Expression and activation of caspases in the brain during epileptogenesis

Temporal lobe epilepsy (TLE) is the most common form of symptomatic epilepsies. TLE is associated with neurodegeneration that can be either the cause or consequence of the underlying pathology or a result of the recurrent spontaneous seizures. Therefore, understanding of the mechanisms of degenerative processes is crucial in designing of new drug therapies for TLE. Caspases are proteolytic enzymes that are activated during programmed cell death. These enzymes are responsible both for the initiation of the death signaling and the cleavage of cellular substrates which ultimately results in cell death. Because in normal healthy cells caspases typically exist in inactivated form, inhibition of their enzymatic activity prior to or during the neurodegenerative events might result in reduced cell death and in a better functional outcome. To model human TLE, several rat models of TLE have been developed in which an initial brain insult such as status epilepticus (SE) causes epileptogenesis and epilepsy. In these models, both pathologic and electrophysiologic features resemble human TLE. The main aim of this study was to investigate the detailed temporal and spatial expression and activation of caspases in rat model of TLE a) acutely after SE, b) during epileptogenesis, and c) epilepsy. Further, the effects of pharmacological inhibition of caspases on the neurodegeneration after SE and the development of epilepsy were evaluated. In addition, expression of caspases in human TLE was assessed from the hippocampal specimens derived from patients operated on for drug refractory TLE. The main findings of the present study were: 1) Caspases are enzymatically activated acutely after SE and also later during the epileptogenesis, 2) Individual caspases have differential cellular and subcellular expression patterns during the course of epilepsy, 3) Caspase 3 inhibition reduces neuronal damage after SE but it does not prevent the development of epilepsy. 4) In TLE patients, caspase 2 localizes in the remaining hippocampal neurons. In summary, these results provide new data about the role of caspases in epileptogenic processes both in rats and humans. National Library of Medicine Classification: WL 385, WL 102.5, QU 136 Medical Subject Headings: epilepsy/pathology; epilepsy, temporal lobe; status epilepticus; caspases; apoptosis; kainic acid; amygdala; electric stimulation; hippocampus; temporal lobe; neurons; neuroglia; seizures; necrosis; electroencephalography; human; rats In memory of Armi Alaluusua