# Chidamide Is Screened to Suppress Epileptogenesis in Mice Models via Blocking Histone Deacetylase 1

## TL;DR

Chidamide, an HDAC inhibitor, reduces epileptogenesis in mice by blocking HDAC1, showing potential as a new anti-epileptic therapy.

## Contribution

Chidamide is identified as a novel HDAC1 inhibitor with anti-epileptogenic effects in preclinical models.

## Key findings

- Chidamide reduced seizure susceptibility in acute PTZ- and KA-induced epilepsy models.
- Chidamide attenuated SRS, improved neuronal survival, and suppressed glial activation in chronic models.
- Neuronal HDAC1 overexpression reversed the anti-epileptogenic effects of chidamide.

## Abstract

Disease‐modifying and anti‐epileptogenic therapies for epilepsy remain limited. Given the critical role of histone deacetylases (HDACs) in epileptogenesis, this study aimed to identify effective HDAC inhibitors and evaluate their anti‐epileptogenic potential.

A Mg2+‐free neuron‐like PC12 cell model was used to screen FDA‐approved HDAC inhibitors in vitro. Acute and chronic epilepsy models were induced in mice using pentylenetetrazol (PTZ) or kainic acid (KA). Spontaneous recurrent seizures (SRS) were monitored by electroencephalogram (EEG). Neuronal survival, mossy fiber sprouting (MFS), and glial activation were assessed by Nissl staining, Timm staining, and immunofluorescence, respectively. HDAC1 expression was analyzed by Western blot and immunofluorescence. Neuron‐specific HDAC1 overexpression was achieved using adeno‐associated virus (AAV2; hereafter referred to as AAV)‐mediated gene transfer.

Chidamide (Chi) exhibited the most inhibitory effect among nine HDAC inhibitors. Chi significantly reduced seizure susceptibility in acute PTZ‐ and KA‐induced models. In the chronic KA model, Chi attenuated SRS, improved neuronal survival, reduced MFS, and suppressed astrocytic and microglial activation. Chi markedly decreased hippocampal HDAC1 expression, while neuronal HDAC1 overexpression abolished its anti‐epileptogenic effects.

Chi attenuates epileptogenesis by inhibiting neuronal HDAC1 and may serve as a promising repurposed anti‐epileptogenic therapy.

Proposed model of the anti‐epileptogenic actions of chidamide. Chidamide mitigates drug‐induced seizure severity during the early stage of epileptogenesis, suppresses status‐epilepticus‐driven spontaneous recurrent seizures, and alleviates key pathological hallmarks, including mossy fiber sprouting, neuronal loss, and reactive astrocytic and microglial proliferation in the middle stage.