The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults, including trauma, stroke, tumors, infections and long seizures (status epilepticus; SE), create a neuronal state of increased metabolic demand or decreased energy supply. Neurons express molecules that monitor their metabolic state, including Sirtuins. Sirtuins deacetylate cytoplasmic proteins and nuclear histones, and their epigenetic modulation of the chromatin governs expression of many genes, influencing neuronal properties. Thus, sirtuins are poised to enduringly modulate neuronal properties following SE, potentially contributing to epileptogenesis, a hypothesis supported by the epilepsy-attenuating effects of blocking a downstream target of Sirt1, NRSF/REST. Here we employed an adult male rat model of epileptogenesis provoked by kainic acid–induced SE (KA-SE). We assessed KA-SE–provoked Sirt1 activity, infused a Sirt1 inhibitor (EX-527) after KA-SE, and examined for epileptogenesis using continuous digital video–EEG. Sirt1 activity, measured using chromatin immunoprecipitation for Sirt1 binding at a target gene, increased rapidly after SE. Post-hoc infusion of the Sirt1 inhibitor prevented Sirt1-mediated–repression of a target gene. Blocking Sirt1 activity transiently after KA-SE had did not significantly influence the time-course and all of the parameters of epilepsy development. Specifically, latency to first seizure and seizure number, duration and severity (employing Racine scale and EEG measures) as well as the frequency and duration of inter-ictal spike series, were all unchanged. KA-SE provoked a robust inflammatory response and modest cell loss, yet neither was altered by blocking Sirt1. In conclusion, blocking Sirt1 activity after KA-SE does not abrogate epilepsy development, suggesting that the mechanisms of such acquired epileptogenesis are independent of Sirt1 function.
Significance Statement Epilepsy is the 3rd most common chronic brain disorder. It is often triggered by insults to the brain such as trauma, stroke, and long seizures. These insults alter neuronal metabolism, which is then sensed by Sirtuins. Here, we examine the role of Sirt1 in the mechanism of insult-induced epilepsy development. We effectively blocked, using post-hoc intervention, the rapid increase in Sirt1 activity. Notably, this intervention did not abrogate insult-provoked epileptogenesis, or the associated inflammatory response and modest cell loss. These findings suggest that Sirt1 activation is not required for KA-SE epileptogenesis or down-stream actions of this potent transcriptional regulator play complex and perhaps suggests opposing roles in epileptogenesis.
1 Authors report no conflict of interest.
3 NIH grants NS 35439; NS 78279.