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Preclinical Profiling and Safety Studies of ABT-769: A Compound with Potential for Broad-spectrum Antiepileptic Activity

William J. Giardina, Michael J. Dart, Richard R. Harris, Robert S. Bitner, Richard J. Radek, Gerard B. Fox, Sanjay R. Chemburkar, Kennan C. Marsh, Jeffrey F. Waring, Julia Y Hui, Jinhua Chen, Peter Curzon, George K. Grayson, Victoria A. Komater, Yiyin Ku, Mark Lockwood, Holly M. Miner, Arthur L. Nikkel, Jia Bao Pan, Yu-Ming Pu, Lei Wang, Youssef Bennani, Niklaus Durmuller, Robert Jolly, Sylvain Roux, James P. Sullivan, and Michael W. Decker

The search for new antiepileptic drugs is driven by the need for drugs with broad-spectrum efficacy and with safety and tolerability better than current agents. This study identified a new compound, ABT-769, that meets these criteria in animal models. In the mouse, ABT-769 protected against convulsive seizures induced by electroshock and by the chemical convulsant pentylenetetrazol. In the rat, ABT-769 suppressed focal seizures produced by repeated brain stimulation. ABT-769 also reduced absence-like seizures in a rat model of nonconvulsive epilepsy, in which spontaneous, abnormal EEG patterns resemble those observed in human absence seizures and are not accompanied by overt convulsions. Thus, ABT-769 was effective against both convulsive and nonconvulsive seizures in rodents. No tolerance was evident after repeated dosing. Moreover, ABT-769 did not impair learning and memory in the mouse at anticonvulsant doses.

Similarly, the compound did not impair motor coordination at anticonvulsant doses in the mouse, although it did disrupt coordination at higher doses. ABT-769 did not alter the oxidation of fatty acids in mitochondria in rat liver, and it did not produce neural tube defects in mice exposed to the compound in utero. Thus, ABT-769 is a potent antiseizure agent in animal models of convulsive and nonconvulsive epilepsy and has a favorable safety profile. ABT-769 has an efficacy profile in these models like that of the broad-spectrum antiepileptic drug, valproic acid. In contrast, its profile in animal models is clearly different from those of several other antiepileptic drugs, including carbamazepine, phenytoin, lamotrigine, topiramate, vigabatrin and tiagabine.

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Long-lasting Antiepileptic Effects of Levetiracetam against Epileptic Seizures in the Spontaneously Epileptic Rat (SER): Differentiation of Levetiracetam from Conventional Antiepileptic Drugs

Cai Ji-qun, Kumatoshi Ishihara, Takashi Nagayama, Tadao Serikawa, and Masashi Sasa

Levetiracetam is a novel antiepileptic drug with broad-spectrum activity in several animal models mimicking both partial and generalized epilepsy. There is evidence to suggest that levetiracetam also possesses antiepileptogenic properties and has a novel mechanism of action. The purpose of this study was to investigate the time-course of seizure protection by levetiracetam compared to that of phenytoin, phenobarbital, valproate and carbamazepine in the Spontaneously Epileptic Rat which is a double mutant (tm/tm, zi/zi) showing both tonic convulsions and absence-like seizures. Both seizure types were inhibited following single administration of levetiracetam at 80 and 160 mg/kg i.p., but not significantly at 40 mg/kg i.p. The number of tonic convulsions and absence-like seizures were significantly reduced to 39.1 % and 38.4 % respectively compared with prevalues on the last day after 5 days of administration (80 mg/kg/day i.p.). Furthermore, significant inhibition of tonic convulsions and absence-like seizures were detected up to 3 days and 8 days, respectively, after the last administration of levetiracetam. These results demonstrate long-lasting seizure protection by levetiracetam after cessation of the treatment. Phenytoin, phenobarbital, valproate and carbamazepine inhibited tonic convulsions more potently by 5 day administration compared with levetiracetam in SER. However, long-lasting protection as with levetiracetam, was not observed with any of these drugs except for phenytoin and carbamazepine, both of which showed moderately prolonged anti-seizure effects. The long-lasting effect of levetiracetam suggests that the drug may possesses an anti-epileptogenic effect distinct from conventional anti-epileptic drugs.

