CA1 neurons was seen, with only scattered neurons showing degenerative changes (Fig 3). A more than fourfold reduction in the number of injured cells was observed in the CA1 sector (Table), and this difference was highly significant (P<.001). Subiculum and CA3 showed a nonsignificant trend toward improvement with high-dose felbamate.
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These results demonstrate that felbamate crosses the blood-brain barrier effectively, penetrates the brain, and after a single intravenous infusion lasting only 5 minutes, sustains therapeutic levels for several hours. This therapeutic window approximates the period during which effective neuroprotection is seen in most experimental models. The extensive neuroprotection obtained with post hoc administration in this model of global ischemia has possible human therapeutic implications. While some global ischemic events in humans can be anticipated (eg, interruption of the cerebral circulation during open heart surgery), most of them (eg, cardiac arrest) are only amenable to postischemic treatment. The present study suggests that felbamate can significantly reduce damage from global ischemia when given post hoc.
Previous studies10 in the rat pup model of hypoxia-ischemia had demonstrated remarkably effective neuroprotection with felbamate in a population of hippocampal dentate granule cells that undergo delayed cell death with nuclear fragmentation, raising the possibility that their death might be apoptotic. It is therefore of interest that the mechanism of CA1 neuronal death in the model used in this study has recently been shown to be apoptotic by several criteria: early nuclear fragmentation was seen, with dense chromatin masses appearing early in the nucleus11 and nuclear DNA fragments being phagocytosed by microglia. Laddering of DNA was demonstrated 4 days after the ischemic insult, nuclear uptake of dUTP was observed, and immunoreactivity for cathepsins B, H, and L, which are lysosomal, increased in CA1 pyramidal cells 3 days after the insult. These data strongly suggest that apoptosis is the mechanism of death of CA1 pyramidal neurons after bilateral transient carotid occlusion. The very effective neuroprotection obtained in this study confirms that felbamate is particularly effective against delayed cell death and suggests that it may do so by blocking apoptosis.
The high serum levels needed to achieve effective neuroprotection in this study are close to the highest levels reported during therapeutic anticonvulsant trials in which oral administration in humans was used. It should be noted that little serious acute toxicity was encountered in those trials, and therefore effective neuroprotection is a realistic goal in acute global ischemia in humans.14 15 16 17 18 However, the levels are clearly higher than the dose required for effective anticonvulsant effect. The serum concentrations ranging from 62 to 68 µg/mL achieved for the first 3 hours in the 100-mg/kg group would be expected to be effective against seizures, yet they failed to achieve significant neuroprotection. These results support previous studies which suggested that the mechanism of the anticonvulsant and neuroprotective effects of this compound might be different4 and that anticonvulsant effects might be obtainable at lower blood concentrations than required for good neuroprotection.2
Recent human use has shown significant felbamate toxicity in the form of 33 cases of aplastic anemia and several cases of hepatic failure. All of those were seen with long-term use, with the shortest period of felbamate exposure in cases of aplastic anemia being 2.5 months.19 20 Therefore, the remarkable lack of toxicity of felbamate in short-term use21 and the effectiveness of a single intravenous injection for neuroprotective purposes (this study) at blood concentrations achievable in humans suggest that the risk of hematologic and hepatic toxicity of felbamate might be very small and acceptable for short-term use in ischemia. The absence of sedation observed with human use would be an asset in human situations of global ischemia such as cardiac arrest.21 22 23 The psychiatric or acute cellular toxicity of other neuroprotective agents such as dizocilpine has not been reported for felbamate.24 25 26
The mechanism of felbamate neuroprotection is not clear. We recently found that transient excitotoxic or hypoxic-ischemic insults lead to sustained opening of NMDA receptor-gated ionic channels and enhanced excitatory amino acid release, which are reversed by felbamate and by NMDA and nitric oxide blockers.27 28 The affinity of felbamate for the glycine site of the NMDA receptor in animals5 and in the human brain29 and the reversal of felbamate neuroprotection by an excess of glycine in slices1 28 suggest that felbamate could interrupt a postexcitotoxic "vicious cycle" in which a transient insult raises intracellular Ca2+ and activates nitric oxide synthase, after which nitric oxide diffuses to the presynaptic terminal, where it enhances glutamate release, thereby perpetuating the cycle.28 However, studies in the present model showed protection of CA1 by the non-NMDA antagonists NBQX and GIKY52466 given after treatment.29 30 31 By contrast, dizocilpine, a blocker of the NMDA receptor that is far more potent than felbamate, has shown mixed results in the gerbil model, with some investigations failing to find significant neuroprotection.31 32 In vivo, felbamate is effective against seizures induced by kainate acid and other non-NMDA agonists8 as well as against NMDA seizures.6 7 8 Thus, felbamate seems uniquely effective in salvaging neurons from postischemic apoptosis by a mechanism that is yet to be elucidated.
