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Proconvulsant effect of aminophylline on cortical epileptic afterdischarges varies during ontogeny
Epilepsy Research 39 (2000) 183 – 190 www.elsevier.com/locate/epilepsyres
Proconvulsant effect of aminophylline on cortical epileptic afterdischarges varies during ontogeny Kla´ra Berna´sˇkova´ a,b, Pavel Maresˇ a,* a b
Institute of Physiology, Academy of Sciences of the Czech Republic, Vı´den˜ska´ 1083, CZ-142 20 Prague 4, Czech Republic Department of Physiology, Pathophysiology and Clinical Physiology, 3rd Medical School, Charles Uni6ersity, Ke Karlo6u 4, CZ 120 00 Prague 2, Czech Republic Received 2 July 1999; received in revised form 8 October 1999; accepted 28 November 1999
Abstract Effect of aminophylline on epileptic afterdischarges (ADs) induced repeatedly by rhythmic electrical stimulation of sensorimotor cortical area was studied in rat pups 12, 18 and 25 days old. The proconvulsant effect of aminophylline (50 and/or 100 mg/kg i.p.) was more expressed in 12- and 18-day-old rats than in the oldest group. In 12-day-old rat pups there was an enormous increase of transition of the spike-and-wave type of ADs into the second, limbic type, a situation observed only exceptionally under control conditions. A prolongation of ADs was related to this transition (limbic ADs are always longer than spike-and-wave ones). Eighteen-day-old rats exhibit this transition less frequently but a marked prolongation of spike-and-wave ADs was recorded in a part of these animals forming a pattern of status lasting some tens of minutes. Aminophylline led only to a transient prolongation of spike-and-wave ADs in the oldest group. The transition into the limbic type of ADs was seen in this age group only exceptionally what is in contrast to age-matched controls in which this transition is common. The effect of aminophylline on cortical ADs which is most marked in the youngest group changes qualitatively during postnatal development. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Cerebral cortex; Epileptic afterdischarges; Theophylline; Development; Rat
1. Introduction Aminophylline, a mixture of theophylline and ethylenediamine (85:15%), is a bronchodilatating and antiasthmatic compound widely used in patients with acute respiratory insufficiency * Corresponding author. Tel.: + 420-2-4752549; fax: + 4202-4752488. E-mail address: [email protected] (P. Maresˇ)
(Zwillich et al., 1975). Focal and generalized seizures occurring during status asthmaticus have often been attributed to hypoxia associated with such attacks. However Zwillich et al. (1975) found, that the occurrence of seizures in neurologically normal patients was observed only in those with serum theophylline levels above 25 mg/ml. Patients with neurological impairment exhibited repetitive generalized seizures at lower levels of theophylline. The suspicion arised that the
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seizures may be due to the direct effect of theophylline on the brain. Therefore many laboratories began to study convulsant effect of aminophylline (Schwartz and Scott, 1974; Yarnell and Chu, 1975; Zwillich et al., 1975). The other compound of the mixture, ethylendiamine, failed to induce any epileptiform activity (Chu, 1981; Ramzan and Levy, 1986). Aminophylline-induced seizures in rodents were found to be rather resistant to anticonvulsant treatment, phenobarbital being the most effective agent (Stone and Javid, 1980; Czuczwar et al., 1987). The convulsant action of theophylline is due to an antagonism at A1 adenosine receptors (Dragunow, 1990). In addition to the action on adenosine receptors theophylline depressed plasma pyridoxal 5%-phosphate (PLP) levels in asthmatics. This decrease might influence gamma-aminobutyric acid (GABA) synthesis and thereby contribute to seizures (Glenn et al., 1995). Adenosine is an endogenous purine nucleoside, which functions as a physiological regulator in a variety of vertebrate tissues. Its inhibitory modulatory role in the central nervous system (Williams, 1987) is mediated through specific cellsurface receptors, presently classified into four categories: A1–A4 (Linden, 1991; Zhou et al., 1992; Abbracchio, 1993). Adenosine which is produced and released in the brain exerts characteristic inhibitory modulation of neuronal firing rates and synaptic transmission (Phillis and Wu, 1981; Snyder, 1985; Chin, 1989; Janusz and Berman, 1993). These effects are mainly due to activation of presynaptic receptors leading to an inhibition of the release of neurotransmitters; the postsynaptic action is less expressed (Proctor and Dunwiddie, 1987). However adenosine exerts also neuroprotective effects: it is released from nerve and glial cells in larger amount after ischemia. Removal of a possible action of endogenous adenosine by receptor antagonists such as theophylline was found to enhance postischemic nerve cell death (Schubert and Kreutzberg, 1993). Adenosine and its analogues have potent anticonvulsant effects on various seizure models including kindling (Cain, 1981; Dragunow, 1986) and genetically seizure-prone mice (Turski et al., 1989), whereas adenosine antagonists, such as
xanthines have been reported to be proconvulsant in adult (Morgan et al., 1989) as well as in young rats (Trommer et al., 1989). Effects of aminophylline in rat pups undergoing amygdala kindling are more dramatic and occur at far lower doses than those reported in adults (Trommer et al., 1989). It was also found, that rat pups needed lower doses of aminophylline to elicit seizures than adult animals and severity of aminophylline induced seizures sharply decreased between postnatal days 18 and 25 (Maresˇ et al., 1994). These data may indicate changes in the action of aminophylline (and thus in the role of adenosine) in brain during development. Cortical epileptic ADs elicited by rhythmic electrical stimulation of the sensorimotor cortex in freely moving rats represent a model allowing to study four different phenomena: (1) movements accompanying stimulation, i.e. direct activation of the motor system; (2) ADs characterized by spikeand-wave EEG rhythm, probably generated in the thalamocortical system; (3) clonic seizures of head and forelimb muscles accompanying ADs, indicating a spread of epileptic activity into the motor system; (4) transition of spike-and-wave ADs into another type characteristic for limbic stimulation, i.e. a spread of epileptic activity into the limbic structures (Kubova´ et al., 1996; Koryntova´ et al., 1997). Cortical ADs may be regularly elicited in rat pups since early developmental stages (postnatal day 12 — Makal et al., 1993) and therefore we decided to use them for a study of interaction of aminophylline with different mechanisms involved in generation of the four above mentioned phenomena at different levels of brain maturation.