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Increased Expression of Ferritin, an Iron-storage Protein, in Specific Regions of the Parahippocampal Cortex of Epileptic Rats

Jan A. Gorter, Ana R.M. Mesquita, Erwin A. Van Vliet, Fernando H. Lopes Da Silva, and Eleonora Aronica

Iron accumulation in the brain has been associated with neurodegenerative disorders, including epilepsy. Ferritin, an iron storage protein, is one of the genes that show overexpression prior to the chronic epileptic phase. In this study we used ferritin as indicator for disturbed iron homeostasis in order to get insight whether this could play a role in the pathogenesis of temporal lobe epilepsy. Using immunocytochemistry, we studied the regional and cellular distribution of ferritin protein in an animal model for temporal lobe epilepsy in which spontaneous seizures develop a few weeks after electrically-induced status epilepticus (SE). Increased ferritin expression was observed in regions known to be vulnerable to cell death, mainly in reactive microglial cells of epileptic rats. Ferritin expression after SE was initially high, especially throughout the hippocampus, but decreased over time. In the chronic epileptic phase it was still upregulated in regions where extensive cell loss occurs during the early acute and latent period. Within the parahippocampal region, the most persistent ferritin overexpression was present in microglial cells in layer III of the medial entorhinal area. The upregulation was most extensive in rats that had developed a progressive form of epilepsy with frequent seizures (∼10 seizures per day). The fact that ferritin upregulation is still present in specific limbic regions in chronic epileptic rats, when neuronal loss is absent or minimal, suggests a role of iron in the pathogenesis and progression of epilepsy.

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Brainstem Seizure Severity Regulates Forebrain Seizure Expression in the Audiogenic Kindling Model

Michelle A. Merrill, Richard W. Clough, Phillip C. Jobe, and Ronald A. Browning

Generalized convulsive seizures can be clonic or tonic–clonic depending on whether they begin in the forebrain or brainstem, respectively. Sound-induced or "audiogenic" seizures in genetically susceptible rat strains originate from the brainstem. However, daily repetition of audiogenic seizures results in seizure spread into the forebrain and “kindling” of the forebrain seizure network. This results in the behavioral manifestations of forebrain-evoked convulsions (i.e., facial and forelimb clonus) and is referred to as “audiogenic kindling.” It has previously been shown that one substrain of Genetically Epilepsy-Prone Rat, the GEPR-9, that display the most severe audiogenic seizure (i.e., tonic extensor convulsions) in response to a loud sound, fails to display a forebrain convulsion following audiogenic kindling. The present study tested the hypothesis that the forebrain networks of GEPR-9s were, in fact, kindled to seize, but that the clonic convulsions are not be expressed due to continued brainstem activity that accompanies the more severe brainstem seizures (e.g. ongoing epileptic discharge). This hypothesis is supported by the present study, in which suppression of the brainstem seizure with either low dose phenytoin or lesions of the midbrain leads to the expression of forebrain convulsions in GEPR-9s after audiogenic kindling. Similarly, rats that display only moderate audiogenic seizures (GEPR-3s) and have distinct forebrain clonus when kindled, became resistant to forebrain clonus when the severity of their brainstem seizures is increased by pharmacological treatment. These findings show that brainstem seizure severity can modulate forebrain seizure expression.

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Modulation of CaM Kinase II Activity Is Coincident with Induction of Status Epilepticus in the Rat Pilocarpine Model

Michael W. Singleton, William H. Holbert II, Anh Tuyet Lee, James M. Bracey, and Severn B. Churn

Status epilepticus (SE), a life-threatening medical emergency, is defined as continuous seizure activity, or recurrent seizure activity without the patient regaining consciousness, for greater than 30 minutes. However, more recent reports state the importance of treating seizures early, within 5 minutes. This is important because as seizure activity progresses in SE, the ability to terminate seizure activity with current medications is lost. Therefore, understanding the early cellular effects of prolonged seizure activity is imperative to understanding the sequence of events through which SE patients lose the ability to respond to medical treatments. The purpose of this study was to characterize the early SE-induced changes in CaM kinase II activity; a neuronally enriched enzyme that has been shown to modulate neuronal excitation. Seizure progression in the pilocarpine model of SE was characterized both behaviorally and electrographically to carefully assess seizure progression. At specific time points, brain tissue was harvested and tested for CaM kinase II activity, and protein expression levels in both whole tissue homogenates and in subcellular fractions. The data demonstrated that inhibition of CaM kinase II activity was co-incident with the induction of SE. Examination of subcellular fractions demonstrated a significant increase in synaptic kinase activity, followed by a continual decline as SE progresses. The results suggest that modulation of CaM kinase II activity is involved in the early cellular responses to SE induction. In addition, the data suggests that CaM kinase II activity is differentially modulated in specific subcellular regions in both the hippocampus and cortex.