Micha³ K. Trojnar 1, Robert Ma³ek 1, Magdalena Chroœciñska 1, Stanis³aw Nowak 2, Barbara B³aszczyk 2, Stanis³aw J. Czuczwar 1,3,#

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1 Copyright 2002 by Institute of Pharmacology Polish Academy of Sciences Polish Journal of Pharmacology Pol. J. Pharmacol., 2002, 54, ISSN REVIEW NEUROPROTECTIVE EFFECTS OF ANTIEPILEPTIC DRUGS Micha³ K. Trojnar 1, Robert Ma³ek 1, Magdalena Chroœciñska 1, Stanis³aw Nowak 2, Barbara B³aszczyk 2, Stanis³aw J. Czuczwar 1,3,# Department of Pathophysiology, Medical University, Jaczewskiego 8, PL Lublin, Poland, Department of Neurology, Neuropsychiatric Care Unit, Grunwaldzka 47, PL Kielce, Poland,! Isotope Laboratory, Institute of Agricultural Medicine, Jaczewskiego 2, PL Lublin, Poland Neuroprotective effects of antiepileptic drugs. M.K. TROJNAR, R. MA- EK, M. CHROŒCIÑSKA, S. NOWAK, B. B ASZCZYK, S.J. CZUCZWAR. Pol. J. Pharmacol., 2002, 54, Experimental and clinical data indicate that epilepsy and seizures lead to neuronal cell loss and irreversible brain damage. This neurodegeneration results not only in the central nervous system dysfunction but may also be responsible for the decreased efficacy of some antiepileptic drugs (AEDs). The aim of this review was to assemble current literature data on neuroprotective properties of AEDs. The list of hypothetical neuroprotectants is long and consists of substances which act via different mechanisms. We focus on AEDs since this heterogeneous group of pharmaceuticals, as far as mechanisms of their action and mechanisms of neuronal death are concerned, should provide protection in addition to antiseizure effect itself. Most studies on neuroprotection are based on animal experimental models of neuronal degeneration. Electrically and pharmacologically evoked seizures as well as different models of ischemia are frequently used. Although our knowledge about properties of AEDs is still not complete and discrepancies occasionally occur, the group seems to be promising in terms of neuroprotection. Some of the drugs, though, turn out to be neutral or even have adverse effects on the central nervous system, especially on immature brain tissue (barbiturates and benzodiazepines). Unfortunatelly, we cannot fully extrapolate animal data to humans, therefore further well designed clinical trials are necessary to determine neuroprotective properties of AEDs in humans. However, there is a hope that AEDs will have a potential to serve as neuroprotectants not only in seizures, but perhaps, in other neurodegenerative conditions in humans as well. The novel AEDs (especially lamotrigine, tiagabine, and topiramate) seem particularly promising. Key words: neuroprotection, neurodegeneration, antiepileptic drugs, seizures, ischemia correspondence; czuczwar@galen.imw.lublin.pl

2 M.K. Trojnar, R. Ma³ek, M. Chroœciñska, S. Nowak, B. B³aszczyk, S.J. Czuczwar Abbreviations: AEDs antiepileptic drugs, BZDs benzodiazepines, CBZ carbamazepine, FBM felbamate, GABA -aminobutyric acid, GBP gabapentin, LTG lamotrigine, NMDA N-methyl-D-aspartate, NO nitric oxide, PhB phenobarbital, PHT phenytoin, TGB tiagabine, TPM topiramate, VGB vigabatrin, VPA valproate INTRODUCTION Research carried out in recent years has demonstrated that epilepsy and seizures are often associated with neuronal lesions and neuronal cell loss. That is why in current literature at least some forms of epilepsy (e.g. temporal lobe epilepsy) are frequently referred to as chronic, neurodegenerative and progressive [46]. Several experimental methods have been applied in order to assess effects of seizures on brain tissue in animals and humans. The experiments have proved that both prolonged and brief repeated seizures result in neuronal death. Certain changes have been reported in rats subjected to limbic status epilepticus after a convulsant dose of the muscarinic cholinergic agonist, pilocarpine hydrochloride [58]. Morphological analysis of the brains has revealed a widespread damage to the forebrain. The substantia nigra, olfactory cortex, amygdala, hippocampus, septum, temporal cortex and thalamus sustained significant morphological injury and cell loss. The most pronounced neurodegenerative changes occurred in pyramidal hippocampal cells in the CA1 and CA2 regions and the neocortex (layers II, III, V). Another model of limbic status epilepticus, where rats were subjected to continuous hippocampal stimulation, has shown that there is a definite link between the degree of cell destruction and the duration of seizure activity [20]. Cavasos and Sutula [9] conclude that the more frequent the seizures in kindled rats, the greater neuronal loss can be observed in limbic areas and somatosensory cortex. This would indicate that also brief repeated seizures produce neuronal destruction. Moreover, some data suggest that even a single seizure episode may cause brain damage [45]. Assessment of neuronal loss in human epilepsy is far more difficult. Yet, evidence of this process can be provided. Magnetic resonance imaging findings in patients with temporal lobe epilepsy point to a correlation between epilepsy duration and hippocampal volume decline [57]. Also histological examination of post-surgical