Anticonvulsant action of a non-competitive antagonist of NMDA receptors (MK-801) in the kindling model of epilepsy

Anticonvulsant action of MK-801, a novel non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptors, was investigated in the kindling model of epilepsy in rats. The results obtained were as follows. (1) Both the seizure stage and afterdischarge duration of previously kindled seizures from the amygdala were significantly suppressed following systemic injection of MK-801 (0.25–4 mg/kg) in a dose-dependent manner. The maximum effects were observed between 2 and 4 h after the injection. (2) The MK-801 also showed significant anticonvulsant effedts on kindled seizures from the frontal cortex and the ventral and dorsal hippocampus. The efficacy however, significantly differed between these kindled sites. (3) Daily treatment of MK-801 (0.25 and 1 mg/kg) prior to each electrical stimulation of the amygdala significantly retarded kindling seizure development and increased the total amount of afterdischarge (accumulated AD) required to reach the first stage 5 seizure. During drug sessions of 1 mg/kg MK-801 for 19 days, all rats showed only partial seizures and the growth of afterdischarge was strongly prevented. (4) Pretreatment with reserpine did not antagonize the anticonvulsant effects of MK-801 on previously kindled seizures from the amydala, suggesting that the effects may not be mediated by catecholaminergic systems. These results indicate that MK-801 has potent anticonvulsant actions on kindled seizures from both limbic and cortical foci, the NMDA system may play a critical role in the seizure-triggering mechanism of kindling. The possible application of NMDA antagonists in clinical epilepsy is suggested.     

Deep brain stimulation of the substantia nigra pars reticulata exerts long lasting suppression of amygdala-kindled seizures

Deep brain stimulation (DBS) has been used to treat a variety of neurological disorders including epilepsy. However, we have limited knowledge about effective target areas, optimal stimulation parameters, and long-term effect of DBS on epileptic seizures. Here we examined the effects of DBS of the substantia nigra pars reticulata (SNr) on amygdala-kindled seizures. Microwire electrodes were implanted into the SNr and amygdala of adult male rats. When stage 5-kindled seizures were achieved by daily amygdala kindling, high frequency stimulation was delivered to the SNr bilaterally 1 s after cessation of kindling. Our DBS protocol completely blocked kindled seizures in 10 out of 23 (43.5%) rats studied. Furthermore, when the same amygdala kindling procedure was performed 24 h later without DBS, the kindling failed to elicit any seizure signs in 6 of these 10 rats. Some of the post-DBS period of seizure suppression lasted for up to 4 days. In other 3 rats, only mild stage 1 to 2 seizures appeared following amygdala kindling. Only 1 of the 10 rats for which DBS had blocked kindled seizures exhibited full-scale 5 stage-kindled seizures 24 h after DBS. These results suggest that highly plastic neural networks are involved in amygdala-kindled seizures and that DBS, if well timed with the onset of amygdala kindling, may exert long lasting effects on the networks that may prevent the recurrence of kindled seizures.     

Preemptive low-frequency stimulation decreases the incidence of amygdala-kindled seizures

PURPOSE: The use of electrical stimulation as a therapy for epilepsy is currently being studied in experimental animals and in patients with epilepsy. This study examined the effect of preemptive, low-frequency, 1-Hz sine wave stimulation (LFS) on the incidence of amygdala-kindled seizures in the rat. METHODS: Electrodes were implanted into the basolateral amygdalae of adult male rats. All animals received a kindling stimulus of 60-Hz, 400-microA, sine wave for 1 s twice a day. Experimental animals received an additional LFS consisting of 1 Hz, 50 microA for 30 s immediately before the kindling stimulus. Afterdischarge (AD) duration, behavioral seizure score, the number of stimulations required to elicit the first stage five seizure and to become fully kindled were measured. After 20 stimulations, a crossover procedure was performed. Fully kindled rats from each group were switched, so that the original controls received LFS plus the kindling stimulus, and the original experimental rats received only the kindling stimulus. RESULTS: During kindling acquisition, LFS induced a significant decrease in AD duration. A significant increase in the number of times the kindling stimulus failed to elicit an AD was noted. Control rats exhibited an AD 99% of the time compared with 70% in experimental rats (p < 0.0001; Fisher's Exact test). In fully kindled animals, the incidence of stage five seizures in the original controls significantly decreased from 98% to 42% (p < 0.0001) when the LFS was added to the kindling paradigm. CONCLUSIONS: The dramatic decrease in the incidence of stage 5 seizures in fully kindled animals after preemptive LFS strongly suggests that LFS may be an effective therapy for the prevention of seizures in patients with epilepsy.     

