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Keywords:

  • Epilepsy;
  • Kindling;
  • Learning;
  • Sleep;
  • Pentylenetetrazole;
  • Piracetam;
  • MK-801;
  • Rat

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary: Purpose: The aim of the study was to define sleep disturbances in pentylenetetrazole (PTZ)-kindled rats and to explore the effects of the nootropic drug piracetam (Pir; 100 mg/kg) and the noncompetitive N-methyl-d-aspartate (NMDA)-antagonist MK-801 (0.3 mg/kg), which normalized learning performance in PTZ-kindled rats, on altered sleep parameters.

Methods: This is the first report showing a significant reduction in paradoxical sleep (PS) as a consequence of PTZ kindling. A correlation analysis revealed a significant correlation between seizure severity and PS deficit.

Results: Pir did not interfere with seizure severity, and the substance did not ameliorate the PS deficit. However, the substance disconnected the correlation between seizure severity and PS deficit. MK-801, which reduced the severity of kindled seizures, counteracted the PS deficit efficaciously.

Conclusions: The results suggest that seizure severity and alterations in sleep architecture are two factors in the comprehensive network underlying learning impairments associated with epilepsy. Considering the results obtained in the experiments with Pir, reduction of seizure severity does not guarantee the reduction of impairments in the domain of learning.

A body of evidence suggests that epilepsy can result in cognitive impairments leading to lowered educational and occupational levels of achievement. It was suggested that a plethora of multiple factors such as seizure type, seizure severity and frequency, seizure duration, and age at seizure onset underlie cognitive impairments associated with epilepsy (Lesser et al., 1986; Dodrill, 1992; Kalviainen et al., 1992; Devinsky, 1995; Aldenkamp et al., 1996; Vuilleumier et al., 1996; Aldenkamp et al., 2001; Samson 2002; Duncan and Thompson, 2003; Helmstaedter et al., 2003; Nolan et al., 2003; 2004; Dodrill, 2004; Sonmez et al., 2004).

The mechanism underlying these impairments is an object of debate and controversy. It was shown that sleep affects epileptic activity and vice versa. In epilepsy patients, altered sleep–wake cycles and an increased number of stage shifts were found. Moreover, quantitative aspects of different sleep stages were reported to be changed (Autret et al., 1997; Bazil and Walczak, 1997; Bazil, 2000; Bazil et al., 2000; Gigli and Valente, 2000; Janz, 2000; Bazil, 2003; 2005). Evidence indicates that sleep plays a role in the processes of learning and memory (Gais and Born, 2004; Paller and Voss, 2004; Maquet et al., 2005; Stickgold, 2005; Stickgold and Walker, 2005). However, alternative views exist (Vertes and Eastman, 2000; Vertes and Siegel, 2005). Discrete stages of sleep appear to be either permissive or obligatory for specific steps in memory formation (Drosopoulos et al., 2005; McNamara et al., 2005; Walker, 2005). Consequently, sleep disturbances accompanying epilepsy might be one factor contributing to cognitive deficits as found in epilepsy patients.

The kindling model is the most widely used model for studies on epileptogenic processes; epilepsy-related behavioral, neurophysiological, neurochemical, and neurohistopathological changes; and finally on drug targets by which epilepsy can be prevented or modified. Evidence suggests that different kindling protocols result in different behavioral outcomes (e.g., anxiety, learning impairments). Kindling refers to a process in which periodic application of initially subeffective chemical or electrical stimuli induces progressive intensification of evoked electroencephalographic and behavioral seizures. It was shown that electrical kindling (Lopes da Silva et al., 1986; Beldhuis et al., 1992; Becker et al., 1997a; Hannesson et al., 2001) and chemical kindling (Voigt and Morgenstern, 1990; Becker et al. 1992; 1995; Pohle et al., 1997; Rössler et al., 2000; Nagaraja et al., 2004; Mortazavi et al., 2005) worsened learning performance of animals that had acquired the kindling syndrome in a variety of learning models. Moreover, electrical kindling in rats (Stone and Gold, 1988; Cammisuli et al., 1997; Raol and Meti, 1998) and cats (Hiyoshi and Wada, 1990; Calvo and Fernandez-Mas, 1991; 1994; Gigli and Gotman, 1992) was found to modify sleep patterns. Previously, the noncompetitive glutamate antagonist MK-801 was shown to exert anticonvulsive effects and to counteract kindling-induced learning deficits (Grecksch et al., 1994), whereas the nootropic drug piracetam was ineffective in counteracting kindled seizures but effective in ameliorating kindling-induced learning deficits (Pohle et al., 1997). The substance showed protective effects (injection during kindling development) as well as restorative efficacy (injection after kindling completion before each shuttle-box session). Moreover, the substance was found to be effective in counteracting neuronal cell loss in distinct hippocampal structures (Pohle et al., 1997). In control animals, both substances did not change learning performance. To the best of our knowledge, the relation between sleep pattern and learning performance in pentylenetetrazole (PTZ)-kindled animals was not studied yet. The present study addresses the investigation of sleep pattern in rats before and after completion of kindling as well as effects of MK-801 and piracetam, which were administered in the process of kindling induction.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Ethical approval was sought according to the requirements of the National Act on the Use of Experimental Animals (Germany) and EC guidelines.

