Abstracts

Rationale: The mechanisms by which brain insults such at traumatic brain injury, infection and status epilepticus, lead to epilepsy remain unclear. All of these insults create a state of increased metabolic demand, or decreased energy supply, in neurons. Many molecules monitor the metabolic state of the cell including Sirtuins. Sirtuins also act as epigenetic modulators that govern expression of many genes, thus influencing neuronal properties and excitability. Sirt1 function rapidly increases after kainic acid induced status epilepticus (KA-SE), promoting abnormal upregulation of neuron-restrictive silencer factor (NRSF). Notably, prior studies found that blocking NRSF function in the same rat model attenuated epileptogenesis short-term. Therefore, we tested if blocking Sirt1 function immediately and transiently following KA-SE aborted the ensuing epileptogenesis. Methods: We identified a Sirt1 inhibitor dose that prevented Sirt1 activity. We then infused the Sirt1 inhibitor, Ex527, ICV immediately after KA-SE in adult male rats. We employed digital video- EEG 24/7 for 2 months to determine if transiently blocking Sirt1 activity prevented epileptogenesis, by quantifying latency to first seizure, seizure number, duration and Racine scale. Results: Ex527 at doses used here blocked Sirt1 activity. Blocking Sirt1 activity after KA-SE does not influence latency to first seizure, seizure number or severity employing both Racine scale and EEG. Neuroanatomical studies identified modest and similar cell loss in all experimental groups. Conclusions: Blocking Sirt1 activity in adult rats after KA-SE does not block epileptogenesis. Funding: NIH grant NS 35439