2. Methods Three age groups of male albino rats of Wistar strain were used: 12, 18 and 25 days old. These age groups were chosen on basis of our previous data on cortical epileptic ADs (Makal et al., 1993; Pola´sˇek et al., 1996) as well as on convulsant action of aminophylline (Maresˇ et al., 1994). The day of birth was counted as zero and all litters were reduced to eight pups. The animals were housed under standard conditions (249 1°C, 12/
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12 h light/dark cycle). The experiments were performed according to the guidelines of the Animal Protection Law of the Czech Republic and were approved by the Ethical Commission of the Institute of Physiology of the Academy of Sciences of the Czech Republic. Surgical implantation of the electrodes was done under light ether anesthesia. A razor blade was used to make the incisions of the skull for the electrodes. Five flat silver electrodes were placed epidurally — two over the right sensorimotor cortical area for stimulation and the remaining three over the right visual and left sensorimotor and visual cortical regions for recording. The sixth silver electrode put into the nasal bone served as an indifferent one. The electrodes were then fixed with fast curing dental acrylic (Duracrol® Dental, Prague). After a resting period (at least 1 h) an orientation neurological examination (righting, placing and suckling reflexes) was done, the animals were fed with a 5% solution of sucrose and the experiment started.
Fig. 1. EEG recordings of cortical afterdischarges (ADs) from two 18-day-old rats. Upper part: spike-and-wave AD accompanied by moderate clonic seizures of head and left forelimb. Lower part: mixed AD with a behavioral automatism (intense sniffing). Individual leads from top to bottom: LF — left frontal (sensorimotor); RO — right occipital (visual); LO — left occipital (visual) area, always in a reference connection. Time mark 1 s, amplitude callibration 0.5 mV.
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Fifteen second-series of 1-ms biphasic rectangular pulses with 8 Hz-frequency were generated by a constant current stimulator of our own construction. Current intensity necessary for elicitation of an AD was established individually in each animal. According to our previous data (Makal et al., 1993; Maresˇ et al., 1996; Kubova´ et al., 1997) stimulation always started with an intensity of 2.5 mA. If AD was not elicited, stimulation was repeated more than 10 min later and the intensity was imcreased by 0.5 mA. This procedure might be repeated up to the intensity of 4 mA. If even this intensity did not induce an AD of at least 1-s duration, the animals were discarded (it happened in only two pups). Average intensities used in control groups (2.79 0.1, 2.79 0.1 and 2.6 9 0.1 mA in 12-, 18- and 25-day-old rats, respectively) did not significantly differ what is in agreement with our original developmental study (Makal et al., 1993) but in variance with the more recent study (Maresˇ et al., 1996). Intensities used in aminophylline treated animals and age-matched controls did not differ in any age group. Ten minutes after the end of the first AD the animals were injected either with aminophylline (Sigma, St. Louis, MO; 50 or 100 mg/kg i.p., freshly dissolved in saline, so that 1 ml of solution contained either 50 or 100 mg of the drug) or with corresponding volume of physiological saline (1 ml/kg i.p.). Stimulation was repeated five times after the injection with 20-min intervals between the end of the preceeding AD and beginning of the next stimulation. Each age and dose group consisted of 8–11 rat pups, animals from the same litter were randomly divided into the control and both dose groups. Type and duration of ADs as well as behavior during the stimulation and AD were evaluated. EEG pattern served for classification of the two types of ADs (Fig. 1). Spike-and-wave type of AD was characterized by regular rhythm of epileptic graphoelements with a clear predominance of activity in sensorimotor area. The end of these ADs was always abrupt and synchronous in all three cortical leads registered. On the other hand, the mixed type of AD (transition into the limbic AD) exhibited higher amplitude in occipital regions and pathological activity did not stop at the same
