The Role of Sirt1 in Epileptogenesis

Abstract

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 (Sirts). Sirtuins deacetylate cytoplasmic proteins and nuclear histones, and their epigenetic modulation of the chromatin governs the 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, Neuron-Restrictive Silencer Factor (NRSF) also know as REST (RE1-Silencing Transcription factor). Here we used 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 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 (using the Racine scale and EEG measures) as well as the frequency and duration of interictal 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.

News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

“…The analysis of the transcription factor was carried out in parallel to the study of cytoplasmic sirtuins, NAD-dependent class III histone deacetylases, employed to monitor the metabolic state of neurons. In mechanistic terms, epilepsy induction was largely independent of metabolic alterations [37]. Another neuronal process, known to participate in the stimulation of epilepsy, is the decrease of miR-124 [38].…”

Epigenetic changes in status epilepticus

“…Overall, the findings suggest complex patterns of increased and decreased expression after status epilepticus, including increased acetylation of histones and up-regulation of select HDACs. 27 The study found that although Sirt1 inhibition recovered expression of genes being suppressed by Sirt1 after status epilepticus, it did not significantly alter the course of epileptogenesis in the model. The common antiepileptic drug sodium valproate has known HDAC inhibitory activity, and some of the reported effects of this drug could be linked to this mode of action.…”

“…26 A recent study investigated whether blocking the class III HDAC Sirt1 affected post-status epilepticus outcomes in rats. 27 The study found that although Sirt1 inhibition recovered expression of genes being suppressed by Sirt1 after status epilepticus, it did not significantly alter the course of epileptogenesis in the model. 27 Thus, the functional significance of histone changes remains to be determined and, as with DNA methylation, tools are needed that allow select manipulation of this category of epigenetic mechanism.…”

“…[23][24][25] Functional studies on the role of histone modifications have focused in particular on HDAC inhibitors. 27 Thus, the functional significance of histone changes remains to be determined and, as with DNA methylation, tools are needed that allow select manipulation of this category of epigenetic mechanism. For example, sodium valproate is neuroprotective in models of status epilepticus and may reduce aberrant neurogenesis and improve cognitive outcomes.…”

The Expanding Therapeutic Potential of Neuronal KCC2

“…SLC12A5 transcription is regulated by a repressor element-1 (RE-1) site in its 5 regulatory region [121], and it has been reported that resveratrol could act via SIRT1 activation to downregulate the expression of RE1-silencing transcription factor/Neuron-restrictive silencer factor (REST/NRSF) [122]. The latter is a downstream target of SIRT1 [123]. Resveratrol is known to be anti-nociceptive and inhibits neuropathic pain [124,125], and also appears to be anti-epileptic [126].…”