samples from patients with temporal lobe epilepsy showed severe hippocampal changes, such as sclerosis, gliosis and pyramidal neuron loss [46]. In humans not surviving status epilepticus, a characteristic pattern of neuronal death has been observed. In patients who died within several hours from the onset of status epilepticus, only ischemic changes in the cerebellum and neocortex were found, whereas in those who died within several days, neurodegeneration in the neocortex, cerebellum and hippocampus ( CA3 and CA4 regions) was attested [11]. MECHANISMS OF NEURONAL DEATH It is believed that there are several different mechanisms and neurochemical modulators of the central nervous system damage. One of the essential mechanisms leading to neuronal cell death is glutamate-induced excitotoxity. It has been demonstrated that increased glutamate binding to postsynaptic receptors induces the opening of sodium and calcium channels. Ion entry is responsible for triggering a chain of biochemical changes leading to cell death. Both apoptosis and necrosis are considered to be involved in this process [59]. Several intracellular proteins, which respond to calcium overload, have been determined. Gelsolin leads to cytoskeletal degeneration, whereas nitric oxide (NO) synthase interferes with oxidative metabolism, resulting in accumulation of free radicals [2, 39]. The effect of excessive calcium entry into mitochondria is energy deprivation and failure of neuronal homeostasis [59]. Another possibility is apoptotic cell destruction through the activation of procaspases [39]. Additional factors contributing to neuronal cell damage may be: growth factor withdrawal, cytokines, toxins or protein accumulation [59]. The aforementioned and possibly some other mechanisms contribute to neuronal cell death not only in epilepsy but also in other neurodegenerative conditions. Hypoxia may not only be a factor conducive to brain damage during seizures or status epilepticus but it may itself lead to neuronal cell death. Animal experiments have shown that ischemic brain injury is biphasic and can be divided into two stages: early necrosis in the forebrain and more delayed apoptotic-like process in the thalamus, brainstem 558 Pol. J. Pharmacol., 2002, 54,

3 NEUROPROTECTION AND ANTIEPILEPTIC DRUGS and other non-forebrain regions [42]. It is also believed that hippocampal CA1, CA2 and CA3 regions are among the most vulnerable ones [6]. As the latter regions are affected over a certain period of time, they could potentially benefit from neuroprotective pharmacological agents. Middle cerebral artery occlusion model is currently one of the best means of assesing neuronal changes which result from brain ischemia. As epilepsy has been proved to cause neurodegeneration and progressive brain damage, neuroprotection seems to play a crucial role in the management of the disease. It has been suggested that anticonvulsant activity of antiepileptic drugs (AEDs) may require intact neuronal structures within certain areas of the brain and that neurodegeneration may decrease their efficacy. Czuczwar et al. [13, 14] have reported that intracerebroventricular injection of kainic acid in mice, which resulted in piramidal cell loss in the CA3 subfield of the hippocampus, significantly reduced the protective effect of diazepam and phenobarbital. Therefore, one may presume that the action of other drugs elevating -aminobutyric acid (GABA) levels in the central nervous system may be attenuated by seizuredependent brain damage. The list of hypothetical neuroprotectants is long and comprises substances with different mechanisms of action. It includes sodium and calcium blockers, glutamate inhibitors, NO inhibitors, antioxidants, apoptosis-related protease inhibitors, not to mention blood flow regulators or neurotrophic factors [39]. We have decided to focus on evidence of neuroprotective properties of AEDs and to check if they offer neuroprotection via mechanisms other than an antiseizure effect alone. AEDs are presumed to act on ion channels, GABAergic and glutamatergic systems or second messengers, hence, theoretically they are good candidates to stabilize neurons and protect them from insults [59]. NEUROPROTECTION AND ANTIEPILEPTIC DRUGS Conventional antiepileptic drugs Benzodiazepines (BZDs) BZDs are a group of antiepileptic drugs acting via GABA A receptor potentiation and concomitant opening of chloride channels [49]. Their neuroprotective properties are fairly well documented in current literature. BZDs have turned out to protect hippocampal neurons from degeneration after transient cerebral ischemia in rodents. Treatment with diazepam completely protected CA1b hippocampal pyramidal neurons in 94% of the animals which underwent occlusion of the carotid arteries, and partially protected pyramidal neurons in 6% of these animals [50]. Imidazenil, a partial BZD receptor agonist, has proved less effective than diazepam. Even postischemic diazepam treatment in a model of global ischemia in rats significantly reduced the CA1 neuron loss [25, 49]. Postischemic hypothermia may have enhanced the neuroprotective effect of diazepam. However, neuroprotection is not conditioned by hypothermia. Also