The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats

Mari N. Willeman, Sarah E. Mennenga, Ashley L. Siniard, Jason J. Corneveaux, Matt De Both, Lauren T. Hewitt, Candy W.S. Tsang, Jason Caselli, Brittany Braden, Heather Bimonte-Nelson, Matthew J. Huentelman

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1 Scopus citations

Abstract

Enzastaurin is a Protein Kinase C-β selective inhibitor that was developed to treat cancers. Protein Kinase C-β is an important enzyme for a variety of neuronal functions; in particular, previous rodent studies have reported deficits in spatial and fear-conditioned learning and memory with lower levels of Protein Kinase C-β. Due to Enzastaurin’s mechanism of action, the present study investigated the consequences of Enzastaurin exposure on learning and memory in 12-month-old Fischer-344 male rats. Rats were treated daily with subcutaneous injections of either vehicle or Enzastaurin, and behaviorally tested using the spatial reference memory Morris Water Maze. Rats treated with Enzastaurin exhibited decreased overnight retention and poorer performance on the latter testing day, indicating a mild, but significant, memory impairment. There were no differences during the probe trial indicating that all animals were able to spatially localize the platform to the proper quadrant by the end of testing. RNA isolated from the hippocampus was analyzed using Next Generation Sequencing (Illumina). No statistically significant transcriptional differences were noted. Our findings suggest that acute Enzastaurin treatment can impair hippocampal-based learning and memory performance, with no effects on transcription in the hippocampus. We propose that care should be taken in future clinical trials that utilize Protein Kinase C-ß inhibitors, to monitor for possible cognitive effects, future research should examine if these effects are fully reversible.

Original languageEnglish (US)
Article numbere0198256
JournalPloS one
Volume13
Issue number6
DOIs
StatePublished - Jun 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Willeman, M. N., Mennenga, S. E., Siniard, A. L., Corneveaux, J. J., De Both, M., Hewitt, L. T., Tsang, C. W. S., Caselli, J., Braden, B., Bimonte-Nelson, H., & Huentelman, M. J. (2018). The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats. PloS one, 13(6), [e0198256]. https://doi.org/10.1371/journal.pone.0198256