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. 2018 Jun 5;13(6):e0198256.
doi: 10.1371/journal.pone.0198256. eCollection 2018.

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

Mari N Willeman  1   2   3   4 , Sarah E Mennenga  4 , Ashley L Siniard  1   2   3 , Jason J Corneveaux  1   2   3 , Matt De Both  1   2   3 , Lauren T Hewitt  4 , Candy W S Tsang  4 , Jason Caselli  4 , B Blair Braden  2   4 , Heather A Bimonte-Nelson  2   4 , Matthew J Huentelman  1   2   3
Affiliations

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

Mari N Willeman et al. PLoS One. .

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. ENZ treatment results in a modest impairment on the Morris Water Maze task of hippocampal-dependent reference memory.
ENZ treatment increased the total swim distance only on Day 3 of testing, indicating an impairment in learning and memory. However, there was no significant difference in total swim distance for either Day 1 or 2.
Fig 2
Fig 2. ENZ treatment impairs overnight retention in the Morris Water Maze.
ENZ treatment led to increased swim distance on the first trial of the final testing day, in comparison to the final trial on the previous day. This is indicative of an absence of overnight retention. Comparatively, vehicle treatment led to similar performance for the two trials, indicating that overnight retention was maintained.
Fig 3
Fig 3. ENZ treated and control groups demonstrate similar performance in the Morris Water Maze probe trial.
During the probe trial, both ENZ-treated and vehicle-treated groups swam for a significantly higher percentage of distance in the quadrant that included the platform during previous testing days in comparison to the opposite quadrant. This indicates that ENZ treatment did not decrease the ability to locate the quadrant in which the platform should be.
Fig 4
Fig 4. Power analysis.
Given our study design and post hoc calculations of variance, this plot shows our power to detect different effect sizes.
See this image and copyright information in PMC

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