clonazepam has proved to display neuroprotective action. Apart from offering inhibition of epileptic activity, it prevented CA1 neuronal loss after 10-minute bilateral carotid occlusion in Mongolian gerbils [32]. In a model of pilocarpineinduced brain damage, BZDs once again turned out to serve as neuroprotectants [58]. Nevertheless, quite opposite results have been obtained in the experiments carried out on immature rodents. Both diazepam and clonazepam dose-dependently triggered neuronal cell death in infant rat brains. Ultrastructural analysis has proved that the cell death was apoptotic [43]. Carbamazepine (CBZ) CBZ belongs to the group of classical anticonvulsants. It blocks sodium ion channels [15]. CBZ seems to be less efficacious in terms of neuroprotection than the novel anticonvulsants in experimentally-induced status epilepticus [11]. Lahtinen et al. [28] have found that administration of CBZ at typical anticonvulsive dose protects only partially against pyramidal cell damage (significant protection in the CA1 subfield, but not in the CA3c) in experimental status epilepticus. Moreover, the drug protected neither against the hilar somatostatin-immunoreactive neuron loss nor the spatial learning deficit. In another study, CBZ reduced N-methyl-D-aspartate (NMDA)-mediated brain injury (a 36% reduction) in an in vivo perinatal rat model [36]. It was, however, completely ineffective against 4-aminopyridine-induced hippocampal damage in rats [44]. Some data indicate that pretreatment with CBZ prevents a reduction of the activity of sodium-potassium-adenosine triphos- ISSN

4 M.K. Trojnar, R. Ma³ek, M. Chroœciñska, S. Nowak, B. B³aszczyk, S.J. Czuczwar phatase, a membrane-bound enzyme, in rat ischemic brain. This may beecome in useful during treatment of cerebral ischemia [40]. Interestingly, Mark et al. [33] have reported that CBZ may attenuate neurotoxic effects of amyloid- peptide (A ) and glutamate on the cultured rat hippocampal neurons. It indicates that the drug may potentially be advantageous in Alzheimer s disease. Toxicity against cerebellar neurons in vitro was only evident when CBZ was added at supratherapeutic concentrations [19]. Phenobarbital (PhB) Anticonvulsive properties of PhB are due to the potentiation of GABA A receptor-mediated effects and inhibition of glutamate activity. It is also believed that PhB blocks sodium ion channels [15]. We have found several studies in which both neuroprotective and neurodegenerative properties of the drug have been suggested. In the experiment carried out by Vizuete et al. [60], PhB exhibited protective effects against 1-methyl-4-phenylpyridinium ion (MPP+)-induced toxicity in rats. PhB turned out to block neuronal cell death also after exposure to methamphetamine and kainic acid [48, 56]. In the latter model, PhB reduced mossy fiber sprouting as well as neuronal damage in the dentate gyrus. However, no evidence of protection against cell loss in CA3 or other regions of the hippocampus have been observed [56]. Quite surprisingly, the study by Fishman et al. [17] demonstrates a 20 30% reduction in cerebellar Purkinje and granule cell count after exposure to PhB early in life. Preand postnatal exposure to PhB also results in profound histological changes of the cerebellar cells as assessed by transmission electron microscopy. The abnormalities include: mitochondrial degeneration, lamellar bodies distribution and myelin sheath degeneration. There are data which suggest that PhB-induced cell death in the infant brain is apoptotic [43]. Phenytoin (PHT) PHT reduces intracellular sodium influx during depolarization [15]. Neuroprotective action of PHT has been well documented in both in vitro and in vivo animal models. There are several studies which have revealed protective properties of PHT in the rat neocortical or hippocampal cultures after exposure to glutamate or in an in vitro model of ischemia [33, 47, 66]. According to Weber and Taylor [66], this protection refers especially to CA1 pyramidal cells and occurs even without blocking synaptic potentials. Also in a rabbit model of spinal cord ischemia in vivo, retrograde venous perfusion with PHT provided significant protection [18]. In another study of a global ischemia model, PHT proved to eliminate nearly all histological signs of hippocampal neuronal injury in rats [16]. In an in vitro model of ischemia (oxygen and glucose deprivation in the rat corticostriatal slices for 10 min), this AED was also effective [7]. Nevertheless, not all researchers agree that PHT acts as a neuroprotectant. Studies by Kochnar et al. [26] showed that the drug was not effective in reducing ischemic injury in a multiple cerebral embolic model in rabbits. Also, PHT did not protect against NMDA-induced neuronal injury in cortical culture [23]. When applied to developing neonatal mouse cerebellar cultures, it even turned out to induce degeneration. The degree of neurotoxicity correlated with the drug concentration. The study showed, however, that mature mouse cerebellar cells were resistant to chronic exposure to high concentrations of PHT [3]. Valproate (VPA) Antiepileptic properties of VPA are linked with the inhibition of sodium channels and