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time in various cortical areas. Duration of ADs was measured from the end of stimulation to the last epileptic graphoelement in any cortical lead. The intensity of movements and clonic seizures was scored according to the modified five point scale of Racine (Racine, 1972; Kubova´ et al., 1996). Incidence of ADs was evaluated by means of Fisher’s exact test, all other parameters by One Way ANOVA on Ranks with subsequent pairwise comparison using Dunn’s test (SigmaStat® Jandel). Level of statistical significance was set at 5%. 3. Results Electrical stimulation of sensorimotor cortex was always accompanied by rhythmic movements of head and forelimbs synchronous with individual stimuli. Rearing could be observed in some of the 18- and 25-day-old rats, falling was uncommon. An AD elicited by the first stimulation was formed by the spike-and-wave rhythm (Fig. 1) in nearly all animals. These ADs were accompanied by clonic seizures of head and/or forelimb muscles. Their EEG pattern could be classified as spike-and-wave rhythm in 18- and 25-day-old rats. Twelve-day-old rat pups were unable to generate spike-and-wave rhythm; instead of it rhythmic sharp delta waves were recorded in this age group. Motor correlate of these sharp waves was formed by clonic seizures identical to those in older animals. Only five rats (four 12- and one 25-day-old) exhibited mixed instead of pure spikeand-wave ADs in response to the first stimulation: irregular sharp waves sometimes combined with fast low-amplitude spikes appeared after an initial section of spike-and-wave rhythm. Behavior changed from motor seizures to epileptic automatisms (e.g. intense orienting in a familiar cage). Under control conditions the incidence of the second, limbic type of ADs (Fig. 1) exhibited a general tendency to an increase with repeated stimulations but the level of statistical significance was not reached in any age group. There was also a tendency to prolongation of ADs with repeated stimulations in all age groups but again without statistical significance.
Aminophylline changed the type of AD in 12day-old rat pups (Fig. 2). Starting from the third stimulation nearly all ADs exhibited a transition from spike-and-wave pattern to the second, limbic type. Similar, but less expressed effect was seen in 18-day-old animals. The increase in the incidence of the mixed type of ADs was not always significant. In contrast to the younger groups, majority of the 25-day-old rats exhibited spike-and-wave type of AD even after aminophylline administration. Only two stimulations after the higher dose of aminophylline led to significantly increased incidence of the mixed type of AD. No relation to the dose of aminophylline could be observed. An increase of the incidence of mixed ADs exhibited a dependence on age: this effect was significantly more frequent in the third to the sixth ADs in 12-day-old rat pups than in corresponding ADs in 25-day-old rats. Aminophylline significantly increased the AD duration in all experimental groups in comparison with saline treated animals. The prolongation of ADs was most markedly expressed in 18-day-old rats, less in 12-day-old ones and only slightly (but still significantly) in 25-day-old rat pups (Fig. 3). Relation to the dose of aminophylline used was not observed in 12-day-old animals. On the contrary, the first postdrug AD was significantly longer after the dose of 50 mg/kg than after the higher dose. In 18-day-old rats the AD prolongation was clearly dose dependent; the difference between the two doses was significant in the fourth and fifth ADs. Aminophylline induced in 18-day-old rats also longlasting (tens of minutes) seizures which might be classified as status epilepticus. They appeared in three out of 11 rat pups after the dose of 50 mg/kg, and in six out of 10 animals after the higher dose. The ADs in 25-dayold rats were not so markedly prolonged like ADs in both younger groups and, in addition, this effect was only transient; durations of the fifth and sixth ADs did never significantly differ from those in the control animals. Intensity of movements directly elicited by electrical stimuli was not significantly influenced by either dose of aminophylline in any age group. As concerns severity of seizures, most animals in all age and dose groups reached only point
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Fig. 2. Incidence of mixed ADs induced by the first to the sixth stimulation in 12-, 18- and 25-day-old rats (from top to bottom). Abscissa: time in relation to the administration of aminophylline and/or solvent (marked by an arrow), ordinates: percentage of animals exhibiting mixed seizures. White columns: control group, stripped columns: animals injected with aminophylline — see inset in the upper right corner. Asterisks denote significant difference in comparison with the appropriate first AD, circles in comparison with the corresponding stimulation in 12-day-old animals.
three in the five-point scale, i.e. clonic seizures of head and forelimb muscles synchronous with sharp elements in the EEG. More severe seizures were seen only exceptionally. The intensity of seizures was never higher than the intensity of movements directly elicited by electrical stimuli. Aminophylline did not increase the severity of seizures in any age group. Motor correlates of longlasting seizures did not differ from those of regular ADs, i.e. point three was common. Transition into the limbic type of AD meant a change from point three to point one. Not all spike-and-wave ADs were accompanied by myoclonic head and/or forelimb seizures.