Postseizure inhibition of kindled seizures by electroconvulsive shock

The inhibitory postseizure effect of electroconvulsive shock (ECS) and of kindled seizures on kindled seizures was assessed. Rats were kindled by daily amygdaloid stimulation. ECS delivered 22 or 24 h before each kindling stimulus markedly reduced the rate of kindling. In fully kindled rats multiple but not single ECS raised the threshold to kindled seizures 24 and 48 h after the last ECS. The threshold returned to normal after a rest period. In a subsequent experiment the threshold of fully kindled seizures was measured once daily for 8 consecutive days. The threshold was found to increase to a plateau, then return to normal after a 15-day rest. Multiple seizures are more effective than single seizures in inducing the postseizure effect; the phenomenon is not seizure specific. It is postulated that multiple seizures induce a homeostatic inhibiting response.     

Resistance to propagation of amygdaloid kindling seizures in rats with genetic absence epilepsy

PURPOSE: The existence of absence epilepsy and temporal partial seizure pattern in the same patient is an uncommon state. In the present study, we aimed to evaluate whether the process of kindling as a model of complex partial seizures with secondary generalization is altered in rats with genetic absence epilepsy. METHODS: Six- to 12-month-old nonepileptic control Wistar rats and genetic absence epileptic rats from Strasbourg (GAERS) were used in the experiments. One week before the experiments, bilateral stimulation and recording electrodes were implanted stereotaxically into the basolateral amygdala and cortex, respectively. Animals were stimulated at their afterdischarge threshold current twice daily for the process of kindling and accepted as fully kindled after the occurrence of five grade 5 seizures. Bilateral EEGs from amygdala and cortex were recorded continuously during 20 min before and 40 min after each stimulus. RESULTS: All control Wistar rats were fully kindled after stimulus 12 to 15. Although the maximal number of stimulations had been applied, GAERS remained at stage 2, and no motor seizures were observed. The afterdischarge duration in bilateral amygdala and the cortex after the kindling stimulus was shorter in GAERS when compared with control rats. CONCLUSIONS: Occurrence of only grade 2 seizures and no observation of grade 3-5 seizures in GAERS with the maximal number of stimulations would suggest that the generalized absence seizures may be the reason of the resistance in the secondary generalization of limbic seizures during amygdala kindling.     

An in vitro autoradiographic analysis of mu and delta opioid binding in the hippocampal formation of kindled rats

Recent studies have shown that opioid peptide levels are altered in hippocampal formation of kindled animals. We therefore studied the distributions of mu and delta opioid binding sites in hippocampal formation of kindled and control rats using quantitative in vitro autoradiography. Animals received daily stimulations of the amygdala until they experienced 3 class 5 seizures. Paired control animals underwent implantation of electrodes but were not stimulated. Mu binding sites were labeled with 125I-FK-33824. Twenty-four hours after the last kindled seizure, mu binding was decreased by 32% in stratum pyramidale of CA1 and stratum radiatum of CA2 and by 17-27% throughout most of the rest of CA1, CA2, and CA3. Few, if any, differences were seen between kindled and control animals at 7 or 28 days after the last kindled seizure. Delta binding sites were labeled with 125I-[D-Ala2,D-Leu5]enkephalin in the presence of the morphiceptin analog PL-032. Twenty-four hours after the last kindled seizure, delta binding was decreased only in stratum moleculare of the dentate gyrus. Seven days after the last kindled seizure, delta binding was decreased by 11-17% throughout CA1, CA3, and the dentate gyrus. At 28 days after the last seizure, however, no differences were found between kindled and control animals. Since the decreases in mu and delta opioid binding are transient, they are unlikely to be the molecular basis of the permanent kindling phenomenon. Rather, these changes in opioid binding may represent responses to repeated seizures.     

Attention deficit hyperactivity disorder in children with epilepsy

Attention deficit hyperactivity disorder (ADHD) is more frequent in children with epilepsy than in general pediatric population. Several factors may contribute to this comorbidity, including the underlying brain pathology, the chronic effects of seizures and of the epileptiform EEG discharges, and the effects of antiepileptic drugs. Symptoms of ADHD are more common in some specific types of epilepsies, such as frontal lobe epilepsy, childhood absence epilepsy and Rolandic epilepsy, and may antedate seizure onset in a significant proportion of cases. In epileptic children with symptoms of ADHD, treatment might become a challenge for child neurologists, who are forced to prescribe drugs combinations, to improve the long-term cognitive and behavioral prognosis. Treatment with psychotropic drugs can be initiated safely in most children with epilepsy and ADHD symptoms.     

