ECoG studies of valproate, carbamazepine and halothane in frontal-lobe epilepsy induced by head injury in the rat

Abstract

The use of electrocorticography (ECoG) with etiologically realistic epilepsy models promises to facilitate the discovery of better anti-epileptic drugs (AEDs). However, this novel approach is labor intensive, and must be optimized. To this end, we employed rostral parasaggital fluid percussion injury (rpFPI) in the adolescent rat, which closely replicates human contusive closed head injury and results in posttraumatic epilepsy (PTE). We systematically examined variables affecting the power to detect antiepileptic effects by ECoG and used a non-parametric bootstrap strategy to test several different statistics, study designs, statistical tests, and impact of nonresponders. We found that logarithmically transformed data acquired in repeated-measures experiments provided the greatest statistical power to detect decreases in seizure frequencies of pre-clinical interest with just 8 subjects and with up to ~40% non-responders. We then used this optimized design to study the antiepileptic effects of acute exposure to halothane, and chronic (1 week) exposures to carbamazepine (CBZ) and valproate (VPA) one month post-injury. While CBZ was ineffective in all animals, VPA induced, during treatment, a progressive decrease in seizure frequency in animals primarily suffering from non-spreading neocortical seizures, but was ineffective in animals with high frequency of spreading seizures. Halothane powerfully blocked all seizure activity. The data show that rpFPI and chronic ECoG can conveniently be employed for evaluation of AEDs, suggest that VPA may be more effective than CBZ to treat some forms of PTE and support the theory that pharmacoresistance may depend on the severity of epilepsy. The data also demonstrate the utility of chronic exposures to experimental drugs in preclinical studies and highlight the need for greater attention to etiology in clinical studies of AEDs.

Antiepileptic and Antiepileptogenic Performance of Carisbamate after Head Injury in the Rat: Blind and Randomized Studies

“…Rostral parasaggital fluid percussion injury was performed as detailed previously (D'Ambrosio et al, 2009;Eastman et al, 2010) with care to ensure consistent procedure. In brief, animals were anesthetized (4% halothane), intubated, and mechanically ventilated (1-1.5% halothane, 30% O 2 , and air).…”

“…Each animal served as its own control. The effect of CRS on neocortical seizures was assessed 5 weeks after injury in two groups of 10 animals that all met a three seizures per baseline week criterion (Eastman et al, 2010) on postinjury week 4. The effect of CRS on limbic (G3) and spreading neocortical (G2) seizures was assessed in a cohort of seven rats, three of which had been used to test the antiepileptic effects of CRS at 4 to 6 weeks.…”

“…Graph shows group size required to provide 80% power to detect uniform decreases in seizure frequency (one-tailed ␣ ϭ 0.05). Data are from Eastman et al (2010). Data Analysis.…”

“…The acute effects of AED administration may not adequately reflect the performance of drugs administered chronically in the clinical setting (Löscher , 2007). They also cannot detect antiepileptic effects that develop slowly, over days to weeks, as observed with valproate (Löscher and Hönack, 1995;Eastman et al, 2010). Third, preclinical studies should probe the entire spectrum of epileptic seizures by electrocorticography (ECoG) and not be exclusively based on convulsive behavior.…”

“…Posttraumatic epilepsy (PTE) was induced by rostral parasaggital fluid percussion injury (rpFPI) in the rat, which is mechanically identical to human contusive head injury and reproduces many of its pathophysiological sequelae (Thompson et al, 2005), including an epileptic syndrome featuring neocortical and limbic seizures (D'Ambrosio et al, 2004(D'Ambrosio et al, , 2005(D'Ambrosio et al, , 2009) that are fully blocked by halothane, partially responsive to valproate, but resistant to carbamazepine (Eastman et al, 2010). These studies were conducted in a blind and randomized fashion, using dosing protocols designed to maintain blood levels of CRS in a therapeutic range for the duration of the on-drug phase of each study.…”