Therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive AMPA receptor antagonist NS1209 following status epilepticus in rats

Langer, Melanie; Brandt, Claudia; Zellinger, Christina; Löscher, Wolfgang

doi:10.1016/j.neuropharm.2011.06.015

Cited by 36 publications

(23 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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]. This suggests that the therapeutic window may be open for a shorter period than commonly assumed, and as recently suggested [28,29].…”

Section: Studies With Aedsmentioning

confidence: 58%

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

White

Löscher²

2014

Neurotherapeutics

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Studies With Aedsmentioning

confidence: 58%

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

White

Löscher²

2014

Neurotherapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Experimental and clinical studies have used antiepileptic drugs to abort post-injury epileptogenesis, but with minimal success (Dichter, 2009; Temkin, 2009; Löscher and Brandt, 2010; Pitkänen, 2010; Eastman et al, 2011; Langer et al, 2011). Although the right drugs may have been tested at the wrong doses, for the wrong duration, or at the wrong time after brain injury, it is also possible that antiepileptic drugs do not influence the injury-induced “epileptogenic” process.…”

Section: What Is “Epileptogenesis” Exactly and How Can It Be Prevented?mentioning

confidence: 99%

“…If the name “epileptogenesis” describes an immediate change in network excitability and behavior caused by neuron loss, as we have proposed (Sloviter, 1994; Bumanglag and Sloviter, 2008), then an antiepileptogenesis strategy should incorporate the possibility that the brain may become immediately “epileptic” even if the disorder is not immediately obvious clinically. If so, a fruitful therapeutic strategy might focus on minimizing delayed cell death in the immediate post-injury period (Sloviter et al, 1996; Poirier et al, 2000; Brandt et al, 2003b; Langer et al, 2011; Sloviter, 2011). Conversely, if “epileptogenesis” necessarily involves the maturation of a slowly developing secondary process triggered by brain injury, then neuron loss may not be directly epileptogenic, and antiepileptogenesis strategies might logically focus on preventing one or more of the secondary processes that injuries initiate (Chang and Lowenstein, 2003; Rakhade and Jensen, 2009).…”

Section: What Is “Epileptogenesis” Exactly and How Can It Be Prevented?mentioning

confidence: 99%

Defining “epileptogenesis” and identifying “antiepileptogenic targets” in animal models of acquired temporal lobe epilepsy is not as simple as it might seem

Sloviter

Bumanglag

2013

Neuropharmacology

View full text Add to dashboard Cite

The “latent period” between brain injury and clinical epilepsy is widely regarded to be a seizure-free, pre-epileptic state during which a time-consuming cascade of molecular events and structural changes gradually mediates the process of “epileptogenesis.” The concept of the “latent period” as the duration of “epileptogenesis” implies that epilepsy is not an immediate result of brain injury, and that anti-epileptogenic strategies need to target delayed secondary mechanisms that develop sometime after an initial injury. However, depth recordings made directly from the dentate granule cell layers in awake rats after convulsive status epilepticus-induced injury have now shown that whenever perforant pathway stimulation-induced status epilepticus produces extensive hilar neuron loss and entorhinal cortical injury, hyperexcitable granule cells immediately generate spontaneous epileptiform discharges and focal or generalized behavioral seizures. This indicates that hippocampal injury caused by convulsive status epilepticus is immediately epileptogenic and that hippocampal epileptogenesis requires no delayed secondary mechanism. When latent periods do exist after injury, we hypothesize that less extensive cell loss causes an extended period during which initially subclinical focal seizures gradually increase in duration to produce the first clinical seizure. Thus, the “latent period” is suggested to be a state of “epileptic maturation,” rather than a prolonged period of “epileptogenesis,” and therefore the antiepileptogenic therapeutic window may only remain open during the first week after injury, when some delayed cell death may still be preventable. Following the perhaps unavoidable development of the first focal seizures (“epileptogenesis”), the most fruitful therapeutic strategy may be to interrupt the process of “epileptic maturation,” thereby keeping focal seizures focal.

show abstract

“…For over 20 years, the AMPA receptor has been investigated for its potential as a target for the treatment of epilepsy and other neurodegenerative diseases based on its direct role in glutamate-mediated excitatory neurotransmission and synaptic plasticity [10][11][12][13]. The AMPA receptor has also been specifically linked to temporal lobe epilepsy [14,15], and it may have a key function in seizure-induced neuronal injury [16].…”

Section: Introductionmentioning

confidence: 99%

Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy

Hibi

2015

Successful Drug Discovery

View full text Add to dashboard Cite

Therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive AMPA receptor antagonist NS1209 following status epilepticus in rats

Cited by 36 publications

References 45 publications

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

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

Defining “epileptogenesis” and identifying “antiepileptogenic targets” in animal models of acquired temporal lobe epilepsy is not as simple as it might seem

Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy

Contact Info

Product

Resources

About