possibly T-type calcium channels. VPA may also enhance GABAergic transmission [12, 15]. The neuroprotective action of VPA has been documented mainly in in vitro studies. Bruno et al. [5] have shown that VPA protects the culture of cerebellar neurons against glutamate-induced neurotoxicity. It comes as no surprise that it protects cultured neuronal cells against low-potassium-induced apoptosis as well [38]. In addition, VPA has shown its neuroprotective effects against amy - loid- peptide (A )- and glutamate-induced injury [33]. There is only one in vivo study on the role of VPA in hippocampal neurodegeneration caused by a convulsant, 4-aminopyridine. Surprisingly, VPA proved completely inactive in rats infused with this potassium channel blocker [44]. In the study carried out by Murakami and Furui [40], VPA turned out not to be efficacious in terms of neuroprotection in a rat ischemic model. When administered chronically, VPA causes some neurodegenerative alterations in the rat brains such as: disseminated nonspecific neuronal lesions and patchy nerve cell loss [55]. 560 Pol. J. Pharmacol., 2002, 54,

5 NEUROPROTECTION AND ANTIEPILEPTIC DRUGS Novel antiepileptic drugs Felbamate (FBM) FBM belongs to the group of novel AEDs. Its antiseizure effect is connected with several mechanisms: blockade of sodium channels (reduction of neurotransmitter release) and voltage-dependent (L-type) calcium channels (reduction of calcium influx), and potentiation of GABA-mediated events. FBM also acts on NMDA glutamate receptor, reducing glutamate-mediated excitation [15]. There are many studies which have tested the efficacy of FBM in either in vitro [63] or animal models of transient brain ischemia [53, 64, 65]. FBM proved to have neuroprotective properties when administered both before and after ischemia. This protection is more significant when the drug is given after the ischemic insult [53] and the window of opportunity for post hoc treatment is within 1 to 4 h [64]. Some results suggest that neuroprotection from hypoxia afforded by FBM is mediated by interaction at glycine receptor [35, 61]. Longo et al. [29] have indicated that FBM selectively blocks in vitro kainate-induced irreversible electrical changes in CA1 neurons but does not affect the disappearance of the CA1 electrical response induced by glutamate agonists, -amino-3-hydroxy-5-methyl-isoxazoleproprionate or NMDA. Another study has confirmed that FBM administered after bilateral carotid occlusion reduces neuronal death in CA1 but this effect is significant only when doses are higher than those given during typical anticonvulsive treatment [65]. In contrast, in a model of traumatic neuronal injury, significant protection of CA1 area has been proved at drug serum concentrations comparable with those measured during monotherapy of seizures [62]. Gabapentin (GBP) There are only limited data on the neuroprotective potential of GBP. The drug has been documented to increase the synthesis of GABA and to block voltage-dependent calcium currents through a specific subunit of voltage-dependent calcium channel [15]. GBP was found effective in an in vitro ischemia test [7] but data on its effects against convulsive agents or procedures are lacking. Lamotrigine (LTG) The antiepileptic effect of LTG is connected with the blockade of sodium and L-type calcium channels [15]. Several studies have demonstrated that LTG reduces hippocampal neuronal damage (particularly in CA1 neurons) in animal models of cardiac arrest-induced global cerebral ischemia [10, 51, 67]. Neuronal protection from transient ischemia offered by LTG was effective irrespective of whether it was administered before or after the insult. Furthermore, Crumrine et al. [10] have found that patients on LTG monotherapy for epilepsy have plasma concentrations very similar to those which proved to be neuroprotective in their study. Another interesting fact is that mild hypothermia associated with LTG treatment is more effective in neuroprotection than hypothermia or LTG alone [27]. It may suggest that the combination of LTG with mild hypothermia could increase its neuroprotective properties. The drug has also been proved effective in an in vitro model of ischemia [7]. In a kainate-induced model of status epilepticus in rats, LTG has reduced hippocampal neuronal loss even at doses not protecting from seizures. The authors conclude that seizure prevention and neuroprotection might not be tightly coupled [31]. Tiagabine (TGB) TGB is a novel GABAergic agonist. It elevates brain GABA levels via inhibition of its neuronal and glial uptake (inhibition of GABA uptake transporter, GAT1) [12]. Current data suggest that the drug may protect not only from seizures, but also from neurodegeneration and neuronal cell death. Halonen et al. [21] have tested TGB in a perforant pathway stimulation model of status epilepticus. Even though two days of TGB treatment did not change GABA levels in the cerebrospinal fluid, it prevented the appearance of seizures during stimulation, reduced CA1 and CA3c pyramidal cell loss as well as the spatial memory impairment in animals. Yang et al. [69] have found that postischemic treatment with TGB improves neurobehavioral outcome and reduces brain infarction volume in focal ischemia model in rats. The neuroprotective effect of TGB is dose-dependent. Another research in an ischemic model has proved that TGB inhibits the development of hippocampal degeneration in the CA1 py- ISSN