Diurnal rhythms of spontaneous recurrent seizures and behavioral alterations of Wistar and spontaneously hypertensive rats in the kainate model of epilepsy

Attention deficit hyperactivity disorder (ADHD) can coexist with epilepsy. Spontaneously hypertensive rats (SHRs) are considered to model ADHD with overactivity, impulsiveness, deficient sustained attention, and alterations in circadian autonomic profiles. The present study explored spontaneous recurrent seizures (SRSs) and behavioral diurnal activity rhythms in normotensive Wistar rats and SHRs in the kainate model of epilepsy. Rats were video monitored (24 h/3 months) to detect SRSs. SHRs manifested a lower seizure frequency during the light phase in the 8th and 10th weeks and a lower frequency of SRSs during the night phase accompanied by attenuated responses in hyperexcitability tests. Both epileptic strains were hyperactive, with lower anxiety levels, and their diurnal rhythms were abolished. Epileptic Wistar rats and SHRs exhibited less exploration during the dark phase. This study suggests that SHRs may be useful in modeling some aspects (particularly hypertension-related diurnal rhythm disturbance) of behavior associated with epilepsy.     

The role of piriform cortex adenosine A1 receptors on hippocampal kindling

INTRODUCTION: The hippocampus and piriform cortex have a critical role in seizure propagation. In this study, the role of adenosine A1 receptors of piriform cortex on CA1 hippocampal kindled seizures was studied in rats. METHODS: Animals were implanted with a tripolar electrode in the right hippocampal CA1 region and two guide cannulae in the left and right piriform cortex. They were kindled by daily electrical stimulation of hippocampus. In fully kindled rats, N6- cyclohexyladenosine (CHA; a selective adenosine A1 receptors agonist) and 1,3-dimethyl-8-cyclopenthylxanthine (CPT a selective adenosine A1 receptor antagonist) were microinfused into the piriform cortex. The animals were stimulated at 5, 15 and 90 minutes (min) after drug injection. RESULTS: Obtained data showed that CHA (10 and 100 microM) reduced afterdischarge duration, stage 5 seizure duration, and total seizure duration at 5 and 15 min after drug injection. There was no significant change in latency to stage 4 seizure. CPT at concentration of 20 microM increased afterdischarge duration, stage 5 seizure duration, and total seizure duration and decreased latency to stage 4 seizure at 5 and 15 min post injection. Pretreatment of rats with CPT (10 microM), 5 min before CHA (100 microM), reduced the effect of CHA on seizure parameters. CONCLUSION: These results suggested that activity of adenosine A1 receptors in the piriform cortex has an anticonvulsant effect on kindled seizures resulting from electrical stimulation of the CA1 region of the hippocampus.     

The effects of right and left amygdala kindling on the female reproductive system in rats

Purpose:   Women with epilepsy often have comorbid reproductive dysfunction. Using the amygdala kindling model in rats, the present study examined the effects of seizures of limbic origin on the reproductive system.
Methods:   Female Wistar rats were kindled from the left or right basolateral amygdala to a criterion of 40 stage V seizures. Sham-kindled subjects were handled but not stimulated. Vaginal cytology was assessed daily for the duration of the study. Twenty-four hours following the last kindled seizure, kindled subjects and their yoked controls were sacrificed and their brains and serum were extracted.
Results:   Kindled subjects displayed significantly more abnormal estrous cycle days and significantly elevated levels of estradiol as compared to controls. There was, however, no total suppression of cycling. No laterality effects were seen for estrous cycle abnormalities.
Discussion:   Seizures of limbic origin cause changes in estrous cycling. Right and left kindling seem to have a similar effect. These findings highlight the need for clinicians to monitor reproductive issues among individuals with epilepsy.     

