Sensitivity of unilateral- versus bilateral-onset spike-wave discharges to ethosuximide and carbamazepine in the fluid percussion injury rat model of traumatic brain injury

Abstract

Unilateral-onset spike-wave discharges (SWDs) following fluid percussion injury (FPI) in rats have been used for nearly two decades as a model for complex partial seizures in human post-traumatic epilepsy (PTE). This study determined if SWDs with a unilateral versus bilateral cortical onset differed. In this experiment, 2-month old rats received severe FPI (3 atm) or sham surgery, and were instrumented for chronic video-electrocorticography (ECoG) recording (up to 9 months). The anti-seizure drug, carbamazepine (CBZ), and the anti-absence drug, ethosuximide (ETX), were administered separately to determine if they selectively suppressed unilateral- versus bilateral-onset SWDs, respectively. SWDs did not significantly differ between FPI and sham rats on any measured parameter (wave-shape, frequency spectrum, duration, or age-related progression), including unilateral (~17%) versus bilateral (~83%) onsets. SWDs with a unilateral onset preferentially originated ipsilateral to the craniotomy in both FPI and sham rats, suggesting that the unilateral-onset SWDs were related to surgical injury and not specifically to FPI. ETX profoundly suppressed SWDs with either unilateral or bilateral onsets, and CBZ had no effect on either type of SWD. These results suggest that SWDs with either a unilateral or bilateral onset have a pharmacosensitivity similar to absence seizures and are very different from the complex partial seizures of PTE. Therefore, SWDs with a unilateral onset after FPI are not a model of the complex partial seizures that occur in PTE, and their use for finding new treatments for PTE could be counterproductive, particularly if their close similarity to normal brain oscillations is not acknowledged.

Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

“…These seizures were poorly responsive to subchronic treatment with carbamazepine, valproate, and carisbamate [147,148] but were prevented by mild focal cooling and brivaracetam [149,150]. However, the definition of focal seizures used by D'Ambrosio et al and their use for drug testing has been criticized [151][152][153], although the principal findings of D'Ambrosio were reproduced more recently by another group [154]. Furthermore, by increasing the severity of lateral FPI-induced brain injury, Smith et al [155] reported that >60% of rats exhibit convulsive SRSs within 2-5 weeks after FPI, which would make the model more suitable for drug testing, provided these findings can be replicated by other groups.…”

Dexmedetomidine, an alpha 2A receptor agonist, triggers seizures unilaterally in GAERS during the pre-epileptic phase: does the onset of spike-and-wave discharges occur in a focal manner?

“…These results suggest that SWDs are completely abolished after bilateral removal of the focal region, most likely by interfering with an intracortical columnar circuit ( 27 ), which also supports the cortical focus, whereas only inhibition of the local cortical network removed all seizures. Another unilateral onset is that SWDs have induced fluid percussion injury in rats, and it serves as a model for complex partial seizures in human post-traumatic epilepsy ( 28 ). In this model, anti-absence ethosuximide has been shown to suppress both unilateral or bilateral SWDs, whereas carbamazepine had no effect ( 28 ).…”

“…Another unilateral onset is that SWDs have induced fluid percussion injury in rats, and it serves as a model for complex partial seizures in human post-traumatic epilepsy ( 28 ). In this model, anti-absence ethosuximide has been shown to suppress both unilateral or bilateral SWDs, whereas carbamazepine had no effect ( 28 ). Some drugs, such as potassium chloride, block SWDs somewhat in the ipsilateral cortex and thalamus ( 29 ).…”