6 M.K. Trojnar, R. Ma³ek, M. Chroœciñska, S. Nowak, B. B³aszczyk, S.J. Czuczwar ramidal cell layer. However, these authors conclude that postischemic hypothermia is partially responsible for the neuroprotective action of the drug [24]. The aforementioned results may suggest that enhancement of GABAergic neurotransmission may protect vulnerable neurons from death. Surprisingly, Lukasiuk and Pitkanen [30] have shown that the increased GABA level may be toxic for a subpopulation of developing hippocampal neurons in vitro. Also, an in vitro study by comet assay has revealed that tiagabine treatment does cause DNA damage in cortical rat astrocytes. As DNA fragmentation occured only at very high concentrations, it is quite likely that at the usual recommended doses TGB treatment is safe [8]. This, however, raises the question of safety of therapies aimed at increasing GABA levels in the immature brain. Topiramate (TPM) Effect of TPM depends on multiple mechanisms of action. The drug inhibits voltage- and receptorgated calcium channels, modulates voltage-dependent chloride channels and blocks excitatory neurotransmission. TPM also enhances GABA-mediated inhibition [12]. There are several studies striving to find out whether TPM has neuroprotective properties. Hanaya et al. [22] report that TPM dose-dependently reduces the severity of kindled seizures and delays their occurrence. The administration of TPM after experimental status epilepticus in adult male Wistar rats attenuates seizure-induced hippocampal neuronal injury (particularly in CA1 area and at higher doses also in CA3 area) [41]. In a rat model of focal ischemia, TPM has also proved to be neuroprotective. The treatment with TPM 2 h after the right middle cerebral artery embolization provided a dose- and use-dependent protection of neurons [70]. In a model of focal cerebral ischemia, Yang et al. [68] tried to test whether the addition of TPM augments the efficacy of low doses of urokinase. The data from their study suggest that the combination of low dose of urokinase with a neuroprotective agent like TPM may benefit ischemic stroke treatment by improving neurologic recovery, reducing the risk of cerebral hemorrhages and attenuating the infarct volume of the brain. Moreover, the administration of TPM in a rat model of global ischemia reduced the degree of motor impairment, seizure severity and hippocampal neuronal injury [16]. All these studies indicate that in animal models of global and focal ischemia, TPM significantly reduces neuronal damage, thus protecting against cerebral ischemia. Vigabatrin (VGB) Ambiguous data have been obtained with respect to VGB ( -vinyl-gaba), another AED with similar mechanisms of action on the central nervous system. VGB inhibits GABA transaminase, thus elevating GABA levels in the brain tissue [54]. Several studies suggest neuroprotective properties of VGB [1, 45]. In the lithium-pilocarpine model of temporal lobe epilepsy, applied by Andre et al. [1], VGB protected against neuronal damage. Their analysis showed that treatment with the drug induced almost total neuroprotection in CA3, efficient protection in CA1 and moderate one in the hilus of the dentate gyrus. On the other hand, damage observed in the entorhinal cortex was slightly worsened by the treatment. The drug was also found effective in preventing the effects of transient global ischemia in gerbils [52]. Some data suggest adverse effects of VGB on the brain. In experiments on adult rats, high-dose (200 mg/kg/day) chronic VGB administration was associated with myelin vacuolation. However, when immature rats were subjected to the treatment, even at doses comparable to those used clinically (15 50 mg/kg/day), more profound changes occurred [54]. The histological findings were as follows: decreased myelin staining in the external capsule, axonal degeneration and glial cell death in the white matter as well as reactive astrogliosis in the frontal cortex. Researchers suggest that direct toxicity of VGB or an indirect effect mediated through elevated GABA levels could constitute the mechanism of damage. Undoubtedly, further detailed studies are necessary to determine the effect of the drug on the brain, especially on the immature and developing one. It is vital in terms of VGB treatment safety in childhood epilepsy. All experimental data on neuroprotection are shown in Table 1. CLINICAL CONSIDERATIONS It is of interest that among 20 patients with temporal lobe epilepsy, examined by Mathern et al. 562 Pol. J. Pharmacol., 2002, 54,