On the contrary, epileptic automatisms characteristic for the other, limbic type of ADs sometimes appeared. It was common under control conditions in 12- and 25-day-old rats — nearly 60% of ADs exhibited this electroclinical dissociation. Aminophylline in either dose abolished this dissociation in 12-day-old pups — only typical mixed ADs were present whereas the same effect was observed only after the higher dose of aminophylline in 25-day-old rats. The 50-mg/kg dose decreased the incidence of this electroclinical dissociation. Eighteenday-old rats never exhibited this dissociated pattern.
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4. Discussion Proconvulsant action of the two doses of aminophylline used was apparent in two measures — in an increased incidence of mixed ADs and in a prolongation of ADs. An increased incidence of transition into the second, limbic type of ADs was surprisingly observed mainly in the youngest group. This finding is in contrast to our developmental data on threshold intensities necessary for elicitation of the two types of cortical ADs: whereas spike-and-wave ADs may be induced in 12-day-old rat pups by lower current intensities than in 25-day-old ones, the limbic type of ADs needed the highest current intensities in 12-dayold rats (Maresˇ et al., 1996). A possible reason for this contradiction might be found in an earlier maturation of adenosinergic system in limbic
Fig. 3. Duration of ADs (mean + SEM) in 12-, 18- and 25-day-old rats (from top to bottom). Details as in Fig. 2, only ordinates: duration of ADs in seconds.
structures. It is supported by data on relatively early development of adenosine A1 receptors in limbic system when compared with motor or sensory structures (Daval et al., 1991). Similar but less expressed increase was found in 18-day-old rats whereas the transition into the limbic seizures appeared only in a minority of 25-day-old rats. Prolongation of the ADs was marked in 12and especially in 18-day-old rats. It might be due either by facilitation of a seizure generator, facilitation of transition into the limbic type of ADs described above or by suppression of mechanisms arresting seizures. Generation of the spike-andwave rhythm is a thalamocortical event (Gloor, 1984; Avanzini et al., 1992). There are no data supporting a direct influence on seizure generator in 12-day-old rat pups, because a marked increase of adenosine A1 receptors in cortex and thalamus took place only after postnatal day 15 (Daval et al., 1991). The other two possibilities are more probable. The limbic type of ADs was found to be always longer than spike-and-wave type of ADs (Kubova´ et al., 1996; Maresˇ et al., 1996) and postictal depression, which might be taken as an expression of overlasting action of mechanisms arresting seizures, involves an adenosinergic component (caffeine was found to shorten substantially the duration of postictal depression after cortical ADs — Maresˇ et al., — submitted). In addition, adenosine-mediated mechanisms were shown to be involved in termination of the discharge activity (Handforth and Treiman, 1994). Compromised mechanisms arresting seizures are the most probable reason for the effect seen in 25-day-old rats, i.e. the transient prolongation of spike-and-wave ADs. A possible direct influence of aminophylline on thalamocortical seizure generator has to be taken into account in this age group. Short duration of this effect might be due to faster metabolism of theophylline in this age group but data on pharmacokinetics of this drug in immature rats are not at disposal. Aminophylline when administered systemically to immature rats was found to elicit both minimal, clonic and major, generalized tonic clonic motor seizures in rats but the convulsant doses were much higher that those used in the present experiment (Maresˇ et al., 1994). The 50- and
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100-mg/kg doses of aminophylline were too small to elicit major seizures even in the combination with electrical stimulation of the cerebral cortex. The transition to generalized tonic-clonic seizures was found in a kindling model (‘hyperkindling’) in adult rats (Pinel and Rovner, 1978) and also in rat pups where generalized tonic-clonic seizures appeared after substantially lower number of amygdala stimulations (Haas et al., 1990). The failure of aminophylline to facilitate the transition from minimal clonic seizures generated in the basal forebrain to generalized tonic clonic seizures generated in the brainstem (Browning and Nelson, 1986) might signify that the action of aminophylline on brainstem structures is not strong. It is in contrast to other epileptogenic agents like homocysteine — our unpublished data demonstrated generalized tonic-clonic seizures after combination of cortical stimulations with a subconvulsant dose of homocysteine in rat pups. Aminophylline also did not change the intensity of movements directly associated with stimulation of the sensorimotor cortex and/or of clonic seizures accompanying spike-and-wave ADs. All these data suggest that motor system is not markedly influenced by a suppression of adenosinergic inhibitory modulation. Adenosine, an inhibitory modulator, has been implicated as an endogenous anticonvulsant agent in numerous models of seizures. Our data on aminophylline, an antagonist of A1 and A2 adenosine receptors, demonstrated that the role of adenosine markedly differs not only according to the systems involved in epileptogenesis but also according to the level of brain maturation.
Acknowledgements This study was supported by grants No. 2209-3 and 3510-3 of the Grant Agency of the Ministry of Health of the Czech Republic.