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Acknowledgments |
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This study was supported in part by the Research Service of the Veterans Health Administration, by research grant NS-13515 from the National Institute of Neurological Disorders and Stroke, and by a grant from Wallace Laboratories. We are indebted to Barbara Blackburn for preparation of the manuscript.
Received February 23, 1996; accepted March 1, 1996.
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3. Adams LM, Schwartz PH, Palos TP, Morin AM, Wasterlain CG. Felbamate reduces neuronal necrosis and behavioral deficits induced by cardiac arrest in rats. Soc Neurosci Abs. 1992;22:610-611. Abstract.
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McCabe RT, Wasterlain CG, Kucharczyk N, Sofia RD, Vogel JR. Evidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors. J Pharmacol Exp Ther. 1993;264:1248-1252.
6. Coffin VL, Cohen-Williams M, Barrett A. Selective antagonism of the anticonvulsant effects of felbamate by glycine. Eur J Pharmacol. 1994;256:R9-R10.[Medline] [Order article via Infotrieve]
7. De Sarro GB, Ongini E, Bertorelli R, Agugula U, De Sarro A. Excitatory amino acid neurotransmission through both NMDA and non-NMDA receptors involved in the anticonvulsant activity of felbamate in DBA/2 mice. Eur J Pharmacol. 1994;262:11-20.[Medline] [Order article via Infotrieve]
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9. Sofia RD, Gordon R, Gels M, Diamentis W. Comparative effects of felbamate and selected compounds on N-methyl-D-aspartic acid-induced convulsions and lethality in mice. Pharmacol Res. 1994;29:139-144.[Medline] [Order article via Infotrieve]
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Wasterlain CG, Adams LM, Schwartz PH, Hattori H, Sofia RD, Wichmann JK. Posthypoxic treatment with felbamate is neuroprotective in a rat model of hypoxia-ischemia. Neurology. 1993;43:2303-2310.
11. Nitatori T, Sato N, Waguri S, Karasawa Y, Araki H, Shibanai K, Kominami E, Uchiyama Y. Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci.. 1995;15:1001-1011.[Abstract]
12. Loskota WL, Lomax P, Verity MA. A Stereotaxic Atlas of the Mongolian Gerbil Brain. Ann Arbor, Mich: Ann Arbor Sci-ence; 1974.
13. Jacala A, Adusumalli VE, Kucharczyk N, Sofia RD. Determination of the anticonvulsant felbamate and its three metabolites in brain and heart tissue of rats. J Chromatogr A.. 1993;614:285-292.
14. Theodore WH, Reeves P, Porter RJ, Nice FJ, Derinsky O, Bromfield E, Balish M. Long-term followup of felbamate therapy in patients with complex partial seizures. Epilepsia. 1990;31:619.
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Leppik IE, Dreyfuss FE, Pledger GW, Graves NM, Santilli N, Drury I, Tsay JY, Ashworth M, Lee SI, Sierzant TL. Felbamate for partial seizures: results of a controlled clinical trial. Neurology. 1991;41:1785-1789.
