1 / 13

Testing the antidepressant efficacy of PF-4645 in M. bovis , BCG challenged mice.

Testing the antidepressant efficacy of PF-4645 in M. bovis , BCG challenged mice. Jason O’COnnor. Overall Progress Report. Established a revised, multi-dimensional, experimental protocol for drug screening in the BCG mouse model of depression

ivy-richard
Download Presentation

Testing the antidepressant efficacy of PF-4645 in M. bovis , BCG challenged mice.

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Testing the antidepressant efficacy of PF-4645 in M. bovis, BCG challenged mice. Jason O’COnnor

  2. Overall Progress Report • Established a revised, multi-dimensional, experimental protocol for drug screening in the BCG mouse model of depression • Drug selection: #1- MagL inhibitor PF-4645, #2 P2X7 antagonist, #3 FAHH inhibitor? • Completed PF-4645 x BCG experiment • Behavioral data (included) • Neuroinflammatory markers (tissue shipped to Pfizer, awaiting confirmation to send tissue to Psycogenics) • New hire made to ensure continuity of project upon departure of Research Assistant • We have received P2X7 antagonist from Lundbeck, mice to arrive May 3.

  3. Experimental Design: PF-4645 x BCG

  4. Experimental Groups: PF-4645 x BCG BEHAVIOR STUDY • Vehicle Control (half injected according to each design schedule, data collapsed into one group) • PF-4645 (10 mg/kg subcut. once daily) Prevention Design Control • PF-4645 (10 mg/kg subcut. once daily) Treatment Design Control • Vehicle-BCG (half injected according to each design schedule, data collapsed into one group) • PF-4645 (10 mg/kg subcut. once daily) Prevention x BCG • PF-4645 (10 mg/kg subcut. once daily) Treatment x BCG • EARLY TIMEPOINT TISSUE COLLECTION • Vehicle control • Vehicle BCG • PF 4645 (10 mg/kg subcut. once daily) prevention x BCG • PF-4645 (10 mg/kg subcut. once daily) treatment x BCG **drug injections took place between 07:00-08:00 daily, behavior and tissue collection began 4 h after**

  5. Tissues collected • Plasma • At the end of behavioral study • In a small parallel group of mice at 8d post BCG • Brains (cortical hemispheres and cerebellum) • At the end of behavioral study • In a small parallel group of mice at 8d post BCG • Lung • At the end of behavioral study • In a small parallel group of mice at 8d post BCG

  6. BCG-induced splenomegaly is not affected by PF-4645

  7. PF-4645 prevention schedule appears to accelerate recovery of BW following BCG Normalized to Baseline Raw data (mg)

  8. PF-4645 prevention schedule accelerates recovery of BW following BCG challenge

  9. No drug x BCG interaction on nesting behavior • Method: Negus SS et. al. Pain. 2015 Jun;156(6):1153-60. 8d post-BCG 12d post-BCG 12d post-BCG

  10. PF-4645 blocks BCG-induced avoidance of the central area during open field test Locomotor activity Anxiety-like behavior

  11. BCG impairs working memory only in control group, but PF-4645 alone does too

  12. PF-4645 reduces baseline and blocks BCG-induced reduction in social interaction

  13. Conclusions & Next steps • Based on behavioral data, it appear that PF-4645 has some efficacy in mitigating BCG-induced depressive-like behaviors, but the drug alone also changes baseline behavioral measures in many of the tests • The possible anti-depressant behavioral effects were more pronounced in the prevention design that the treatment design, which when combined with the effect on BW data, suggest that PF-4645 is probably attenuating elements of the early inflammation induced by BCG to have this effect on behavior. • Tissue analyses will illuminate the underlying effects of PF-4645 on inflammation • Representation of the data relative to within group control would isolate the BCG effect within groups and more clearly illustrate where BCG is or is not changing behavior, but this also masks baseline effects of drug. • Aggregation of the behavioral data into a single figure, using an integrated behavioral Z-scoring method, may reduce variability across tests and improve clarity. (J Neurosci Methods. 2011 Apr 15;197(1):21-31.) • Preparations to begin the P2X7 antagonist study are underway.

More Related