Project Title

PARP1 inhibition produces unique antidepressant effects in an animal model of treatment-resistant depression

Authors' Affiliations

Hebah F. Alkhateeb, Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, TN. Michelle J. Chandley, Department of Health Sciences, College of Public Health, East Tennessee State University, Johnson City, TN. Gregory A. Ordway, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Russell W. Brown, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. W. Drew Gill, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Joshua B. Coleman, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Hui Wang-Heaton, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Zachary Carter, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Rachel Meek, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Jacob Couthard, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN. Libby Ligon, Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Location

White Top Mtn

Start Date

4-12-2019 9:00 AM

End Date

4-12-2019 2:30 PM

Poster Number

120

Faculty Sponsor’s Department

Health Sciences

Name of Project's Faculty Sponsor

Dr. Michelle Chandley

Type

Poster: Competitive

Classification of First Author

Undergraduate Student

Project's Category

Neuroscience, Nervous System, Depression

Abstract Text

Major depressive disorder (MDD) is a prevalent and enervating mental illness affecting millions globally. Unfortunately, a significant proportion of patients do not receive clinical benefit from existing antidepressant medications. The limited effectiveness of currently available antidepressant drugs emphasizes the need to identify more effective medications for individuals who are treatment-resistant. We have previously reported abnormally elevated poly (ADP-ribose) polymerase-1 (PARP1) gene expression levels in the postmortem brain from MDD brain donors. PARP1 is a DNA damage repair enzyme that is also linked to neuroinflammation through multiple biochemical pathways. PARP1 upregulation in MDD could indicate a role for this enzyme in the etiopathology of MDD, particularly as it relates to neuroinflammation. In fact, we have shown that drugs that inhibit PARP1 produce antidepressant-like properties in two different rodent behavioral models that mimic depressed mood in humans. In the present study, we utilized a unique rodent behavioral model that produces depressive-like behavior by combining psychological stress with stimulation of inflammation. Depressive behavior produced by this experimental paradigm is not reversed by the prototypical antidepressant fluoxetine. This treatment-resistant depression was elicited by treating rats with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily exposure to chronic unpredictable stress (CUS) for 28 days. Depressive behaviors were measured with sucrose preference and forced swim tests in 5 treatment groups (n=6-8 rats per group) including unstressed rats, CUS rats, CUS+LPS rats, and CUS+LPS rats treated with either the PARP1 inhibitor 3-aminobenzamide (3AB) or the antidepressant fluoxetine. We evaluated the role of neuroinflammation in this model by measuring the amount of microglial activation in several brain regions in rats from all treatment groups. Microglia activation was measured by quantifying the relative amount of expression of the microglia marker protein, IBA1, using an anti-IBA1 antibody. 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the treatment-resistant rat model. IBA1-immunoreactivity levels were elevated in brains from CUS and CUS+LPS rats, although there was no evidence that LPS increased IBA1-immunoreactivity above levels found in CUS rats that did not receive LPS. Levels of IBA1-immunoreactivity in the brains from rats treated with either fluoxetine or 3AB trended lower as compared to the CUS and CUS+LPS groups, although this effect did not reach statistical significance. The lack of significant differences is likely related to small sample sizes; experiments are underway to increase the sample sizes of each group. The findings provide further support for the potential of PARP1 inhibitors in treating MDD and suggest that these drugs may be more effective, or more broadly effective than standard antidepressants.

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Apr 12th, 9:00 AM Apr 12th, 2:30 PM

PARP1 inhibition produces unique antidepressant effects in an animal model of treatment-resistant depression

White Top Mtn

Major depressive disorder (MDD) is a prevalent and enervating mental illness affecting millions globally. Unfortunately, a significant proportion of patients do not receive clinical benefit from existing antidepressant medications. The limited effectiveness of currently available antidepressant drugs emphasizes the need to identify more effective medications for individuals who are treatment-resistant. We have previously reported abnormally elevated poly (ADP-ribose) polymerase-1 (PARP1) gene expression levels in the postmortem brain from MDD brain donors. PARP1 is a DNA damage repair enzyme that is also linked to neuroinflammation through multiple biochemical pathways. PARP1 upregulation in MDD could indicate a role for this enzyme in the etiopathology of MDD, particularly as it relates to neuroinflammation. In fact, we have shown that drugs that inhibit PARP1 produce antidepressant-like properties in two different rodent behavioral models that mimic depressed mood in humans. In the present study, we utilized a unique rodent behavioral model that produces depressive-like behavior by combining psychological stress with stimulation of inflammation. Depressive behavior produced by this experimental paradigm is not reversed by the prototypical antidepressant fluoxetine. This treatment-resistant depression was elicited by treating rats with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily exposure to chronic unpredictable stress (CUS) for 28 days. Depressive behaviors were measured with sucrose preference and forced swim tests in 5 treatment groups (n=6-8 rats per group) including unstressed rats, CUS rats, CUS+LPS rats, and CUS+LPS rats treated with either the PARP1 inhibitor 3-aminobenzamide (3AB) or the antidepressant fluoxetine. We evaluated the role of neuroinflammation in this model by measuring the amount of microglial activation in several brain regions in rats from all treatment groups. Microglia activation was measured by quantifying the relative amount of expression of the microglia marker protein, IBA1, using an anti-IBA1 antibody. 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the treatment-resistant rat model. IBA1-immunoreactivity levels were elevated in brains from CUS and CUS+LPS rats, although there was no evidence that LPS increased IBA1-immunoreactivity above levels found in CUS rats that did not receive LPS. Levels of IBA1-immunoreactivity in the brains from rats treated with either fluoxetine or 3AB trended lower as compared to the CUS and CUS+LPS groups, although this effect did not reach statistical significance. The lack of significant differences is likely related to small sample sizes; experiments are underway to increase the sample sizes of each group. The findings provide further support for the potential of PARP1 inhibitors in treating MDD and suggest that these drugs may be more effective, or more broadly effective than standard antidepressants.