Development of Tolerance During Chronic Treatment of Kindled Rats With the Novel Antiepileptic Drug Levetiracetam

doi:10.1111/j.1499-1654.2000.001499.x

Cited by 41 publications

(6 citation statements)

References 15 publications

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“…For instance, a previous poor response to drug treatment seemed to induce severe SRSs in patients, after carbamazepine withdrawal [5,29]. In monotherapy, one explanation for the increased seizure frequency above pre-AED values upon discontinuation of treatment could be the development of tolerance to the antiseizure effect of LEV, which was a mechanism described by several groups [15,30,31]. Particularly, tolerance to LEV could be a result of functional adaptation of LEV's target(s) to the presence of the AED, which might result in increased seizure frequency after AED discontinuation.…”

Section: Discussionmentioning

confidence: 99%

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect

et al. 2021

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Abrupt withdrawal from antiepileptic drugs is followed by increased occurrence of epileptic seizures, a phenomenon known as the “rebound effect”. By stopping treatment with levetiracetam (LEV 300 mg/kg/day, n = 15; vs saline, n = 15), we investigated the rebound effect in adult male Sprague-Dawley rats. LEV was continuously administered using osmotic minipumps, 7 weeks after the intraperitoneal administration of kainic acid (15 mg/kg). The effects of LEV were determined by comparing time intervals, treatments, and interactions between these main factors. Seizures were evaluated by video-electrocorticographic recordings and power band spectrum analysis. Furthermore, we assessed endogenous neurosteroid levels by liquid chromatography-electrospray-tandem mass spectrometry. LEV significantly reduced the percentage of rats experiencing seizures, reduced the seizure duration, and altered cerebral levels of neurosteroids. In the first week of LEV discontinuation, seizures increased abruptly up to 700% (p = 0.002, Tukey’s test). The power of delta band in the seizure postictal component was related to the seizure occurrence after LEV withdrawal (r2 = 0.73, p < 0.001). Notably, allopregnanolone hippocampal levels were positively related to the seizure occurrence (r2 = 0.51, p = 0.02) and to the power of delta band (r2 = 0.67, p = 0.004). These findings suggest a role for the seizure postictal component in the rebound effect, which involves an imbalance of hippocampal neurosteroid levels.

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Section: Discussionmentioning

confidence: 99%

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect

et al. 2021

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“…The suppression of evoked focal seizures, by increased afterdischarge threshold and/or decreasing afterdischarge durations, is thought to be the primary target for phenytoin's anticonvulsant action (Ebert et al, 1997 ). Levetiracetam also increases afterdischarge thresholds or decreases afterdischarge durations (Löscher et al, 1998 , 2016 ; Löscher and Hönack, 2000 ). Benzodiazepine GABA enhancers such as diazepam and clonazepam at low doses can decrease generalized motor seizures with or without weak effects on evoked focal afterdischarges (Löscher et al, 1986 ; Voits and Frey, 1994 ).…”

Section: Discussionmentioning

confidence: 99%

“…Levetiracetam. Applied at 100 mg or 400 mg/kg, similar to the doses used in other rodent models (160–800 mg/kg; Löscher et al, 1993 ; Löscher and Hönack, 2000 ; Zhang et al, 2003 ; Ji-qun et al, 2005 ; Lee et al, 2013 ; Shetty, 2013 ; Twele et al, 2015 ; Duveau et al, 2016 ). In mice submitted to intra-peritoneal injections at 200 mg/kg, the half-life of levetiracetam plasma elimination is about 1.5 h and its brain-to-blood ratio is 0.8 at 4 h post-injection (Benedetti et al, 2004 ; Markowitz et al, 2010 ).…”

Section: Methodsmentioning

confidence: 99%

“…In mice submitted to intra-peritoneal injections at 200 mg/kg, the half-life of levetiracetam plasma elimination is about 1.5 h and its brain-to-blood ratio is 0.8 at 4 h post-injection (Benedetti et al, 2004 ; Markowitz et al, 2010 ). In order to maintain the anti-seizure actions of levetiracetam over a period of time comparable to that of phenytoin or lorazepam, we adapted a three-injection protocol (Löscher and Hönack, 2000 ). This way, we applied levetiracetam every 4 h at 100 or 400 mg/kg per injection.…”

Section: Methodsmentioning

confidence: 99%

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Effects of Antiepileptic Drugs on Spontaneous Recurrent Seizures in a Novel Model of Extended Hippocampal Kindling in Mice

et al. 2018

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Epilepsy is a common neurological disorder characterized by naturally-occurring spontaneous recurrent seizures and comorbidities. Kindling has long been used to model epileptogenic mechanisms and to assess antiepileptic drugs. In particular, extended kindling can induce spontaneous recurrent seizures without gross brain lesions, as seen clinically. To date, the development of spontaneous recurrent seizures following extended kindling, and the effect of the antiepileptic drugs on these seizures are not well understood. In the present study we aim to develop a mouse model of extended hippocampal kindling for the first time. Once established, we plan to evaluate the effect of three different antiepileptic drugs on the development of the extended-hippocampal-kindled-induced spontaneous recurrent seizures. Male C57 black mice were used for chronic hippocampal stimulations or handling manipulations (twice daily for up to 70 days). Subsequently, animals underwent continuous video/EEG monitoring for seizure detection. Spontaneous recurrent seizures were consistently observed in extended kindled mice but no seizures were detected in the control animals. The aforementioned seizures were generalized events characterized by hippocampal ictal discharges and concurrent motor seizures. Incidence and severity of the seizures was relatively stable while monitored over a few months after termination of the hippocampal stimulation. Three antiepileptic drugs with distinct action mechanisms were tested: phenytoin, lorazepam and levetiracetam. They were applied via intra-peritoneal injections at anticonvulsive doses and their effects on the spontaneous recurrent seizures were analyzed 10–12 h post-injection. Phenytoin (25 mg/kg) and levetiracetam (400 mg/kg) abolished the spontaneous recurrent seizures. Lorazepam (1.5 mg/kg) decreased motor seizure severity but did not reduce the incidence and duration of corresponding hippocampal discharges, implicating its inhibitory effects on seizure spread. No gross brain lesions were observed in a set of extended hippocampal kindled mice submitted to histological evaluation. All these data suggests that our model could be considered as a novel mouse model of extended hippocampal kindling. Some limitations remain to be considered.

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“…Analogously, it is possible to administer the antiepileptic drugs in mixture in high doses so as to determine their tolerability and adverse effect profiles, but such experiments are usually conducted in various behavioral animal models assessing untoward effects exerted by the antiepileptic drugs when injected in high doses [79,[109][110][111][112]. Of note, chronically administered antiepileptic drugs can change their own profiles due to the development of resistance and/or tolerance to the drugs [113,114]. On the other hand, the chronic induction of 6 Hz corneal stimulation-induced seizures associated with repeated electric stimulations in experimental animals is responsible for progressive seizure aggravation in rodents [47,93,94].…”

Section: Treatment (Mg/kg) Grip-strength (N)mentioning

confidence: 99%

Polygonogram and isobolographic analysis of interactions between various novel antiepileptic drugs in the 6-Hz corneal stimulation-induced seizure model in mice

et al. 2020

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Pharmacotherapy with two antiepileptic drugs in combination is usually prescribed to epilepsy patients with refractory seizures. The choice of antiepileptic drugs in combination should be based on synergistic cooperation of the drugs with respect to suppression of seizures. The selection of synergistic interactions between antiepileptic drugs is challenging issue for physicians, especially, if 25 antiepileptic drugs are currently available and approved to treat epilepsy patients. The aim of this study was to determine all possible interactions among 5 second-generation antiepileptic drugs (gabapentin (GBP), lacosamide (LCM), levetiracetam (LEV), pregabalin (PGB) and retigabine (RTG)) in the 6-Hz corneal stimulation-induced seizure model in adult male albino Swiss mice. The anticonvulsant effects of 10 various two-drug combinations of antiepileptic drugs were evaluated with type I isobolographic analysis associated with graphical presentation of polygonogram to visualize the types of interactions. Isobolographic analysis revealed that 7 two-drug combinations of LEV+RTG, LEV+LCM, GBP+RTG, PGB+LEV, GBP+LEV, PGB+RTG, PGB+LCM were synergistic in the 6-Hz corneal stimulation-induced seizure model in mice. The additive interaction was observed for the combinations of GBP+LCM, GBP+PGB, and RTG+LCM in this seizure model in mice. The most beneficial combination, offering the highest level of synergistic suppression of seizures in mice was that of LEV+RTG, whereas the most additive combination that protected the animals from seizures was that reporting additivity for RTG +LCM. The strength of interaction for two-drug combinations can be arranged from the synergistic to the additive, as follows: LEV+RTG > LEV+LCM > GBP+RTG > PGB+LEV > GBP +LEV > PGB+RTG > PGB+LCM > GBP+LCM > GBP+PGB > RTG+LCM.

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Development of Tolerance During Chronic Treatment of Kindled Rats With the Novel Antiepileptic Drug Levetiracetam

Cited by 41 publications

References 15 publications

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect

Effects of Antiepileptic Drugs on Spontaneous Recurrent Seizures in a Novel Model of Extended Hippocampal Kindling in Mice

Polygonogram and isobolographic analysis of interactions between various novel antiepileptic drugs in the 6-Hz corneal stimulation-induced seizure model in mice

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