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Proconvulsant effect of aminophylline on cortical epileptic afterdischarges varies during ontogeny Kla´ra Berna´sˇkova´ a,b, Pavel Maresˇ a,* a b
Institute of Physiology, Academy of Sciences of the Czech Republic, Vı´den˜ska´ 1083, CZ-142 20 Prague 4, Czech Republic Department of Physiology, Pathophysiology and Clinical Physiology, 3rd Medical School, Charles Uni6ersity, Ke Karlo6u 4, CZ 120 00 Prague 2, Czech Republic Received 2 July 1999; received in revised form 8 October 1999; accepted 28 November 1999
Abstract Effect of aminophylline on epileptic afterdischarges (ADs) induced repeatedly by rhythmic electrical stimulation of sensorimotor cortical area was studied in rat pups 12, 18 and 25 days old. The proconvulsant effect of aminophylline (50 and/or 100 mg/kg i.p.) was more expressed in 12- and 18-day-old rats than in the oldest group. In 12-day-old rat pups there was an enormous increase of transition of the spike-and-wave type of ADs into the second, limbic type, a situation observed only exceptionally under control conditions. A prolongation of ADs was related to this transition (limbic ADs are always longer than spike-and-wave ones). Eighteen-day-old rats exhibit this transition less frequently but a marked prolongation of spike-and-wave ADs was recorded in a part of these animals forming a pattern of status lasting some tens of minutes. Aminophylline led only to a transient prolongation of spike-and-wave ADs in the oldest group. The transition into the limbic type of ADs was seen in this age group only exceptionally what is in contrast to age-matched controls in which this transition is common. The effect of aminophylline on cortical ADs which is most marked in the youngest group changes qualitatively during postnatal development. © 2000 Elsevier Science B.V. All rights reserved. Keywords: Cerebral cortex; Epileptic afterdischarges; Theophylline; Development; Rat
1. Introduction Aminophylline, a mixture of theophylline and ethylenediamine (85:15%), is a bronchodilatating and antiasthmatic compound widely used in patients with acute respiratory insufficiency * Corresponding author. Tel.: + 420-2-4752549; fax: + 4202-4752488. E-mail address: [email protected] (P. Maresˇ)
(Zwillich et al., 1975). Focal and generalized seizures occurring during status asthmaticus have often been attributed to hypoxia associated with such attacks. However Zwillich et al. (1975) found, that the occurrence of seizures in neurologically normal patients was observed only in those with serum theophylline levels above 25 mg/ml. Patients with neurological impairment exhibited repetitive generalized seizures at lower levels of theophylline. The suspicion arised that the
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seizures may be due to the direct effect of theophylline on the brain. Therefore many laboratories began to study convulsant effect of aminophylline (Schwartz and Scott, 1974; Yarnell and Chu, 1975; Zwillich et al., 1975). The other compound of the mixture, ethylendiamine, failed to induce any epileptiform activity (Chu, 1981; Ramzan and Levy, 1986). Aminophylline-induced seizures in rodents were found to be rather resistant to anticonvulsant treatment, phenobarbital being the most effective agent (Stone and Javid, 1980; Czuczwar et al., 1987). The convulsant action of theophylline is due to an antagonism at A1 adenosine receptors (Dragunow, 1990). In addition to the action on adenosine receptors theophylline depressed plasma pyridoxal 5%-phosphate (PLP) levels in asthmatics. This decrease might influence gamma-aminobutyric acid (GABA) synthesis and thereby contribute to seizures (Glenn et al., 1995). Adenosine is an endogenous purine nucleoside, which functions as a physiological regulator in a variety of vertebrate tissues. Its inhibitory modulatory role in the central nervous system (Williams, 1987) is mediated through specific cellsurface receptors, presently classified into four categories: A1–A4 (Linden, 1991; Zhou et al., 1992; Abbracchio, 1993). Adenosine which is produced and released in the brain exerts characteristic inhibitory modulation of neuronal firing rates and synaptic transmission (Phillis and Wu, 1981; Snyder, 1985; Chin, 1989; Janusz and Berman, 1993). These effects are mainly due to activation of presynaptic receptors leading to an inhibition of the release of neurotransmitters; the postsynaptic action is less expressed (Proctor and Dunwiddie, 1987). However adenosine exerts also neuroprotective effects: it is released from nerve and glial cells in larger amount after ischemia. Removal of a possible action of endogenous adenosine by receptor antagonists such as theophylline was found to enhance postischemic nerve cell death (Schubert and Kreutzberg, 1993). Adenosine and its analogues have potent anticonvulsant effects on various seizure models including kindling (Cain, 1981; Dragunow, 1986) and genetically seizure-prone mice (Turski et al., 1989), whereas adenosine antagonists, such as
xanthines have been reported to be proconvulsant in adult (Morgan et al., 1989) as well as in young rats (Trommer et al., 1989). Effects of aminophylline in rat pups undergoing amygdala kindling are more dramatic and occur at far lower doses than those reported in adults (Trommer et al., 1989). It was also found, that rat pups needed lower doses of aminophylline to elicit seizures than adult animals and severity of aminophylline induced seizures sharply decreased between postnatal days 18 and 25 (Maresˇ et al., 1994). These data may indicate changes in the action of aminophylline (and thus in the role of adenosine) in brain during development. Cortical epileptic ADs elicited by rhythmic electrical stimulation of the sensorimotor cortex in freely moving rats represent a model allowing to study four different phenomena: (1) movements accompanying stimulation, i.e. direct activation of the motor system; (2) ADs characterized by spikeand-wave EEG rhythm, probably generated in the thalamocortical system; (3) clonic seizures of head and forelimb muscles accompanying ADs, indicating a spread of epileptic activity into the motor system; (4) transition of spike-and-wave ADs into another type characteristic for limbic stimulation, i.e. a spread of epileptic activity into the limbic structures (Kubova´ et al., 1996; Koryntova´ et al., 1997). Cortical ADs may be regularly elicited in rat pups since early developmental stages (postnatal day 12 — Makal et al., 1993) and therefore we decided to use them for a study of interaction of aminophylline with different mechanisms involved in generation of the four above mentioned phenomena at different levels of brain maturation.