Animals

Experiments were carried out with male Wistar rats [Shoe: Wist(Shoe), DIMED Schönwalde GmbH Schönwalde, Germany] aged 7 weeks at surgery. The animals were kept under controlled laboratory conditions (light regime of 12 h light/12 h dark, light on at 06:00 a.m.; temperature, 20 ± 2°C; air humidity, 55–60%). They had free access to commercial rat pellets (Altromin 1326) and tap water. The rats were housed in groups of five per cage (Macrolon IV).

For comparison with previously published data (Pohle et al., 1997), the same experimental protocol was used.

Surgery

Under deep pentobarbital (Synopharm, Barsbüttel, Germany) anesthesia (40 mg/kg intraperitoneally), all animals were permanently implanted with cortical electroencephalogram (EEG) and neck-muscle electromyogram (EMG) electrodes (stainless steel) for sleep recording. The electrodes were connected to a socket, and the entire assembly was cemented (Paladur; Heraeus Kulzer, Hanau, Germany) to the calvarium.

Sleep recording

In all experiments, the sleep–waking pattern was recorded during 8-h periods on consecutive days (08:00 am–04:00 p.m.). During the 1-week postoperative recovery period, the animals were habituated to the recording conditions. For the following 3 days, the baseline was recorded. Twenty-four hours after induction of acute PTZ seizures or 24 h after completion of kindling when the animals were 12 weeks old, further 3-day recordings were taken as described earlier to assess treatment-dependent alterations in sleep pattern. In this period, the animals did not receive any further injections.

EEG and EMG, recorded by a Nihon-Kohden polygraph, were evaluated visually by using standard criteria (Wetzel and Matthies, 1986; Wetzel et al., 1994; 2003). Thus each 8-h record was scored as waking (W), slow-wave sleep (SWS), or paradoxical sleep (PS) according to 30-s epochs (Fig. 1), and the following parameters were calculated: SWS latency; PS latency; 8-h percentage amounts (i.e., percentage of total recording time) of W, SWS, PS, TS (total sleep = SWS + PS), and PS/TS; number (n) and duration (d) of W, SWS, and PS episodes. From the data obtained on 3 consecutive days, means and standard errors of the means were calculated from both the pre- and postkindling periods. No significant differences in sleep parameters were found between the single-recording days. For that reason, the data were pooled.

image

Figure 1. Typical EEG and EMG recordings for waking (W), paradoxical sleep (PS), and slow-wave sleep (SWS) in the rat.

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Seizure induction

The experiments described later were performed from 08:00 to 10:00 a.m.

Acute seizures

To study the effects of a single generalized seizure, the animals were intraperitoneally (ip) dosed with 45.0 mg/kg body weight PTZ (Karl Roth GmbH, Karlsruhe, Germany). Control animals received the solvent isotonic saline solution (sal). Injection volume was always 10 ml/kg body weight.

Kindling

To investigate the effects of chronic seizures, the animals were kindled. At the beginning of kindling, the animals were aged 8 weeks. Kindling is considered to be a clinically relevant model of human epilepsy (McNamara, 1986; Schmutz, 1987; Vataev and Oganesian, 1993). Kindling was induced by repeated injections of PTZ. For kindling, a dose of 37.5 mg/kg body weight PTZ (ED16 related to clonic seizures established in a separate group of animals) was injected ip once every 48 h. Immediately after each injection, the convulsive behavior was observed for 20 min. The resultant seizures were classified according to a modified Racine scale as follows (Becker et al., 1995; Becker and Grecksch, 1995).

