Galanin is an endogenous neuropeptide that modulates seizures in the brain. Because this neuropeptide does not penetrate the blood-brain barrier, we designed truncated galanin analogues in which nonessential amino acid residues were replaced by cationic and/or lipoamino acid residues. The analogues prevented seizures in the 6 Hz mouse model of epilepsy following intraperitoneal administration. The most active analogue, Gal-B2 (NAX 5055), contained the -Lys-Lys-Lys(palmitoyl)-Lys-NH(2) motif and exhibited high affinity for galanin receptors (K(i) = 3.5 nM and 51.5 nM for GalR1 and GalR2, respectively), logD = 1.24, minimal helical conformation and improved metabolic stability. Structure-activity-relationship analysis suggested that cationization combined with position-specific lipidization was critical for improving the systemic activity of the analogues. Because the anticonvulsant activity of galanin is mediated by the receptors located in hippocampus and other limbic brain structures, our data suggest that these analogues penetrate into the brain. Gal-B2 may lead to development of first-in-class antiepileptic drugs.

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.

Since 1993, the Anticonvulsant Drug Development Program has contributed to the successful development of nine clinically effective drugs for the symptomatic treatment of epilepsy. These include felbamate (1993), gabapentin (1994), lamotrigine (1994), fosphenytoin (1996), topiramate (1996), tiagabine (1997), levetiracetam (1999), zonisamide (2000), and oxcarbazepine (2000). Despite the apparent success of the current discovery process, a significant need persists for more efficacious and less toxic antiepileptic drugs (AEDs). This is particularly true for patients whose seizures remain refractory to the currently available AEDs. This chapter will review the current process for AED discovery employed by the Anticonvulsant Drug Development Program at the University of Utah and other laboratories working toward the common goal of discovering better therapeutic options for patients living with epilepsy. It will discuss some of the inherent advantages and limitations of the primary animal models employed, while offering insight into potential future directions as we seek to better understand the pathophysiology underlying acquired epilepsy, therapy resistance, and epileptogenesis.

This article reports a secondary analysis of past therapy outcome meta-analysis. Fifteen meta-analysis provided effect sizes from 56 studies in previous reviews that met 1 of 3 increasingly stringent levels of criteria for clinical representativeness. The effect sizes were synthesized and compared with results from the original meta-analyses. Effect sizes from more clinically representative studies are the same size at all 3 criteria levels as in past meta-analyses. Almost no studies exist that meet the most stringent level of criteria. Results are interpreted cautiously because of controversy about what criteria best capture the notion of clinical representativeness, because so few experiments have tested therapy in clinical conditions, and because other models for exploring the generalizability of therapy outcome research to clinical conditions might yield different results.

The management of seizures in the patient with epilepsy relies heavily on antiepileptic drug (AED) therapy. Fortunately, for a large percentage of patients, AEDs provide excellent seizure control at doses that do not adversely affect normal function. At the molecular level, the majority of AEDs are thought to modify excitatory and inhibitory neurotransmission through effects on voltage-gated ion channels (e.g., sodium and calcium) and gamma-aminobutyric acid (GABA)(A) receptors, respectively. In addition to these effects, two of the "second-generation" AEDs have been found to limit glutamate-mediated excitatory neurotransmission (i.e., felbamate and topiramate). Not surprisingly, those AEDs with broad spectrum clinical activity are often found to exert an action at more than one molecular target. Emerging evidence suggests that receptor and voltage-gated subunits are modified by chronic seizures. Thus, attempts to understand the relationship between target and effect continue to provide important information about the neuropathology of the epileptic network and to facilitate the development of novel therapies for the treatment of refractory epilepsy.