7 NEUROPROTECTION AND ANTIEPILEPTIC DRUGS Table 1. Neuroprotective properties of antiepileptic drugs in experimental models of ischemia and seizures in animals Antiepileptic drugs Neuroprotection in ischemia Neuroprotection against convulsants or convulsive procedures Induction of neurodegeneration Benzodiazepines Carbamazepine + +/ + Felbamate + + ND Gabapentin + ND ND Lamotrigine + + ND Phenobarbital ND + + Phenytoin +/ +/ + Tiagabine Topiramate + + ND Valproate +/ + Vigabatrin (+) action present, ( ) no activity detected, (+/ ) variable data, (ND) not determined. See text for further explanations [34], 90% had an initial precipitating injury, followed by mesial temporal sclerosis. The authors conclude that hippocampal cell loss and mossy fiber sprouting seem to be progressive events after the initial injury [34]. According to Meldrum [37], pharmacological neuroprotection may be divided into two main strategies primary neuroprotection and secondary one. The first strategy aims to reduce the initial insult by inhibiting seizure activity and related sodium and calcium ion entry into the neurons. Some AEDs, especially these acting on ionic fluxes and inhibiting glutamate-mediated events, appear to be good candidates for primary neuroprotection. Possibly, secondary neuroprotection might be provided by agents suppressing the neurodenegenerative cascade. Among such agents, free radical scavengers, NO synthase or caspase inhibitors bear the significant clinical potential. Actually, caspases are involved in the apoptopic brain damage and their inhibitors have been documented to possess neuroprotective potential in experimental animals [4]. It is quite clear that any clinical trials of neuroprotective agents in adults with chronic epilepsy encounter considerable practical problems but severe childhood epilepsies offer a good clinical opportunity for intensive testing of existing drugs and novel compounds in this regard [37]. FINAL CONCLUSIONS Even though our knowledge about neuroprotection by AEDs is still not complete, in this review we have tried to assemble experimental data which support the thesis that anticonvulsants do perform neuroprotective action. This neuroprotective effect of AEDs is of great importance in the management of a chronic condition like epilepsy. Apart from its influence on brain function and concomitant progressive mental depletion in epilepsy patients, neurodegeneration may also be responsible for decreased long-term efficacy of AEDs. Experiments have shown that anti-seizure effect of diazepam and phenobarbital are dependent on the intact function of the hippocampus [13, 14]. This, of course, may also be true with reference to other anticonvulsants, especially those acting on the GABA A receptor complex. The experimental data concerning neuroprotection afforded by AEDs do not always coincide, e.g. in one study FLB proved to have anticonvulsant and neuroprotective properties at clinically effective doses, whereas in another, to obtain a neuroprotective effect, higher doses than those used in clinical therapy were required. Moreover, some of the drugs turned out to have reverse effect on brain tissue, especially on immature one (results given in Table 1). This of course necessitates further research. Another problem with neuroprotection by AEDs is the fact that we cannot fully extrapolate animal data to human epilepsy and seizures. Only well designed clinical trials could provide definite evidence for neuroprotective properties of AEDs in humans. So far, there have been very few convincing data. There is, however, strong hope and belief that antiepileptics will turn out to serve as neuroprotective agents not only in seizures but also in other neurodegenerative conditions. The novel groups of AEDs seem to hold promise. REFERENCES 1. Andre V., Ferrandon A., Marescaux C., Nehlig A.: Vigabatrin protects against hippocampal damage but is not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy. Epilepsy Res., 2001, 47, Bittigau P., Ikonomidou C.: Glutamate in neurologic diseases. J. Child Neurol., 1997, 12, ISSN

8 M.K. Trojnar, R. Ma³ek, M. Chroœciñska, S. Nowak, B. B³aszczyk, S.J. Czuczwar 3. Blank N.K., Nishimura R.N., Seil F.: Phenytoin neurotoxicity in developing mouse cerebellum in tissue culture. J. Neurol. Sci., 1982, 55, Braun J.S., Tuomanen E.I., Cleveland, J.L.: Neuroprotection by caspase inhibitors. Expert Opin. Investig. Drugs, 1999, 8, Bruno V., Sortino M.A., Scapagnini U., Nicoletti F., Canonico P.L.: Antidegenerative effects of Mg (2+) -valproate in cultured cerebellar neurons. Funct. Neurol., 1995, 10, Butler T.L., Kassed C.A., Sanberg P.R., Willing A.E., Pennypacker K.R.: Neurodegeneration in the rat hippocampus and striatum after middle cerebral artery occlusion. Brain Res., 2002, 929, Calabresi P., Picconi B., Saulle E., Centonze D., Hainsworth A.H., Bernardi G.: Is pharmacological neuroprotection dependent on reduced glutamate release? Stroke, 2000, 31, Cardile V., Palumbo M., Renis M., Pavone A., Maci T., Perciavalle V.: Tiagabine treatment and DNA damage in rat astrocytes: an in vitro study by comet assay. Neurosci. Lett., 2001, 306, Cavasos J.M., Sutula T.P.: Progressive neuronal loss induced by kindling: a possible mechanism for mossy fiber synaptic reorganization and hippocampal sclerosis. Brain Res., 1990, 527, Crumrine R.C., Bergstrand K., Cooper A.T., Faison W.L., Cooper B.R.: Lamotrigine protects hippocampal CA1 neurons from ischemic damage after cardiac arrest. Stroke, 1997, 28, Czuczwar S.J.: Pathological mechanisms of status epilepticus (Polish). Medipress, 1988, Suppl. 