Stage 0: no response

Stage 1: ear and facial twitching

Stage 2: myoclonic jerks without rearing

Stage 3: myoclonic jerks, rearing

Stage 4: turning over into side position, bilateral clonic–tonic seizures

Stage 5: turning over into back position, generalized clonic and tonic seizures.

In total, rats received 13 kindling injections and were considered to be kindled after reaching at least three consecutive stage 4 or 5 seizures. Control animals received the same number of sal injections at a corresponding time schedule.

Substance effects

For the study of pharmacologic modifications of kindling-induced alterations in sleep pattern, piracetam (Pir; Arzneimittelwerk Dresden, Germany) and MK-801 (Tocris, Bristol, U.K.) were used. Pir was ip injected in a dose of 100 mg/kg 60 min before the kindling injection (Becker and Grecksch, 1995), and MK-801 was ip injected in a dose of 0.3 mg/kg 30 min before the kindling injection (Grecksch et al., 1994). Resultant seizures after PTZ administration were scored as described earlier.

The following groups were used:

  • 1
    experiment with piracetam: sal-sal, sal-PTZ, Pir-sal, Pir-PTZ.
  • 2
    experiment with MK-801: sal-sal, sal-PTZ, MK-801-Sal, MK-801-PTZ.

Statistics

To test the effects of an acute single seizure attack on sleep parameters, the Mann–Whitney U test was used to analyze between-group effects, and the Wilcoxon test was used to analyze within-group effects.

To assess seizure severity in the course of kindling, the repeated-measure model was used. To evaluate differences between the groups, analysis of variance (ANOVA) and the post hoc Bonferroni test were applied.

Correlations between seizure intensity and PS deficits were verified with Spearman correlation analysis. Seizure intensity was calculated on the basis of the seizure scores in reaction to the last three PTZ injections. In previous studies, this value was taken as a kindling criterion (Becker and Grecksch, 1995).

Significance threshold was set at 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Effect of an acute generalized PTZ-induced seizure attack on sleep

After a single acute seizure attack (stage 4–5 according to this referred rating scale), no significant differences (p > 0.05) were found in the sleep parameters analyzed before and after seizure induction between the groups (U test) and within a group (Wilcoxon test; Table 1). For exemplification, percentage of paradoxical sleep (%PS) and percentage of paradoxical sleep related to total sleep (%PS/TS) are presented.

Table 1. Percentage of paradoxical sleep (%PS) and paradoxical sleep related to total sleep (%PS/TS) in control rats that received saline (sal) and rats that received a single injection of 45.0 mg/kg pentylenetetrazole (PTZ)
 Sal (n = 7)PTZ (n = 6)
  1. Comparison of the baseline before the injection and sleep 24–96 h after application. Sleep was recorded for 8 h on 3 consecutive days. No significant differences appear between the experimental groups (p > 0.05). n, Number of animals used. Values expressed as mean ± SEM; U test.

%PS
 Before10.6 ± 0.81  9.6 ± 0.38
 After10.4 ± 0.2710.42 ± 0.34
%PS/TS
 Before13.5 ± 0.7413.35 ± 0.54
 After13.66 ± 0.39 13.81 ± 0.42

Effects of piracetam on kindling and sleep parameters

As shown in Fig. 2, seizure severity did gradually increase in animals repetitively injected with PTZ. Treatment with Pir did not interfere with seizure severity (F1, 13= 1.79; p = 0.204).

image

Figure 2. Effect of piracetam (Pir) treatment (100 mg/kg) on pentylenetetrazole-kindling (PTZ) development. n, number of animals used. Mean seizures scores ± SEM, repeated measures.