Prophylaxis of amygdala kindling-induced epileptogenesis: comparison of a GABA uptake inhibitor and diazepam

The prophylactic effect of an inhibitor of synaptosomal GABA uptake, SK&F 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid), on the development of amygdala kindled seizures was studied in adult female rats. For comparative purposes, the action of diazepam was also investigated. Dosages of SK&F 89976-A and diazepam which were previously shown to be the ED50 for seizure inhibition in fully kindled rats (15 mg/kg and 2 mg/kg i.p., respectively) were administered daily 30 min prior to amygdala stimulation in naive, unkindled rats. Both drugs inhibited the evolution of full kindled seizure activity and markedly suppressed kindling-associated increases in the duration of behavioral and electrographic seizures. Control rats developed fully kindled stage 5 seizures after 8.9 +/- 1.1 amygdala stimulations but drug-treated rats did not progress beyond an early stage of kindled seizures as long as the animals were treated with the drugs (22 days). Diazepam produced significant CNS depressant effects throughout the course of administration but SK&F 89976-A prevented kindling with no depressant side effects. The ability of SK&F 89976-A and diazepam to inhibit the development of full amygdala kindled seizures may be related to enhancement of central inhibitory GABAergic systems.     

Sleep-Wakefulness Alterations in Amygdala-Kindled Rats

Summary: Purpose: Our aim was to study the relation between epilepsy and sleep–wakefulness cycles in the amygdalakindling model of temporal lobe epilepsy.
Methods: Adult male Wistar rats were electrically kindled through bipolar electrodes implanted in the anterior amygdala. Polysomnographic recordings were taken before and after kindled seizures for 6 h. For the studies on the effects of a single, full-blown seizure, recordings were taken immediately after the seizure and daily thereafter until the recordings returned to baseline values. For studies on the effects of five full-blown seizures, recordings were taken immediately after the fifth seizure and then on day 1, 2, 3, 5, 7, 14, 21, and 28.
Results: Polysomnographic recordings taken immediately after the first full-blown seizure revealed an initial increase in the duration of deep slow-wave sleep (SII), a decrease in the light slow-wave sleep (SI) stage of non-rapid eye movement (NREM) sleep, and a decrease in the quiet wakefulness (W,) stage of wakefulness. All these parameters returned to baseline values after 24 h. The duration of rapid eye movement (REM) sleep increased and returned to the baseline value after 48 h. Five consecutive full-blown seizures caused an increase in the duration of SII from the day the seizures occurred until day 28, whereas the duration of SI decreased for 72 h. The duration of REM sleep, decreased only on the day of the seizures and day 1, while decreases in the number of REM episodes were observed on the day of the seizure, day 2 and day 14.
Conclusions: Our study indicates that even a single, full-blown seizure can cause alterations in the architecture of sleep–wakefulness cycles for a short duration, and that multiple seizures produce long-term effects.     

Omega-3 supplementation in children with ADHD and intractable epilepsy

BackgroundOmega-3 may have a role in the treatment of drug- resistant epilepsy.ObjectivesTo evaluate omega-3 supplementation in seizure control in children with attention deficit hyperactivity disorder (ADHD) and intractable epilepsy.Patients and MethodsSixty children with ADHD and intractable epilepsy were enrolled. They were randomly assigned in a double-blind fashion in a 1:1 ratio into the omega-3 supplementation group or the placebo group in addition to risperidone and antiepileptic drugs. All patients were assessed for the frequency and severity of the epileptic attacks at baseline, monthly, and at 6 months from the beginning of the study; 30 children received omega-3 and the other 30 children received placebo.ResultsAt baseline, the median number of seizures per month was 5 in both groups. After one month, this median decreased to 3 and became 2 after two months of supplementation with omega-3 in the supplementation group while it remained 5 in the control group. After 3 months and till the end of the study, this median decreased to 0 while it remained 5 in the control group throughout the study period.Children who were supplemented with omega-3 showed a significant decrease in the monthly frequency of seizure attacks after six months of supplementation compared to the baseline before supplementation (P < 0.05) There was no significant decrease in the severity of the seizures attacks among our patients with omega-3 supplementation (P > 0.05).ConclusionOmega 3 may help in achieving good seizure control in children with ADHD and intractable epilepsy.     

Early Changes in Prodynorphin mRNA and ir-Dynorphin A Levels after Kindled Seizures in the Rat

Prodynorphin mRNA and immunoreactive dynorphin A (ir-dynorphin A) levels were measured in different brain areas at various time points after amygdala kindled seizures. In the hippocampus, striatum and hypothalamus, prodynorphin mRNA levels were not significantly changed in kindled rats (killed 1 week after the last stimulus-evoked seizure), but they were significantly increased 1 h after seizures. The relative increase was the highest in the hippocampus (∼3-fold). In the brainstem, midbrain and cerebral cortex no changes in prodynorphin mRNA were detected in kindled rats, 1 h or 1 week after a kindled seizure. ir-Dynorphin A levels were significantly reduced in the hippocampus and in the striatum of kindled rats, as well as 5 and 60 min after kindled seizures, but they were increased back to control levels after 120 min. In the hypothalamus, ir-dynorphin A levels were significantly increased 120 min after a kindled seizure. ir-Dynorphin A levels were also significantly reduced in the brainstem and in the frontal, parietal and temporal cortex 120 min, but not 5 or 60 min, after a kindled seizure. Taken together, these data support the hypothesis that the dynorphinergic system is activated after amygdala kindled seizures, with different kinetics in different brain areas.     