5, Czuczwar S.J., Patsalos P.N.: The new generation of GABA enhancers. CNS Drugs, 2001, 15, Czuczwar S.J., Turski L., Kleinrok Z.: Anticonvulsant action of phenobarbital, diazepam, carbamazepine and diphenylhydantoin in the electroshock test in mice after lesion of hippocampal pyramidal cells with intracerebroventricular kainic acid. Epilepsia, 1982, 23, Czuczwar S.J., Turski L., Turski W., Kleinrok Z.: Effects of some antiepileptic drugs in pentetrazoleinduced convulsions in mice lesioned with kainic acid. Epilepsia, 1981,22, Deckers C.L., Czuczwar S.J., Hekster Y.A., Keyser A., Kubova H., Meinardi H., Patsalos P.N., Renier W.O., Van Rijn C.M.: Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia, 2000, 41, Edmonds H.L. Jr., Jiang Y.D., Zhang P.Y., Shank R.: Topiramate as a neuroprotectant in a rat model of global ischemia-induced neurodegeneration. Life Sci., 2001, 69, Fishman R.H., Ornoy A., Yanai J.: Ultrastructural evidence of long lasting cerebellar degeneration after early exposure to phenobarbital in mice. Exp. Neurol., 1983, 79, Gangemi J.J., Kern J.A., Ross S.D., Shockey K.S., Kran J.L., Tribble C.G.: Retrograde perfusion with a sodium channel antagonist provides ischemic spinal cord protection. Ann. Thorac. Surg., 2000, 69, Gao X.M., Margolis R.L., Leeds P., Hough C., Post R.M., Chuang D.M.: Carbamazepine induction of apoptosis in cultured cerebellar neurons: effects of N-methyl-D-aspartate, aurintricarboxylic acid and cycloheximide. Brain Res., 1995, 703, Gruenthal M.: Electroencephalographic and histologic characteristics of a model of limbic status epilepticus permitting direct control over seizure duration. Epilepsy Res., 1998, 29, Halonen T., Nissinen J., Jansen J.A., Pitkanen A.: Tiagabine prevents seizures, neuronal damage and memory impairment in experimental status epilepticus. Eur. J. Pharmacol., 1996, 299, Hanaya R., Sasa M., Ujihara H., Ishihara K., Serikawa T., Iida K., Akimitsu T., Arita K., Kurisu K.: Suppression by topiramate of epileptiform burst discharges in hippocampal CA3 neurons of spontaneously epileptic rat in vitro. Brain Res., 1998, 789, Hartley D.M., Choi D.W.: Delayed rescue of N-methyl-D-aspartate receptor-mediated neuronal injury in cortical culture. J. Pharmacol. Exp. Ther., 1989, 250, Inglefield J.R., Perry J.M., Schwartz R.D.: Postischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus. Hippocampus, 1995, 5, Johansen F.F., Diemer N.H.: Enhancement of GABA neurotransmission after cerebral ischemia in the rat reduces loss of hippocampal CA1 pyramidal cells. Acta Neurol. Scand., 1991, 84, Kochhar A., Zivin J.A., Mazzarella V.: Pharmacologic studies of the neuroprotective actions of a glutamate antagonist in ischemia. J. Neurotrauma, 1991, 8, Koinig H., Morimoto Y., Zornow M.H.: The combination of lamotrigine and mild hypothermia prevents ischemia-induced increase in hippocampal glutamate. J Neurosurg. Anesthesiol., 2001, 13, Lahtinen H., Ylinen A., Lukkarinen U., Sirvio J., Miettinen R., Riekkinen P. Sr.: Failure of carabamazepine to prevent behavioural and histopathologhical sequels of experimentally induced status epilepticus. Eur. J. Pharmacol., 1996, 297, Longo R., Domenici M.R., Scotti de Carolis A., Sagratella S.: Felbamate selectively blocks in vitro hippocampal kainate-induced irreversible electrical changes. Life Sci., 1995, 56, Lukasiuk K., Pitkanen A.: GABA(A)-mediated toxicity of hippocampal neurons in vitro. J. Neurochem., 2000, 74, Maj R., Fariello R.G., Ukmar G., Varasi M., Pevarello P., McArthur R.A., Salvati P.: PNU E protects against kainate-induced status epilepticus and hippocampal lesions in the rat. Eur. J. Pharmacol., 1998, 359, Marciani M.G., Santone G., Sancesario G., Massa R., Stanzione P., Bernardi G.: Protective effect of clona- 564 Pol. J. Pharmacol., 2002, 54,

9 NEUROPROTECTION AND ANTIEPILEPTIC DRUGS zepam on ischemic brain damage induced by 10- minute bilateral carotid occlusion in Mongolian gerbils. Funct. Neurol., 1993, 8, Mark R.J., Ashford J.W., Goodman Y., Mattson M.P.: Anticonvulsants attenuate amyloid beta-peptide neurotoxicity, Ca2+ deregulation and cytoskeletal pathology. Neurobiol. Aging, 1995, 16, Mathern G.W., Pretorius J.K., Babb T.L.: Influence of the type of initial precipitating injury and at what age it occurrs on course and outcome in patients with temporal lobe seizures. J. Neurosurg., 1995, 82, McCabe R.T., Wasterlain C.G., Kucharczyk N., Sofia R.D., Vogel J.R.: Evidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors. J. Pharmacol. Exp. Ther., 1993, 264, McDonald J.W., Johnston M.V.: Pharmacology of N- methyl-d-aspartate-induced brain injury in an in vivo perinatal rat model. Synapse, 1990, 6, Meldrum B.S.: Implications for neuroprotective treatments. Prog. Brain Res., 2002, 135, Mora A., Gonzalez-Polo R.A., Fuentes J.M., Soler G., Centeno F.: Different mechanisms of protection against apoptosis by valproate and Li +. Eur. J. Biochem., 1999, 266, Moshe S.L., Decker J.F.: Neuroprotection and epilepsy. World Wide Web: pages/editorial/resourcecenters/public/epilepsy. 