16. Wagner ML, Leppik IE, Graves NM, Remme RP, Campbell JI. Felbamate serum concentrations: effect of valproate, carbamazepine, phenytoin and phenobarbital. Epilepsia. 1990;31:642. Abstract.
17. Garofalo EA, Olson LD, Sackellares JC, Child J, Tornow MA, Komarynski MA. Felbamate for the treatment of Lennox-Gastaut syndrome. Epilepsia. 1990;31:619. Abstract.
18. Ward DL, Wagner ML, Perhach JL, Kramer L, Graves N, Leppik I, Shumaker RC. Felbamate steady-state pharmacokinetics during coadministration of valproate. Epilepsia. 1991;329(suppl 3):8. Abstract.
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Editorial Comment
Apoptosis Research GroupInstitute for Biological SciencesNational Research Council of CanadaOttawa, Ontario, Canada
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Apoptosis research is very trendy, and therefore an article with a title indicating that a drug prevents apoptotic death of ischemic neurons will receive much attention. This statement implies that apoptosis does occur in gerbils after ischemia, which is by no means acceptable to all.
The drug in question is the anticonvulsant felbamate. The authors are to be congratulated for going to the lengths of using implanted radio transmitter probes in the brain to ensure that there was no lowering of brain temperature after drug treatment. This rock is one upon which other compounds have foundered in the past, but in this case it cannot be the cause of felbamate's neuroprotection. The 200-mg/kg dose undoubtedly decreased the number of injured eosinophilic hippocampal neurons at the single time of observation. This is just one step on the long hard road to a possible clinical treatment for stroke. One is left wondering how other injured parts of the brain fared after treatment. Were striatal neurons also protected? Was neuronal function preserved or just gross cellular anatomy? One also has to wonder whether this drug really protects or only delays cell death at 72 hours after ischemia. Such concerns are indeed valid because of the recent findings of fleeting protection by MK801 or NBQX in focal or global ischemia models.1R 2R A similar delay of cell death rather than permanent neuroprotection was demonstrated several years ago for postischemic hypothermia.3R
The reader should also be aware that felbamate was not shown to protect from apoptosis, despite the title. No apoptotic indices, either morphological or biochemical, were measured before or after drug treatment. Reference is made to one study in gerbils in which those authors concluded that "the results suggest that delayed death of the CA1 pyramidal neurons after brief ischemia is not necrotic but apoptotic." This remains a controversial suggestion not only in gerbils but in other mouse and rat models. At the recent Princeton Conference on Cerebrovascular Disease held in Memphis, Tenn, in March 1996, no consensus was reached on whether ischemic cell death is apoptotic. Although classic apoptotic DNA fragmentation can be observed after an ischemic insult in all models including gerbils, the fact remains that in the vast majority of cases the classic morphology of apoptosis is not evident. A quote from one of the founders of the apoptosis field will illustrate the dilemma: "The need for ultrastructural confirmation of light microscopic identification of dying cells will be evident. Despite the difference between the processes of apoptosis and necrosis, the terms pyknosis and karyorrhexis can be legitimately used to describe the appearances in the light microscope of certain phases in the evolution of both."4R One wise participant at the Princeton Conference suggested that ischemic cell death should be studied in its own right and targets found for drug intervention. Such targets may turn out to be common to either a necrotic or apoptotic cell death pathway. In the long run the patient doesn't care how the brain cells die. It makes not a whit of difference to the efficacy of felbamate whether it prevents apoptosis, only that there is significant durable protection of neuronal function.
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1R. Valtysson J, Hillered L, Andine P, Hagberg H, Persson L. Neuropathological endpoints in experimental stroke pharmacology: the importance of both early and late evaluation. Acta Neurochir (Wien). 1994;129:58-63.[Medline] [Order article via Infotrieve]
2R. Nurse S, Corbett D. Neuroprotection following several days of mild drug-induced hypothermia. J Cereb Blood Flow Metab. In press.
3R. Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res. 1994;654:265-272.[Medline] [Order article via Infotrieve]
4R. Wyllie AH, Kerr JFR, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251-306.[Medline] [Order article via Infotrieve]
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