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Before kindling, no significant differences in PS duration were found between the groups (F3, 40= 1.83; p = 0.16); Fig. 3. After kindling completion, we found significant differences (F3, 40= 8.54; p < 0.001) in the following sleep parameters: PS was significantly reduced in the kindled group (sal-PTZ) in comparison with the sal-injected (sal-sal) control group (p = 0.001). This deficit was not counteracted by Pir treatment (sal-PTZ vs. Pir-PTZ; p = 0.36). Similar changes were found in %PS/TS. Before kindling, the groups showed similar ratios (F3, 40= 2.41; p = 0.082). However, after kindling, the groups differed significantly (F3, 40= 10.07; p < 0.001). In comparison with sal-sal, the kindled groups had significantly reduced %PS/TS (p = 0.001), and no differences were noted between the sal-PTZ and the Pir-PTZ groups (p = 0.38).

image

Figure 3. Paradoxical sleep (%PS) and paradoxical sleep related to total sleep (%PS/TS) in saline-injected control rats (sal) and pentylenetetrazole-kindled rats (PTZ) after treatment with piracetam (Pir, 100 mg/kg). n, number of animals used. Means ± SEM; U test.

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Before kindling, the duration of PS episodes was similar between the experimental groups (F3, 40= 1.41; p = 0.26). After kindling, the groups differed significantly (F3, 40= 4.48; p = 0.009). Compared with duration of PS episodes before kindling, the duration of PS episodes was significantly reduced in the sal-PTZ (p = 0.015). In the sal-sal and Pir-PTZ groups, the differences before kindling and after kindling are insignificant (p > 0.05) (Table 2).

Table 2. Duration of paradoxical sleep episodes (min) in control animals (sal) and rats before and after kindling with saline (sal) or piracetam (Pir) treatment
 Sal-sal (n = 20)Pir-sal (n = 6)Sal-PTZ (n = 8)Pir-PTZ (n = 7)
  1. Values expressed as mean ± SEM.

  2. ap < 0.05; U test.

Before2.0 ± 0.032.0 ± 0.12.01 ± 0.07 1.93 ± 0.07
After2.0 ± 0.032.1 ± 0.11.84 ± 0.05a1.86 ± 0.07

The reduction in %PS in the sal-PTZ group after kindling completion was significantly correlated with seizure scores (rS= 0.747, p < 0.05; Fig. 4).

image

Figure 4. Difference in percentage of paradoxical sleep (%PS) before and after kindling completion in animals of the sal-PTZ group independent of seizure score. The Spearman rank correlation coefficient is significant (p = 0.017).

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Interestingly, in the kindled group treated with Pir (Pir-PTZ), this correlation between sleep parameters and seizure score was insignificant (rS= 0.067, p > 0.05), Fig. 5.

image

Figure 5. Difference in percentage of paradoxical sleep (%PS) before and after kindling completion in animals treated with 100 mg/kg piracetam before each kindling stimulation independent of seizure severity. The Spearman rank correlation coefficient is insignificant (rs= 0.067; p = 0.485).

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In the sleep parameter SWS no differences were found between the groups before (F3, 40= 0.55; p = 0.65) or after kindling (F3, 40= 1.40; p = 0.26); data not shown. Similarly, no differences were seen in W (before kindling: F3, 40= 0.11; p = 095; after kindling completion: F3, 40= 2.37; p = 0.09), Table 3.

Table 3. Percentage of waking (related to the 8-h recording period) and %SWS (related to the 8-h recording period) in control animals (sal) and rats before and after kindling with saline (sal), piracetam (Pir), or MK-801 treatment
 Sal-sal (n = 20)Pir-sal (n = 6)Sal-PTZ (n = 8)Pir-PTZ (n = 7)MK-801-sal (n = 6)MK-801-PTZ (n = 6)
  1. Values expressed as mean ± SEM.

%Waking
 Before25.4 ± 1.024.5 ± 0.625.8 ± 1.223.7 ± 0.723.7 ± 1.323.7 ± 0.7
 After27.4 ± 1.324.3 ± 0.728.7 ± 1.827.2 ± 0.426.9 ± 1.727.0 ± 0.4
%SWS
 Before63.2 ± 0.964.8 ± 0.762.9 ± 1.264.7 ± 1.565.3 ± 1.363.8 ± 0.7
 After61.7 ± 1.164.9 ± 0.760.1 ± 1.663.2 ± 1.663.0 ± 1.762.6 ± 0.8

Effects of MK-801 on kindling and sleep parameters

Again, seizure severity did gradually increase in the groups repetitively injected with PTZ. Treatment with MK-801, however, did result in significantly reduced seizure severity (F1, 12= 5.20; p = 0.042); Fig. 6.

image

Figure 6. Effect of MK-801 treatment (0.03 mg/kg) on pentylenetetrazole-kindling (PTZ) development. n, number of animals used. Mean seizure scores ± SEM. *p < 0.05, repeated measures.

