Characterization of a Rat Model of Human Temporal Lobe Epilepsy

Epilepsy is the second most common neurologic disorder, and among epilepsies temporal lobe epilepsy (TLE) is the most common form of symptomatic epilepsy. Symptomatic TLE generally develops in three phases: initial -insult → epileptogenesis → epilepsy (i.e., spontaneous seizures). Several cellular and molecular alterations occur in epileptic brain, including neuronal loss, neurogenesis, and axonal sprouting. Therefore, understanding the mechanisms involved in seizure development and the subsequent degenerative process is crucial for designing new drug treatment strategies for TLE. The development of specific tools (i.e., experimental models) is one of the first steps toward this understanding. The aim of this study was to develop an epilepsy model that would mimic different aspects of human TLE, including symptomatology of spontaneous seizures, neuropathology, and behavioral impairment. The developed model, in which spontaneous seizures occurred in the majority of the animals, was used to study whether mossy fiber sprouting contribute to the generation of spontaneous seizures in epileptic rats. Pharmacologic manipulation of the epileptogenesis using two different antiepileptic drugs with different mechanisms of action was also studied. In addition, the efficacy of four antiepileptic drugs that are used in human TLE patients was examined in this model. The main findings of the present study were: 1) After status epilepticus as an initial insult, 87% of stimulated animals developed spontaneous seizures after an approximately 1-month latency period. 2) Histopathologic findings resembled those observed in human TLE patients. 3) At the time of epilepsy diagnosis, there was increased sprouting of granule cell axons in epileptic animals. Sprouting can occur, however, without spontaneous seizures. 4) Modulation of epileptogenesis with the gamma-aminobutyric acid (GABA)-ergic drug vigabatrin did not prevent the development of epilepsy. Modulation of epileptogenesis with Na-channel blocker lamotrigine did not prevent the development of epilepsy. 5) Rats with focal epilepsy responded to the same compounds used to treat seizures of focal onset in humans. In summary, the developed experimental epilepsy model for chronic TLE in rats provides a valuable tool to investigate the evolution of chronic epilepsy and develop new pharmacological approaches for prevention and treatment of human TLE. National Library of Medicine Classification: WL 385, WL 340, QY 58 Medical Subject Headings: epilepsy, temporal lobe; disease models, animal; epilepsy/pathology; seizures; mossy fibers, hippocampal; hippocampus/pathology; amygdala; neurons; behavior; memory; status epilepticus; epilepsy/drug therapy; anticonvulsants; rats