Cognitive Function in Childhood Epilepsy: Importance of Attention Deficit Hyperactivity Disorder

Background and Purpose

To determine how cognitive function is related to epilepsy classification and comorbid attention deficit hyperactivity disorder (ADHD) in children with newly diagnosed epilepsy of genetic or unknown etiology.

Methods

The medical records of children aged 6-16 years with newly diagnosed epilepsy of genetic or unknown etiology were reviewed retrospectively. The Korean Education Development Institute-Wechsler Intelligence Scale for Children and the Comprehensive Attention Test were used to evaluate intelligence and attention/executive function, respectively.

Results

The data of a total of 149 children, 103 with focal seizures and 46 with generalized seizures, were reviewed. The prevalence of ADHD was 49.2% (59 out of 120 examined patients), and ADHD patients exhibited significantly worse auditory selective attention, flanker test results, and spatial working memory. Patients with generalized seizures exhibited significantly worse auditory selective and sustained attention than patients with focal seizures. In patients with generalized seizures, sustained attention, flanker test findings, and spatial working memory were found to be affected by ADHD, and auditory selective and sustained attention were significantly worse in patients with benign childhood epilepsy with centrotemporal spikes and ADHD than in their counterparts without ADHD.

Conclusions

Cognitive processes are affected by seizure type and comorbid ADHD. Proper characterization of these neuropsychiatric impairments may allow earlier intervention during the disease course.     

The usefulness of olfactory bulb kindling as a model for evaluation of antiepileptics

Purpose: The present study was undertaken to clarify the behavioral and electroencephalographic characteristics of olfactory bulb (OB) kindling in rats, in comparison with those of amygdala (AMG) kindling. In addition, the usefulness of OB kindling as a model to evaluate antiepileptics was studied. Methods: Bipolar electrical stimulation was applied to the OB or AMG every day until generalized seizure was achieved. Antiepileptics (carbamazepine, sodium valproate, zonisamide, clobazam, and topiramate), which are used for complex partial epilepsy or secondary generalized epilepsy in clinical practice, were orally administrated to kindled rats. Results: The afterdischarge (AD) threshold of OB kindling is not different from that of AMG kindling. OB‐kindled rats showed more rapid development of the seizure stage and AD duration than AMG‐kindled rats; however, fully kindled AD duration did not differ between groups. In AMG kindled rats, AD on day 1 was localized only at the stimulation site, whereas in OB‐kindled rats, AD on day 1 was observed at not only the stimulation site (OB) but also in the frontal cortex, hippocampus, and AMG. All five antiepileptics significantly inhibited both the seizure stage and AD duration in OB‐kindled rats. In addition, carbamazepine, zonisamide, and topiramate were more effective in suppressing OB‐kindled seizures. Zonisamide was not effective at any dose tested in AMG‐kindled rats. Discussion: OB kindling can be used as a new valuable model to evaluate antiepileptic drugs, with the advantage of its rapid development and the efficacy of antiepileptics.     

Hippocampal calcium-binding protein during commissural kindling-induced epileptogenesis: Progressive decline and effects of anticonvulsants

Changes in hippocampal calcium-binding protein (CaBP) were examined in rats given kindling stimuli via electrodes chronically implanted in the midline commissural pathway. CaBP levels decreased progressively and were significantly lower (16.6%) than controls after only 10 kindling trials. The maximum fall (33%) was achieved prior to the production of stage 5 motor seizures and additional kindling-induced seizures produced no further decline. Induction of motor seizures with pentylenetetrazol had no effect upon hippocampal CaBP levels. Diazepam treatment during the course of kindling significantly increased the number of stimulation trials required to produce stage 5 motor seizures but did not inhibit the fall in CaBP. Diazepam treatment of fully kindled rats was effective in blocking generalized motor seizures without causing any restoration of the depleted levels of CaBP. Diphenylhydantoin was neither effective during the course of kindling nor in modifying the effect of further stimulations in fully kindled rats. These data indicate that the highly specific decrease in hippocampal CaBP, previously demonstrated to be localized to dentate granule cells and their processes following kindling-induced epilepsy, does not result from the expression of full tonic-clonic (stage 5) motor seizures. The loss of CaBP may be a biochemical factor contributing either to the predisposition of neuronal tissue to seizure activity or to a protective attempt to overcome the deleterious effect of repeated high-frequency stimulation.     