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Again, before kindling, the four experimental groups did not differ in %PS (F3, 39= 0.95; p = 0.42). Kindling did result in a decreased amount of %PS (F3, 39= 5.31, p = 0.004). The MK-801-sal and the MK-801-PTZ had similar percentages compared with the sal-sal group (p < 0.05); Fig. 7.

image

Figure 7. Paradoxical sleep (%PS) and paradoxical sleep related to total sleep (%PS/TS) in saline-injected control rats (sal) and pentylenetetrazole-kindled rats (PTZ) after treatment with MK-801 (0.03 mg/kg). n, number of animals used. Means ± SEM; U test.

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No differences were found between the groups before kindling (F3, 39= 0.97; p = 0.42). A reduction in%PS/TS was observed in the sal-PTZ group after kindling only (F3, 39= 4,85; p = 0.006; Bonferroni post hoc p = 0.003). In comparison with sal-sal, the MK-801-sal and the MK-801-PTZ groups were not different from sal-sal; Fig. 7.

We did not find differences in the duration of PS episodes before (F3, 39= 062; p = 0.61) and after kindling completion (F3, 39= 1.59; p = 0.21); Table 4.

Table 4. Duration of paradoxical sleep episodes (min) in control animals (sal) and rats before and after kindling with saline (sal) or MK-801 treatment
 Sal-sal (n = 20)MK-801-sal (n = 6)Sal-PTZ (n = 8)MK-801-PTZ (n = 6)
  1. Values expressed as mean ± SEM.

  2. ap < 0.05; U test.

Before2.0 ± 0.032.01 ± 0.072.01 ± 0.07  2.1 ± 0.03
After2.0 ± 0.031.84 ± 0.051.84 ± 0.05a2.1 ± 0.1

Moreover, the groups did not differ in SWS (before F3, 39= 0.61; p = 0.61; after kindling completion, F3, 39= 0.52; p = 0.67) and W (before F3, 39= 0.55, p = 0.64; after kindling completion, F3, 39= 1.46; p = 0.24); Table 3. This clearly indicates that treatment with MK-801 normalized sleep alterations in kindled rats.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Epilepsy is studied most commonly with kindling models because kindling reflects neurophysiologic, neurochemical, neurohistopathologic, and behavioral alterations associated with human epilepsy (McNamara et al., 1985; McNamara, 1986; Schmutz, 1987; Becker et al., 1992; Majkowski, 1999; Lagae et al., 2003). Several studies have shown the impact of epilepsy on higher cognitive function with special regard to memory impairment. Although the pathophysiologic mechanisms underlying these impairments are multifactorial, seizure frequency was reported to exert deleterious effects on cognition (Stafstrom, 2002; Tromp et al., 2003; Nolan et al., 2004; Hoie et al., 2005). Thus seizure suppression appears to be appropriate in the prevention of cognitive deficits after epilepsy. In a kindling experiment, it was shown that diazepam injected before each kindling stimulation prevented motor seizures and hippocampal cell loss (Becker et al., 1994, 1997b). However, the kindling-induced deficit in two-way active avoidance learning was evident regardless of the diazepam treatment, suggesting that motor seizures are only one component in the comprehensive network underlying cognitive impairments in epilepsy. Another factor in this network is the effect of various antiepileptic drugs that impair memory to quite different degrees (Devinsky, 1995; Drane and Meador, 1996; Bourgeois, 1998; Aldenkamp et al., 2003; Fritz et al., 2005). As a logical consequence, it was hypothesized that the use of memory-enhancing nootropic drugs might be a useful attempt at compensating for the cognitive deficits in epilepsy patients (Mondadori et al., 1984; Mondadori and Schmutz, 1986; Becker and Grecksch, 1995). The mode of action of this heterogeneous group of agents is not completely understood. Therefore the present study was designed to answer the following questions: (a) does chemical kindling result in changes in sleep pattern; and (b) do substances which are known to either counteract epilepsy-associated learning deficits or seizure attacks rebalance altered sleep patterns?