2. Methods Three age groups of male albino rats of Wistar strain were used: 12, 18 and 25 days old. These age groups were chosen on basis of our previous data on cortical epileptic ADs (Makal et al., 1993; Pola´sˇek et al., 1996) as well as on convulsant action of aminophylline (Maresˇ et al., 1994). The day of birth was counted as zero and all litters were reduced to eight pups. The animals were housed under standard conditions (249 1°C, 12/
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12 h light/dark cycle). The experiments were performed according to the guidelines of the Animal Protection Law of the Czech Republic and were approved by the Ethical Commission of the Institute of Physiology of the Academy of Sciences of the Czech Republic. Surgical implantation of the electrodes was done under light ether anesthesia. A razor blade was used to make the incisions of the skull for the electrodes. Five flat silver electrodes were placed epidurally — two over the right sensorimotor cortical area for stimulation and the remaining three over the right visual and left sensorimotor and visual cortical regions for recording. The sixth silver electrode put into the nasal bone served as an indifferent one. The electrodes were then fixed with fast curing dental acrylic (Duracrol® Dental, Prague). After a resting period (at least 1 h) an orientation neurological examination (righting, placing and suckling reflexes) was done, the animals were fed with a 5% solution of sucrose and the experiment started.
Fig. 1. EEG recordings of cortical afterdischarges (ADs) from two 18-day-old rats. Upper part: spike-and-wave AD accompanied by moderate clonic seizures of head and left forelimb. Lower part: mixed AD with a behavioral automatism (intense sniffing). Individual leads from top to bottom: LF — left frontal (sensorimotor); RO — right occipital (visual); LO — left occipital (visual) area, always in a reference connection. Time mark 1 s, amplitude callibration 0.5 mV.
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Fifteen second-series of 1-ms biphasic rectangular pulses with 8 Hz-frequency were generated by a constant current stimulator of our own construction. Current intensity necessary for elicitation of an AD was established individually in each animal. According to our previous data (Makal et al., 1993; Maresˇ et al., 1996; Kubova´ et al., 1997) stimulation always started with an intensity of 2.5 mA. If AD was not elicited, stimulation was repeated more than 10 min later and the intensity was imcreased by 0.5 mA. This procedure might be repeated up to the intensity of 4 mA. If even this intensity did not induce an AD of at least 1-s duration, the animals were discarded (it happened in only two pups). Average intensities used in control groups (2.79 0.1, 2.79 0.1 and 2.6 9 0.1 mA in 12-, 18- and 25-day-old rats, respectively) did not significantly differ what is in agreement with our original developmental study (Makal et al., 1993) but in variance with the more recent study (Maresˇ et al., 1996). Intensities used in aminophylline treated animals and age-matched controls did not differ in any age group. Ten minutes after the end of the first AD the animals were injected either with aminophylline (Sigma, St. Louis, MO; 50 or 100 mg/kg i.p., freshly dissolved in saline, so that 1 ml of solution contained either 50 or 100 mg of the drug) or with corresponding volume of physiological saline (1 ml/kg i.p.). Stimulation was repeated five times after the injection with 20-min intervals between the end of the preceeding AD and beginning of the next stimulation. Each age and dose group consisted of 8–11 rat pups, animals from the same litter were randomly divided into the control and both dose groups. Type and duration of ADs as well as behavior during the stimulation and AD were evaluated. EEG pattern served for classification of the two types of ADs (Fig. 1). Spike-and-wave type of AD was characterized by regular rhythm of epileptic graphoelements with a clear predominance of activity in sensorimotor area. The end of these ADs was always abrupt and synchronous in all three cortical leads registered. On the other hand, the mixed type of AD (transition into the limbic AD) exhibited higher amplitude in occipital regions and pathological activity did not stop at the same
