Many anti-epileptic drugs (AEDs) have been introduced over the last 30 years, but the proportion of patients with inadequate control of seizures has remained unchanged at ~30%. This has led to doubts about the acute seizure models employed in preclinical AED screening because they may not capture the mechanisms most important for precipitation and control of pharmacoresistant chronic spontaneous recurrent seizures (CSRSs) in humans. Thus, there is an urgent need to develop preclinical models of pharmacoresistant epilepsy. In addition, no agent has been identified that prevents epilepsy in patients at risk, and models of epileptogenesis are also needed. Thus, substantial recent efforts have focused on the development of acquired CSRS models that closely reproduce brain insults known to be epileptogenic in humans and are, thus, likely to recruit mechanisms of ictogenesis and epileptogenesis that are relevant to the corresponding human syndrome: stroke, head injury, early-life febrile seizures, and hypoxia-ischemia. We have developed one of these etiologically realistic acquired CSRS-models in the rat, the fluid percussion injury (FPI) model of posttraumatic epilepsy (PTE), and have recently adapted it to the identification of antiepileptic (AE) and antiepileptogenic (AEG) activity. FPI is mechanically identical to human contusive closed head injury, and reproduces many of its pathophysiological sequelae. It displays focal spontaneous seizures of neocortical and limbic origin, pathology as in human PTE, and a latent period between the initiating injury and the onset of PTE. The rat frontal neocortex is more sensitive to FPI than other brain areas, resulting in faster epileptogenesis than parietal/occipita cortices and limbic structures, and generates CRSSs that are fully blocked by halothane, partially blocked by valproate, and very resistant to carbamazepine and carisbamate. Thus, FPI-induced frontal lobe PTE is a promising model of pharmacoresistant epilepsy for drug screening. However, there are substantial costs involved in all ECoG-based drug screening in chronic epilepsy models, including FPI. Further optimization of the model is needed to make FPI cost-effective for systematic preclinical drug studies. To this end we will conduct a comprehensive optimization of several parameters of FPI and ensuing injury. We will determine whether 1) controlling acute posttraumatic apnea/hypoxia allows higher incidence of PTE and more uniform seizure frequency, 2) variations in location and severity of injury better recruit frontal lobe epileptogenesis, and 3) the severity of subdural hemorrhage predicts which animals will not become epileptic. These data will be used to decrease inter- subject variability, and increase speed of epileptogenesis and incidence of PTE, which will permit cost- effective use of the FPI model in the identification of novel antiepileptic and antiepileptogenic treatments.

Public Health Relevance

Many anti-epileptic drugs have been introduced over the last 30 years, but the proportion of patients with inadequate control of seizures has remained unchanged at ~30%, and no cure for epilepsy has been found. Better models of epilepsy are urgently needed to screen for novel antiepileptic and antiepileptogenic treatments. Our proposed studies will optimize a promising new model of posttraumatic epilepsy that is resistant to classic and new antiepileptic drugs, and adapt it for efficient routine drug screening.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Stewart, Randall R
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University of Washington
Schools of Medicine
United States
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Eastman, Clifford L; Fender, Jason S; Temkin, Nancy R et al. (2015) Optimized methods for epilepsy therapy development using an etiologically realistic model of focal epilepsy in the rat. Exp Neurol 264:150-62
D'Ambrosio, Raimondo; Eastman, Clifford L; Darvas, Felix et al. (2013) Mild passive focal cooling prevents epileptic seizures after head injury in rats. Ann Neurol 73:199-209
D'Ambrosio, Raimondo; Eastman, Clifford L; Fattore, Cinzia et al. (2013) Novel frontiers in epilepsy treatments: preventing epileptogenesis by targeting inflammation. Expert Rev Neurother 13:615-25