Treatment with valproate after status epilepticus: Effect on neuronal damage, epileptogenesis, and behavioral alterations in rats

Brandt, Claudia; Gastens, Alexandra M.; Sun, Mei zhen; Hausknecht, Maria; Löscher, Wolfgang

doi:10.1016/j.neuropharm.2006.05.021

Cited by 136 publications

(95 citation statements)

References 55 publications

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“…Rats treated with this protocol exhibited significantly reduced anxiety-like behavior in the open field. In the elevated plus maze, in which epileptic rats from the pilocarpine model typically exhibit an increase in time spent on the aversive open arms (Detour et al, 2005;Dos Santos et al, 2005;Brandt et al, 2006), which has been explained by enhanced impulsive inadapted behavior (Detour et al, 2005), treatment with bumetanide infusion plus phenobarbital counteracted this behavior. It is also interesting to note that this treatment group did not exhibit significantly increased behavioral hyperexcitability in the pick-up test described by Rice et al (1998); a similar effect was also determined for the group in which bumetanide was infused alone.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…It is therefore not surprising that some of these AEDs, particularly valproate, levetiracetam, and topiramate, were reported to exert disease-modifying effects in rat SE models of epileptogenesis [4]. More recently, we used valproate, which we found previously to exert disease-modifying and neuroprotective effects in an electrical SE model of epileptogenesis [26], to determine the therapeutic window of this effect. By using a protocol that allowed us to effectively interrupt SE and compare various treatment protocols with valproate administered after SE, we found that continuous infusion of valproate for 24 h immediately after the SE was the most effective neuroprotective treatment, preventing most of the neuronal damage in the hippocampal formation, including the dentate hilus [27].…”

Section: Studies With Aedsmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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“…In a subsequent study in our laboratory, using a model in which SE is induced by sustained electrical stimulation of the basolateral amygdala (BLA), prolonged treatment with valproate after SE exerted no antiepileptogenic or disease-modifying effect on the development of spontaneous seizures (Brandt et al, 2006a). However, the treatment prevented damage in the hippocampal formation, including the dentate hilus, and most of the behavioral alterations associated with epilepsy in this model.…”

mentioning

confidence: 94%

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

Löscher¹,

Brandt²

2010

Pharmacol Rev

365

366

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Treatment with valproate after status epilepticus: Effect on neuronal damage, epileptogenesis, and behavioral alterations in rats

Cited by 136 publications

References 55 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

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

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