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time in various cortical areas. Duration of ADs was measured from the end of stimulation to the last epileptic graphoelement in any cortical lead. The intensity of movements and clonic seizures was scored according to the modified five point scale of Racine (Racine, 1972; Kubova´ et al., 1996). Incidence of ADs was evaluated by means of Fisher’s exact test, all other parameters by One Way ANOVA on Ranks with subsequent pairwise comparison using Dunn’s test (SigmaStat® Jandel). Level of statistical significance was set at 5%. 3. Results Electrical stimulation of sensorimotor cortex was always accompanied by rhythmic movements of head and forelimbs synchronous with individual stimuli. Rearing could be observed in some of the 18- and 25-day-old rats, falling was uncommon. An AD elicited by the first stimulation was formed by the spike-and-wave rhythm (Fig. 1) in nearly all animals. These ADs were accompanied by clonic seizures of head and/or forelimb muscles. Their EEG pattern could be classified as spike-and-wave rhythm in 18- and 25-day-old rats. Twelve-day-old rat pups were unable to generate spike-and-wave rhythm; instead of it rhythmic sharp delta waves were recorded in this age group. Motor correlate of these sharp waves was formed by clonic seizures identical to those in older animals. Only five rats (four 12- and one 25-day-old) exhibited mixed instead of pure spikeand-wave ADs in response to the first stimulation: irregular sharp waves sometimes combined with fast low-amplitude spikes appeared after an initial section of spike-and-wave rhythm. Behavior changed from motor seizures to epileptic automatisms (e.g. intense orienting in a familiar cage). Under control conditions the incidence of the second, limbic type of ADs (Fig. 1) exhibited a general tendency to an increase with repeated stimulations but the level of statistical significance was not reached in any age group. There was also a tendency to prolongation of ADs with repeated stimulations in all age groups but again without statistical significance.
Aminophylline changed the type of AD in 12day-old rat pups (Fig. 2). Starting from the third stimulation nearly all ADs exhibited a transition from spike-and-wave pattern to the second, limbic type. Similar, but less expressed effect was seen in 18-day-old animals. The increase in the incidence of the mixed type of ADs was not always significant. In contrast to the younger groups, majority of the 25-day-old rats exhibited spike-and-wave type of AD even after aminophylline administration. Only two stimulations after the higher dose of aminophylline led to significantly increased incidence of the mixed type of AD. No relation to the dose of aminophylline could be observed. An increase of the incidence of mixed ADs exhibited a dependence on age: this effect was significantly more frequent in the third to the sixth ADs in 12-day-old rat pups than in corresponding ADs in 25-day-old rats. Aminophylline significantly increased the AD duration in all experimental groups in comparison with saline treated animals. The prolongation of ADs was most markedly expressed in 18-day-old rats, less in 12-day-old ones and only slightly (but still significantly) in 25-day-old rat pups (Fig. 3). Relation to the dose of aminophylline used was not observed in 12-day-old animals. On the contrary, the first postdrug AD was significantly longer after the dose of 50 mg/kg than after the higher dose. In 18-day-old rats the AD prolongation was clearly dose dependent; the difference between the two doses was significant in the fourth and fifth ADs. Aminophylline induced in 18-day-old rats also longlasting (tens of minutes) seizures which might be classified as status epilepticus. They appeared in three out of 11 rat pups after the dose of 50 mg/kg, and in six out of 10 animals after the higher dose. The ADs in 25-dayold rats were not so markedly prolonged like ADs in both younger groups and, in addition, this effect was only transient; durations of the fifth and sixth ADs did never significantly differ from those in the control animals. Intensity of movements directly elicited by electrical stimuli was not significantly influenced by either dose of aminophylline in any age group. As concerns severity of seizures, most animals in all age and dose groups reached only point
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Fig. 2. Incidence of mixed ADs induced by the first to the sixth stimulation in 12-, 18- and 25-day-old rats (from top to bottom). Abscissa: time in relation to the administration of aminophylline and/or solvent (marked by an arrow), ordinates: percentage of animals exhibiting mixed seizures. White columns: control group, stripped columns: animals injected with aminophylline — see inset in the upper right corner. Asterisks denote significant difference in comparison with the appropriate first AD, circles in comparison with the corresponding stimulation in 12-day-old animals.
three in the five-point scale, i.e. clonic seizures of head and forelimb muscles synchronous with sharp elements in the EEG. More severe seizures were seen only exceptionally. The intensity of seizures was never higher than the intensity of movements directly elicited by electrical stimuli. Aminophylline did not increase the severity of seizures in any age group. Motor correlates of longlasting seizures did not differ from those of regular ADs, i.e. point three was common. Transition into the limbic type of AD meant a change from point three to point one. Not all spike-and-wave ADs were accompanied by myoclonic head and/or forelimb seizures.