Effectiveness and safety of methylphenidate in adult attention deficit hyperactivity disorder in patients with epilepsy: an open treatment trial

OBJECTIVE: The purpose of this study was to evaluate the effectiveness and safety of methylphenidate treatment in epilepsy patients with comorbid adult attention deficit hyperactivity disorder (ADHD). METHODS: Six of 156 consecutive patients attending a tertiary epilepsy clinic for diagnostic evaluation of new seizures, 3 patients with epilepsy and 3 patients with psychogenic non-epileptic seizures, were diagnosed with comorbid adult ADHD. These 6 patients entered an open trial of methylphenidate 10 mg twice daily. Clinical improvement was assessed at 6 weeks of follow-up. RESULTS: Both groups showed clinical improvement of ADHD symptoms during treatment. None of the patients with comorbid epilepsy experienced adverse effects on seizure control or antiepileptic drug use. CONCLUSION: In this open trial methylphenidate was safely used in patients with epilepsy and adult ADHD. It was effective against adult ADHD, and there were no adverse effects on seizure severity and frequency. A randomized study is needed to further establish effectiveness and safety.     

Is amygdala kindling in rats a model for drug-resistant partial epilepsy?

Amygdala-kindled female rats were used to compare the effects of seven antiepileptic drugs that are clinically used for treatment of partial epilepsy with complex symptomatology, on generalized seizures, focal seizures, or electrographic seizure activity at the focus. As a second approach of drug evaluation, drug effects on mean latency, severity, and duration of the seizures were determined. Anticonvulsant potencies obtained were compared with those determined in the maximal electroshock seizure test in female rats. Phenobarbital, phenytoin, carbamazepine, valproic acid, diazepam, clonazepam, but not primidone dose-dependently suppressed generalized motor seizures in kindled rats; however, except for the benzodiazepines, ED50S were substantially higher than those determined in the maximal electroshock seizure test. Compared with their effect on generalized motor seizures, all drugs were much less potent in blocking focal seizures and afterdischarges recorded from the amygdala. The data suggest that with respect to behavioral and pharmacologic characteristics of the amygdala kindling model, fully kindled rats may be a useful model for drug-resistant complex partial seizures with secondary generalization. Results of experiments with novel inhibitors of GABA uptake, which were inactive in the maximal electroshock seizure test but highly potent against kindled seizures, suggest that such drugs might be more effective than current antiepileptic drugs for treatment of partial epilepsy.     

Antiepileptic effects of silk-polymer based adenosine release in kindled rats

Pharmacotherapy for epilepsy is limited by high incidence of pharmacoresistance and failure to prevent development and progression of epilepsy. Using the rat hippocampal kindling model, we report on the therapeutic potential of novel silk-based polymers engineered to release the anticonvulsant adenosine. Polymers were designed to release 1000 ng adenosine per day during a time span of ten days. In the first experiment rats were kindled by hippocampal electrical stimulation until all animals reacted with stage 5 seizures. Adenosine-releasing or control polymers were then implanted into the infrahippocampal fissure ipsilateral to the site of stimulation. Subsequently, only recipients of adenosine-releasing implants were completely protected from generalized seizures over a period of ten days corresponding to the duration of sustained adenosine release. To monitor seizure development in the presence of adenosine, adenosine-releasing or control polymers were implanted prior to kindling. After 30 stimulations – delivered from days 4 to 8 after implantation – control animals had developed convulsive stage 5 seizures, whereas recipients of adenosine-releasing implants were still protected from convulsive seizures. Kindling was resumed after nine days to allow expiration of adenosine release. During additional 30 stimulations, recipients of adenosine-releasing implants gradually resumed kindling development at seizure stages corresponding to those when kindling was initially suspended, while control rats resumed kindling development at convulsive seizure stages. Blockade of adenosine A₁ receptors did not exacerbate seizures in protected animals. We conclude that silk-based adenosine delivery exerts potent anti-ictogenic effects, but might also have at least partial anti-epileptogenic effects. Thus, silk-based adenosine augmentation holds promise for the treatment of epilepsy.