The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats
AuthorWilleman, Mari N.
Mennenga, Sarah E.
Siniard, Ashley L.
Corneveaux, Jason J.
De Both, Matt
Hewitt, Lauren T.
Tsang, Candy W. S.
Braden, B. Blair
Bimonte-Nelson, Heather A.
Huentelman, Matthew J.
AffiliationUniv Arizona, Evelyn F McKnight Brain Inst
MetadataShow full item record
PublisherPUBLIC LIBRARY SCIENCE
CitationWilleman MN, Mennenga SE, Siniard AL, Corneveaux JJ, De Both M, Hewitt LT, et al. (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
Rights© 2018 Willeman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractEnzastaurin is a Protein Kinase C-beta selective inhibitor that was developed to treat cancers. Protein Kinase C-beta 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-beta. 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 (lllumina). 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.
NoteOpen access journal.
VersionFinal published version
SponsorsNIH-NINDS [R01-NS059873]; State of Arizona DHS
- Protein kinase C β inhibition by enzastaurin leads to mitotic missegregation and preferential cytotoxicity toward colorectal cancer cells with chromosomal instability (CIN).
- Authors: Ouaret D, Larsen AK
- Issue date: 2014
- Over activation of hippocampal serine/threonine protein phosphatases PP1 and PP2A is involved in lead-induced deficits in learning and memory in young rats.
- Authors: Rahman A, Khan KM, Al-Khaledi G, Khan I, Al-Shemary T
- Issue date: 2012 Jun
- Lewis and Fischer 344 rats as a model for genetic differences in spatial learning and memory: Cocaine effects.
- Authors: Fole A, Miguéns M, Morales L, González-Martín C, Ambrosio E, Del Olmo N
- Issue date: 2017 Jun 2
- Isoflurane induces cognitive deficits in the Morris water maze task in rats.
- Authors: Callaway JK, Jones NC, Royse CF
- Issue date: 2012 May
- Neonatal hippocampal damage in rats: long-term spatial memory deficits and associations with magnitude of hippocampal damage.
- Authors: Altemus KL, Almli CR
- Issue date: 1997