Proteomic profile of mouse hippocampus following kainate-induced epileptogenesis C4PR_LIV

ABSTRACT: Anti-epileptogenic agents that prevent the development of epilepsy following a brain insult remain the holy grail of epilepsy therapeutics. In order to identify such drugs, it is necessary to first understand the cellular and molecular events that underlie the epileptogenic process, from initial insult to the onset of spontaneous recurrent seizures. We have employed a label-free proteomic approach that allows quantification of large numbers of brain-expressed proteins in a single analysis in the well-established kainate (KA) mouse (C57BL/6J) model of epileptogenesis. In addition, we have incorporated two putative antiepileptogenic drugs, PSD95BP and 1400W, to give an insight into how such agents might ameliorate the epileptogenesis. The test drugs were administered at appropriate time-points after induction of status epilepticus (SE) and animals were euthanized at 7 days, their hippocampi removed, and subjected to LC-MS/MS analysis. A total of 2,579 proteins were identified; their normalized abundance was compared between treatment groups using ANOVA, with correction for multiple testing by false discovery rate. Significantly altered proteins were subjected to gene ontology analysis to look for enrichment of specific biological processes. KA-induced SE was most robustly associated with an increase in proteins involved in neuroinflammation, oxidative stress, cell-cell interactions and synaptic plasticity. Treatment with PSD95BP (Tat-NR2B9c) or an iNOS inhibitor, 1400W modulated several of these proteins. Our observations require validation in a larger-scale investigation, with candidate proteins explored in more detail. Nevertheless, this study has identified several mechanisms by which epilepsy might be developed and several targets for novel drug development.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Deborah Simpson  

LAB HEAD: Thimmasettappa Thippeswamy

PROVIDER: PXD010986 | Pride | 2019-05-23

REPOSITORIES: Pride