Background: Major depressive disorder is associated with elevated levels of DNA oxidation, DNA damage, and gene expression of DNA repair enzymes including poly (ADP-ribose) polymerase-1 (PARP1). Elevated PARP1 activity is directly linked to neuroinflammation and PARP inhibitors are anti-inflammatory and neuroprotective. We previously showed that PARP inhibitors produce antidepressant-like effects equivalent to fluoxetine in rodent models. Here, we examined whether the PARP inhibitor 3-aminobenzamide (3AB) is effective in a rat model of treatment-resistant depression.
Methods: Treatment-resistant depression was modeled with injections of lipopolysaccharide (LPS; 0.1 ug/kg/day) and daily chronic unpredictable stress (CUS) for 28 days. Anhedonia and helplessness were indexed with sucrose preference and forced swim tests, respectively, in 5 groups of rats (n¼6-8 rats/group) including unstressed, CUS, and CUS+LPS rats treated with saline, and CUS+LPS rats treated with either 3AB or fluoxetine.
Results: Anhedonia induced by CUS+LPS was significantly attenuated by 3AB (p¼0.01), while fluoxetine failed to do so. Likewise, 3AB was superior to fluoxetine in reducing helplessness, where latency to immobility times were significantly lower in CUS+LPS rats treated with fluoxetine (p¼0.001) compared to unstressed rats, but not significantly different for 3AB-treated CUS+LPS rats.
Conclusions: The PARP inhibitor 3AB demonstrated robust and unique antidepressant activity superior to fluoxetine in the TRD rat model. PARP is linked to neuroinflammation through release of microglia-activating factors including poly (ADP-ribose) and HMGB1, and through NF-kB activation, pathways under investigation by our lab. PARP inhibitors are currently used clinically to facilitate cytotoxicity of DNA-damaging anti-cancer treatments. Further research could implicate re-purposing non-cytotoxic PARP inhibitors for treatment-resistant depression.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:etsu-works-9907 |
| Date | 01 May 2019 |
| Creators | Ordway, Gregory A., Gill, W. D., Coleman, J. B., Wang-Heaton, Hui, Brown, Russell W. |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Detected Language | English |
| Type | text |
| Source | ETSU Faculty Works |
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