40. Murakami A., Furui T.: Effects of the conventional anticonvulsants: phenytoin, carbamazepine and valproic acid on sodium-potassium-adenosine triphosphatase in acute ischemic brain. Neurosurgery, 1994, 34, Niebauer M., Gruenthal M.: Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res.,1999, 837, Northington F.J., Ferriero D.M., Martin L.J.: Neurodegeneration in the thalamus following neonatal hypoxia-ischemia is programmed cell death. Dev. Neurosci., 2001, 23, Olney J.W., Farber N.B., Wozniak D.F., Jevtovic- Todorovic V., Ikonomidou C.: Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain. Environ. Health Perspect., 2000, 108, Pena F., Tapia R.: Seizures and neurodegeneration induced by 4-aminopyridine in rat hippocampus in vivo: role of glutamate- and GABA-mediated neurotransmission and of ion channels. Neuroscience, 2000, 101, Pitkanen A.: Treatment with antiepileptic drugs: possible neuroprotective effects. Neurology, 1996, 47, Privitera M.D.: The progressive nature of epilepsy as a consideration in patient management decisions. World Wide Web: editorial/ resourcecenters/public/epilepsy. 47. Probert A.W., Borosky S., Marcoux F.W., Taylor C.P.: Sodium channel modulators prevent oxygen and glucose deprivation injury and glutamate release in rat neocortical cultures. Neuropharmacology, 1997, 36, Schmued L.C., Bowyer J.F.: Methamphetamine exposure can produce neuronal degeneration in mouse hippocampal remnants. Brain Res.,1997, 759, Schwartz R.D.,Yu X., Katzman M.R., Hayden-Hixson D.M., Perry J.M.: Diazepam, given postischemia, protects selectively vulnerable neurons in the rat hippocampus and striatum. J. Neurosci., 1995, 15, Schwartz-Bloom R.D., Miller K.A., Evenson D.A., Crain B.J., Nadler J.V.: Benzodiazepines protect hippocampal neurons from degeneration after transient cerebral ischemia: an ultrastructural study. Neuroscience, 2000, 98, Shuaib A., Mahmood R.H., Wishart T., Kanthan R., Murabit M.A., 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, Shuaib A., Murabit M.A., Kanthan R., Howlett W., Wishart T.: The neuroprotective effects of gammavinyl GABA in transient global ischemia: a morphological study with early and delayed evaluations. Neurosci. Lett., 1996, 204, Shuaib A., Waqaar T., Ijaz M.S., Kanthan R., Wishart T., Howlett W.: Neuroprotection with felbamate: a 7- and 28-day study in transient forebrain ischemia in gerbils. Brain Res., 1996, 727, Sidhu R.S., Del Bigio M.R., Tuor U.I., Seshia S.S.: Low-dose vigabatrin (gamma-vinyl GABA)-induced damage in the immature rat brain. Exp. Neurol.,1997, 144, Sobaniec-Lotowska M., Sobaniec W.: Effect of chronic administration of sodium valproate on the morphology of the rat brain hemispheres. Neuropatol. Pol., 1993, 31, Sutula T., Cavazos J., Golarai G.: Alteration of longlasting structural and functional effects of kainic acid in the hippocampus by brief treatment with phenobarbital. J. Neurosci., 1992, 12, Theodore W.H., Bhatia S., Hatta J., Fazilat S., DeCarli C., Bookheimer S.Y., Gaillard W.D.: Hippocampal atrophy, epilepsy duration and febrile seizures in patients with partial seizures. Neurology, 1999, 52, Turski L., Cavalheiro E.A., Sieklucka-Dziuba M., Ikonomidou-Turski C., Czuczwar S.J., Turski W.A.: Seizures produced by pilocarpine: neuropathological sequelae and activity of glutamate decarboxylase in the rat forebrain. Brain Res., 1986, 398, Vajda F.J.E.: Neuroprotection and neurodegenerative disease. J. Clin. Neurosci., 2002, 9, Vizuete M.L., Merino M., Cano J., Machado A.: In vivo protection of striatal dopaminergic system against 1-methyl-4-phenylpyridinium neurotoxicity by phenobarbital. J. Neurosci. Res., 1997, 49, ISSN

10 M.K. Trojnar, R. Ma³ek, M. Chroœciñska, S. Nowak, B. B³aszczyk, S.J. Czuczwar 61. Wallis R.A., Panizzon K.L.: Glycine reversal of felbamate hypoxic protection. NeuroReport, 1993, 4, Wallis R.A., Panizzon K.L.: Felbamate neuroprotection against CA1 traumatic neuronal injury. Eur. J. Pharmacol., 1995, 294, Wallis R.A., Panizzon K.L., Fairchild M.D., Wasterlain C.G.: Protective effects of felbamate against hypoxia in the rat hippocampal slice. Stroke, 1992, 23, Wasterlain C.G., Adams L.M., Schwartz P.H., Hattori H., Sofia R.D., Wichmann J.K.: Posthypoxic treatment with felbamate is neuroprotective in a rat model of hypoxia-ischemia. Neurology,1993, 43, Wasterlain C.G., Adams L.M., Wichmann J.K., Sofia R.D.: Felbamate protects CA1 neurons from apoptosis in a gerbil model of global ischemia. Stroke, 1996, 27, Weber M.L., Taylor C.P.: Damage from oxygen and glucose deprivation in hippocampal slices is prevented by tetrodotoxin, lidocaine and phenytoin without blockade of action potentials. Brain Res., 1994, 664, Wiard R.P., Dickerson M.C., Beek O., Norton R., Cooper B.R.: Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia. Stroke, 1995, 26, Yang Y., Li Q., Shuaib A.: Enhanced neuroprotection and reduced hemorrhagic incidence in focal cerebral ischemia of rat by low dose combination therapy of urokinase and topiramate. Neuropharmacology, 2000, 9, Yang Y., Li Q., Wang C.X., Jeerakathil T., Shuaib A.: Dose-dependent neuroprotection with tiagabine in a focal cerebral ischemia model in rat. NeuroReport, 2000, 11, Yang Y., Shuaib A., Li Q., Siddiqui M.M.: Neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization. Brain Res.,1998, 804, Received: September 17, 2002; in revised form: October 21, Pol. J. Pharmacol., 2002, 54,