Targeted suppression of BRD7 with BI-9564 prevents seizure behaviors in pentylenetetrazol and pilocarpine-induced mouse model of epilepsy

Abstract

Epilepsy is a serious neurological disorder, but its underlying cellular and molecular mechanisms remains incomplete. As a member of the bromodomain-containing protein (BCP) family, BRD7 has been implicated in a variety of cellular processes, including chromatin remodeling, transcriptional regulation, and cell cycle progression. However, the role of BRD7 in epilepsy in vivo is still poorly understood. In the present study, we found that pentylenetetrazole (PTZ)-induced epilepsy increased hippocampal BRD7, which was mainly localized in neurons. In addition, the enhanced expression of hippocampal BRD7 was normalized by using the anti-epilepsy drug valproic acid (VPA). Furthermore, we identified that the BRD7 inhibitor BI-9564 could dose dependently alleviated the seizure behavior in PTZ treated mice, which was also validated in pilocarpine mouse model. Mechanistically, the anti-seizure effect of BI- 9564 might be due to its negative-regulation of hippocampal TRPV4 that downregulated neuronal over-excitability. Importantly, BRD7 blockade retained its antiepileptic activity over chronic dosing that was not related to psychomotor or cognitive effects. To our knowledge, these results are the first evidence to demonstrate that BRD7 inhibitor can down-regulate neuronal over-excitation caused by epilepsy possible by regulating TRPV4. Targeting BRD7 through the development of selective inhibitors may lead to disease-modifying therapies that reduce seizure behavior.