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

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Protein Kinase C-β is crucial for neuronal functions, including learning and memory.
• Previous studies link lower Protein Kinase C-β levels to deficits in spatial and fear learning.
• Enzastaurin is a selective inhibitor of Protein Kinase C-β, initially developed for cancer treatment.

Purpose of the Study:

• To investigate the impact of Enzastaurin on learning and memory in adult male rats.
• To assess the behavioral consequences of Protein Kinase C-β inhibition on hippocampal-dependent functions.
• To explore potential transcriptional changes in the hippocampus following Enzastaurin exposure.

Main Methods:

• Adult male Fischer-344 rats received daily subcutaneous injections of Enzastaurin or vehicle.
• Behavioral testing included the Morris Water Maze to assess spatial reference memory.
• Hippocampal RNA was analyzed using Next Generation Sequencing (Illumina) to detect transcriptional alterations.

Main Results:

• Enzastaurin treatment resulted in decreased overnight memory retention.
• Rats treated with Enzastaurin showed poorer performance on later days of spatial learning.
• No significant differences were observed in the probe trial, indicating preserved spatial localization ability.
• Next Generation Sequencing revealed no statistically significant changes in hippocampal gene transcription.

Conclusions:

• Acute Enzastaurin administration can induce mild, yet significant, memory impairments in rats.
• The observed cognitive effects occurred without detectable alterations in hippocampal gene expression.
• Caution is advised regarding potential cognitive side effects of Protein Kinase C-β inhibitors in clinical settings.
• Further research is needed to determine the reversibility of these memory deficits.