The principal findings of the present study are the following:

  • • 
    24 h after a single seizure attack, sleep patterns were found to be unchanged
  • • 
    pentylenetrazole kindling results in a reduction in paradoxical sleep
  • • 
    the nootropic drug piracetam did not normalize altered sleep pattern in kindled rats
  • • 
    the noncompetitive NMDA-receptor antagonist MK-801 ameliorated the deficit in paradoxical sleep in kindled rats.

Clinical observations in patients with epilepsy have shown altered sleep–waking cycles and an increased number of stage shifts. Conversely, it is well documented that sleep deprivation results in an impairment of memory retention (Fishbein and Gutwein, 1977; Smith, 1995; Forest and Godbout, 2000; Bjorness et al., 2005). Similar alterations were found in animal experiments that are considered to be useful tools in the study of correlative relations between sleep disturbances and cognitive deficits. After electrical kindling in different animal species and different brain structures, a reduced amount of sleep with special regard to paradoxical sleep was found (Stone and Gold, 1988; Hiyoshi and Wada, 1990; Calvo and Fernandez-Mas, 1991; 1994; Gigli and Gotman, 1992; Cammisuli et al., 1997; Raol and Meti, 1998). Interestingly, in chemically kindled rats, these changes in sleep patterns also are evident. Although the significant differences in paradoxical sleep parameters before and after completion of kindling appear to be marginal (e.g., Table 2), the size of the changes observed in sleep in the present experiment is comparable to the results obtained by other laboratories (Amici et al., 2001; Lena et al., 2004). A single seizure attack induced by PTZ, however, was without any obvious effect on sleep (Table 1). This is in line with other results showing that a single seizure attack did not modify glutamate binding or parameters of hippocampal long-term potentiation, as found in animals after kindling completion (Schröder et al., 1993; Ruethrich et al., 1996). In contrast,%PS was significantly reduced in the animals that acquired the kindling syndrome (Fig. 3), suggesting that altered sleep patterns are dependent on long-lasting plastic-adaptive alterations in central functioning. This well correlates with other reports. There it was concluded that an increase in PS sleep after a single seizure attack may represent an adaptive mechanism. Sustaining seizure activity breaks down this mechanism and results in loss of PS sleep (Raol and Meti, 1998).

PTZ kindling resulted in long-lasting learning impairment, which is still ascertainable 4 weeks after the last kindling stimulation (Becker et al., 1992). Detailed analysis revealed a significant relation between the learning impairment and seizure severity. A similar correlation was found between seizure severity and PS deficit (Fig. 4), which might suggest that the PS deficits contribute to kindling-induced learning impairment.

To elucidate the relation between sleep disturbances and learning impairments, we injected the nootropic drug Pir and the NMDA-receptor antagonist MK-801 in the course of kindling before each kindling injection. In previous studies, a dose of 100 mg/kg Pir was found efficaciously to counteract kindling-associated learning deficits without affecting seizure development (Becker and Grecksch, 1995). In contrast, MK-801 (0.3 mg/kg) significantly reduced seizure development, and it reduced the kindling-associated learning deficits (Grecksch et al., 1994). Surprisingly, Pir was without effect on the PS deficit in kindled rats, but this substance disconnected the significant correlation between seizure severity and PS deficit (Fig. 5). In previous experiments, Pir was found to enhance PS in rats. This is not contrasting because these results were obtained after brief Pir injection (Aldenkamp et al., 1996), whereas in the present experiment, sleep was analyzed after timely-spaced subchronic Pir treatment followed by washout (Wetzel, 1985). Conversely, MK-801–lowered seizure severity counteracted the kindling-induced PS and the kindling-associated learning deficit as well. This implies that beneficial effects on cognitive impairments in epilepsy may derive from both (i.e., reduction of seizure severity and rebalance in qualitative and quantitative parameters of paradoxical sleep). However, this does not exclude that factors other than seizure severity and changes in sleep structure are involved in learning impairments associated with epilepsy.

On the basis of animal experiments, certain AEDs may usefully be combined with nootropics (Mondadori et al., 1984). We are far from understanding impairments in the domain of cognition in epilepsy patients. Therefore more data are needed on the efficacy of AEDs and their combinations to control epilepsy-related cognitive dysfunctions.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES