Comparison of valproate and phenobarbital treatment after status epilepticus in rats

Bolanos, Addison; Sarkisian, Matthew R.; Yang, Yili; Hori, Ariyuki; Helmers, Sandra L.; Mikati, Mohamad A.; Tandon, Pushpa; Stafstrom, Carl E.; Holmes, Gregory L.

doi:10.1212/wnl.51.1.41

Cited by 122 publications

(65 citation statements)

References 23 publications

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“…This disease-modifying effect of phenobarbital was unexpected, because prolonged administration of phenobarbital in juvenile rats did not alter the development of SRS in the kainate model of TLE ( Bolanos et al, 1998). However, in the present study, treatment with phenobarbital was started 90 min after onset of SE, whereas Bolanos et al (1998) started treatment with phenobarbital 24 h after onset of SE, so that the therapeutic window of opportunity may have been missed. Thus, one novel and important finding of the present study is that prophylactic treatment with phenobarbital after a brain insult such as SE modifies the development of epilepsy.…”

Section: Discussionmentioning

confidence: 56%

Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy

Brandt¹,

Nozadze²,

Heuchert³

et al. 2010

Journal of Neuroscience

164

166

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Accumulating evidence suggests that changes in neuronal chloride homeostasis may be involved in the mechanisms by which brain insults induce the development of epilepsy. A variety of brain insults, including status epilepticus (SE), lead to changes in the expression of the cation-chloride cotransporters KCC2 and NKCC1, resulting in intracellular chloride accumulation and reappearance of immature, depolarizing synaptic responses to GABA A receptor activation, which may critically contribute to the neuronal hyperexcitability underlying epileptogenesis. In the present study, it was evaluated whether prolonged administration of the selective NKCC1 inhibitor, bumetanide, after a pilocarpine-induced SE modifies the development of epilepsy in adult female rats. The antiepileptic drug phenobarbital, either alone or in combination, was used for comparison. Based on pharmacokinetic studies with bumetanide, which showed extremely rapid elimination and low brain penetration of this drug in rats, bumetanide was administered systemically with different dosing protocols, including continuous intravenous infusion. As shown by immunohistochemistry, neuronal NKCC1 expression was markedly upregulated shortly after SE. Prophylactic treatment with phenobarbital after SE reduced the number of rats developing spontaneous seizures and decreased seizure frequency, indicating a disease-modifying effect. Bumetanide did not exert any significant effects on development of spontaneous seizures nor did it enhance the effects of phenobarbital. However, combined treatment with both drugs counteracted several of the behavioral consequences of SE, which was not observed with single drug treatment. These data do not indicate that bumetanide can prevent epilepsy after SE, but the disease-modifying effect of this drug warrants further studies with more lipophilic prodrugs of bumetanide.

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Section: Discussionmentioning

confidence: 56%

Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy

Brandt¹,

Nozadze²,

Heuchert³

et al. 2010

Journal of Neuroscience

164

166

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“…Interestingly, it has been reported previously that patients with TLE display deficits in recognition memory (for review, see Elger et al, 2004). In addition, a previous study showed the prevention of cognitive impairment after KAinduced seizures by VPA treatment using the Morris water maze (Bolanos et al, 1998). Therefore, the inhibition of aberrant seizure-induced neurogenesis and the morphological normalization of neurons that were generated in response to SE by VPA treatment might at least partially explain the observed protection from seizure-associated cognitive impairment.…”

Section: Discussionmentioning

confidence: 86%

Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline

Jessberger¹,

Nakashima²,

Clemenson³

et al. 2007

J. Neurosci.

322

231

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The conceptual understanding of hippocampal function has been challenged recently by the finding that new granule cells are born throughout life in the mammalian dentate gyrus (DG). The number of newborn neurons is dynamically regulated by a variety of factors. Kainic acid-induced seizures, a rodent model of human temporal lobe epilepsy, strongly induce the proliferation of DG neurogenic progenitor cells and are also associated with long-term cognitive impairment. We show here that the antiepileptic drug valproic acid (VPA) potently blocked seizure-induced neurogenesis, an effect that appeared to be mainly mediated by inhibiting histone deacetylases (HDAC) and normalizing HDAC-dependent gene expression within the epileptic dentate area. Strikingly, the inhibition of aberrant neurogenesis protected the animals from seizure-induced cognitive impairment in a hippocampus-dependent learning task. We propose that seizure-generated granule cells have the potential to interfere with hippocampal function and contribute to cognitive impairment caused by epileptic activity within the hippocampal circuitry. Furthermore, our data indicate that the effectiveness of VPA as an antiepileptic drug may be partially explained by the HDAC-dependent inhibition of aberrant neurogenesis induced by seizure activity within the adult hippocampus.

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“…The present study with LEV shows that interesting results can be obtained by drug testing in epileptic rats, which are much closer to data from clinical evaluation of this drug in patients with epilepsy than are data from short-term drug testing in traditional seizure models, in which only elicited seizures are examined. In addition to using models with spontaneous recurrent seizures, such as the pilocarpine or kainate models, for evaluation of AED effects during prolonged treatment, these models also can be used to evaluate antiepileptogenic drug effects by starting treatment shortly after the SE (34,35). Automated seizurerecording systems, including EEG monitoring via telemetric devices, will certainly make long-term studies in such models less labor dependent and increase the use of epileptic animals for evaluation of anticonvulsant and antiepileptogenic drug effects.…”

Section: Discussionmentioning

confidence: 99%

Effects of the Novel Antiepileptic Drug Levetiracetam on Spontaneous Recurrent Seizures in the Rat Pilocarpine Model of Temporal Lobe Epilepsy

et al. 2002

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Summary:Purpose: Animal models in which seizures are elicited by chemical or electrical means are commonly used for identification and preclinical testing of novel antiepileptic drugs (AEDs). Such models have been successful in discovering all the new AEDs. However, despite the high efficacy of AEDs against elicited seizures in rodent models, a significant proportion of epilepsy patients with spontaneous recurrent seizures is resistant to these drugs. It is not known whether drug testing in rodent models with spontaneous recurrent seizures would yield a more predictive result with respect to AED efficacy in the clinic. This led us to test one of the novel AEDs, levetiracetam (LEV), in a rat model of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures.Methods: Wistar rats were subjected to pilocarpine-induced status epilepticus and recorded for spontaneous recurrent seizures in the months after pilocarpine treatment. A group of rats with frequent spontaneous seizures was used for the drug trial with LEV. The experimental protocol for drug testing in these rats was as follows. For 2 weeks, rats received subcutaneous implantation of osmotic minipumps filled with saline (predrug control period), followed by a 2-week period with implantation of LEV-filled minipumps (drug period), after which pumps were replaced by drug-free pumps for 2 weeks (postdrug control period). The LEV concentration in the pumps during the drug period was adjusted to give daily doses resulting in the maximal plasma concentration range determined previously in patients with TLE during prolonged treatment with LEV. During the 6 weeks of the experiment in epileptic rats, seizures were recorded by video monitoring.Results: Average seizure frequency during the pre-and postdrug control period in a group of eight epileptic rats was 21 and 25 seizures. This was reduced to an average seizure frequency of 8 seizures during the 2 weeks of treatment with LEV. However, the individual response of rats to LEV varied markedly from complete seizure control to no effect at all, although plasma drug levels were within the therapeutic range in all rats. When seizure frequency was separately calculated for the first and second week of treatment, the significant anticonvulsant effect determined in the first week was partially diminished in the second week, suggesting that tolerance may have developed in some of the rats.Conclusions: The data demonstrate that interesting results can be obtained by drug testing in epileptic rats, giving a more realistic prediction of clinical efficacy than results from drug testing in animal models with elicited seizures. Thus, although drug trials in rats with spontaneous recurrent seizures are laborious and time-consuming, such trials should be added to the preclinical characterization of novel AEDs.

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Comparison of valproate and phenobarbital treatment after status epilepticus in rats

Abstract: The long-term consequences of AED treatment during development are related to the drug used. VPA treatment after KA-induced status epilepticus prevents many of the neurologic sequelae typically seen after KA.

Cited by 122 publications

References 23 publications

Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy

Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy

Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline

Effects of the Novel Antiepileptic Drug Levetiracetam on Spontaneous Recurrent Seizures in the Rat Pilocarpine Model of Temporal Lobe Epilepsy

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