Tse, K., Hammond, D., Simpson, D., Beynon, R. J., Beamer, E., Tymianski, M., Salter, M. W., Sills, G. J. and Thippeswamy, T. (2019) The impact of post-synaptic density 95 blocking peptide (Tat-NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate-induced epileptogenesis. Journal of Neuroscience Research, 97(11), pp. 1378-1392. (doi: 10.1002/jnr.24441) (PMID:31090233)
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Abstract
Antiepileptogenic agents that prevent the development of epilepsy following a brain insult remain the holy grail of epilepsy therapeutics. We have employed a label‐free proteomic approach that allows quantification of large numbers of brain‐expressed proteins in a single analysis in the mouse (male C57BL/6J) kainate (KA) model of epileptogenesis. In addition, we have incorporated two putative antiepileptogenic drugs, postsynaptic density protein‐95 blocking peptide (PSD95BP or Tat‐NR2B9c) and a highly selective inducible nitric oxide synthase inhibitor, 1400W, to give an insight into how such agents might ameliorate epileptogenesis. The test drugs were administered after the induction of status epilepticus (SE) and the 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 and KEGG pathway enrichment analyses. KA‐induced SE was most robustly associated with an alteration in the abundance of proteins involved in neuroinflammation, including heat shock protein beta‐1 (HSP27), glial fibrillary acidic protein, and CD44 antigen. Treatment with PSD95BP or 1400W moderated the abundance of several of these proteins plus that of secretogranin and Src substrate cortactin. Pathway analysis identified the glutamatergic synapse as a key target for both drugs. 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 develop and several targets for novel drug development.
| Item Type: | Articles |
|---|---|
| Additional Information: | Funding information: The National Institute of Health (NIH), Grant/Award Number: 1R21NS099007‐01A1; BBSRC, UK, Grant/Award Number: Proteomics/TT‐GJS/2010; University of Liverpool, Grant/Award Number: IACD/TT/Ph.D/2011 |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Sills, Dr Graeme |
| Authors: | Tse, K., Hammond, D., Simpson, D., Beynon, R. J., Beamer, E., Tymianski, M., Salter, M. W., Sills, G. J., and Thippeswamy, T. |
| College/School: | College of Medical Veterinary and Life Sciences |
| Journal Name: | Journal of Neuroscience Research |
| Publisher: | Wiley |
| ISSN: | 0360-4012 |
| ISSN (Online): | 1097-4547 |
| Published Online: | 15 May 2019 |
| Copyright Holders: | Copyright © 2019 Wiley Periodicals, Inc. |
| First Published: | First published in Journal of Neuroscience Research 97(11):1378-1392 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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