On the contrary, epileptic automatisms characteristic for the other, limbic type of ADs sometimes appeared. It was common under control conditions in 12- and 25-day-old rats — nearly 60% of ADs exhibited this electroclinical dissociation. Aminophylline in either dose abolished this dissociation in 12-day-old pups — only typical mixed ADs were present whereas the same effect was observed only after the higher dose of aminophylline in 25-day-old rats. The 50-mg/kg dose decreased the incidence of this electroclinical dissociation. Eighteenday-old rats never exhibited this dissociated pattern.
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4. Discussion Proconvulsant action of the two doses of aminophylline used was apparent in two measures — in an increased incidence of mixed ADs and in a prolongation of ADs. An increased incidence of transition into the second, limbic type of ADs was surprisingly observed mainly in the youngest group. This finding is in contrast to our developmental data on threshold intensities necessary for elicitation of the two types of cortical ADs: whereas spike-and-wave ADs may be induced in 12-day-old rat pups by lower current intensities than in 25-day-old ones, the limbic type of ADs needed the highest current intensities in 12-dayold rats (Maresˇ et al., 1996). A possible reason for this contradiction might be found in an earlier maturation of adenosinergic system in limbic
Fig. 3. Duration of ADs (mean + SEM) in 12-, 18- and 25-day-old rats (from top to bottom). Details as in Fig. 2, only ordinates: duration of ADs in seconds.
structures. It is supported by data on relatively early development of adenosine A1 receptors in limbic system when compared with motor or sensory structures (Daval et al., 1991). Similar but less expressed increase was found in 18-day-old rats whereas the transition into the limbic seizures appeared only in a minority of 25-day-old rats. Prolongation of the ADs was marked in 12and especially in 18-day-old rats. It might be due either by facilitation of a seizure generator, facilitation of transition into the limbic type of ADs described above or by suppression of mechanisms arresting seizures. Generation of the spike-andwave rhythm is a thalamocortical event (Gloor, 1984; Avanzini et al., 1992). There are no data supporting a direct influence on seizure generator in 12-day-old rat pups, because a marked increase of adenosine A1 receptors in cortex and thalamus took place only after postnatal day 15 (Daval et al., 1991). The other two possibilities are more probable. The limbic type of ADs was found to be always longer than spike-and-wave type of ADs (Kubova´ et al., 1996; Maresˇ et al., 1996) and postictal depression, which might be taken as an expression of overlasting action of mechanisms arresting seizures, involves an adenosinergic component (caffeine was found to shorten substantially the duration of postictal depression after cortical ADs — Maresˇ et al., — submitted). In addition, adenosine-mediated mechanisms were shown to be involved in termination of the discharge activity (Handforth and Treiman, 1994). Compromised mechanisms arresting seizures are the most probable reason for the effect seen in 25-day-old rats, i.e. the transient prolongation of spike-and-wave ADs. A possible direct influence of aminophylline on thalamocortical seizure generator has to be taken into account in this age group. Short duration of this effect might be due to faster metabolism of theophylline in this age group but data on pharmacokinetics of this drug in immature rats are not at disposal. Aminophylline when administered systemically to immature rats was found to elicit both minimal, clonic and major, generalized tonic clonic motor seizures in rats but the convulsant doses were much higher that those used in the present experiment (Maresˇ et al., 1994). The 50- and
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100-mg/kg doses of aminophylline were too small to elicit major seizures even in the combination with electrical stimulation of the cerebral cortex. The transition to generalized tonic-clonic seizures was found in a kindling model (‘hyperkindling’) in adult rats (Pinel and Rovner, 1978) and also in rat pups where generalized tonic-clonic seizures appeared after substantially lower number of amygdala stimulations (Haas et al., 1990). The failure of aminophylline to facilitate the transition from minimal clonic seizures generated in the basal forebrain to generalized tonic clonic seizures generated in the brainstem (Browning and Nelson, 1986) might signify that the action of aminophylline on brainstem structures is not strong. It is in contrast to other epileptogenic agents like homocysteine — our unpublished data demonstrated generalized tonic-clonic seizures after combination of cortical stimulations with a subconvulsant dose of homocysteine in rat pups. Aminophylline also did not change the intensity of movements directly associated with stimulation of the sensorimotor cortex and/or of clonic seizures accompanying spike-and-wave ADs. All these data suggest that motor system is not markedly influenced by a suppression of adenosinergic inhibitory modulation. Adenosine, an inhibitory modulator, has been implicated as an endogenous anticonvulsant agent in numerous models of seizures. Our data on aminophylline, an antagonist of A1 and A2 adenosine receptors, demonstrated that the role of adenosine markedly differs not only according to the systems involved in epileptogenesis but also according to the level of brain maturation.
Acknowledgements This study was supported by grants No. 2209-3 and 3510-3 of the Grant Agency of the Ministry of Health of the Czech Republic.
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