Antidepressant-Like Actions of Inhibitors of Poly(ADP-Ribose) Polymerase in Rodent Models

Abstract

BackgroundMany patients suffering from depressive disorders are refractory to treatment with currently available antidepressant medications, while many more exhibit only a partial response. These factors drive research to discover new pharmacological approaches to treat depression. Numerous studies demonstrate evidence of inflammation and elevated oxidative stress in major depression. Recently, major depression has been shown to be associated with elevated levels of DNA oxidation in brain cells, accompanied by increased gene expression of the nuclear base excision repair enzyme, poly(ADP-ribose) polymerase-1. Given these findings and evidence that drugs that inhibit poly(ADP-ribose) polymerase-1 activity have antiinflammatory and neuroprotective properties, the present study was undertaken to examine the potential antidepressant properties of poly(ADP-ribose) polymerase inhibitors.MethodsTwo rodent models, the Porsolt swim test and repeated exposure to psychological stressors, were used to test the poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide, for potential antidepressant activity. Another poly(ADP-ribose) polymerase inhibitor, 5-aminoisoquinolinone, was also tested.ResultsPoly(ADP-ribose) polymerase inhibitors produced antidepressant-like effects in the Porsolt swim test, decreasing immobility time, and increasing latency to immobility, similar to the effects of fluoxetine. In addition, 3-aminobenzamide treatment increased sucrose preference and social interaction times relative to vehicle-treated control rats following repeated exposure to combined social defeat and unpredictable stress, mediating effects similar to fluoxetine treatment.ConclusionsThe poly(ADP-ribose) polymerase inhibitors 3-aminobenzamide and 5-aminoisoquinolinone exhibit antidepressant-like activity in 2 rodent stress models and uncover poly(ADP-ribose) polymerase as a unique molecular target for the potential development of a novel class of antidepressants.

Increased Axin expression enhances adult hippocampal neurogenesis and exerts an antidepressant effect

“…Of note, patients with major depressive disorders have elevated PARP1 levels 31 . Moreover, in a recent study, PARP inhibitors exhibited antidepressant effects in the sucrose preference and forced swim tests, similar to the effects of fluoxetine 32 . Hence, further investigation is warranted to determine whether XAV939 exerts its antidepressant effects through the modulation of PARP activity.…”

Rapid and temporary improvement of depression and anxiety observed following niraparib administration: a case report

“…However, activation of PARP1 is also directly linked to inflammation cascades, including activation of NF-κB and production of downstream cytokines. Besides anti-cancer effects, PARP inhibitors have anti-inflammatory and neuroprotective properties and have demonstrated predicted therapeutic activity in animal models of diseases that involve oxidative stress and inflammation, including Parkinson's disease [6], Alzheimer's disease [7], ischemic brain injury [8], and most recently depression [9]. PARP may lie in a pathway leading to neuroinflammatory cascades in MDD.…”

“…Recently, two PARP inhibitors, 3-aminobenzaminde and 5-isoquinolinone, have been shown to demonstrate antidepressant-like activity in preclinical rodent models (social defeat and chronic unpredictable stress, forced swim test) with efficacy similar to fluoxetine. Additionally, PARP inhibition appeared to have an additive antidepressant effect when combined with fluoxetine [9]. PARP inhibitors have also been shown to protect rodents from helplessness behavior in inflammationinduced sickness behavior [19].…”

Drug repositioning for treatment-resistant depression: Hypotheses from a pharmacogenomic study

“…fasudil) have rapid antidepressant-like effects in mice, comparable to ketamine, which is presumably linked to the promotion of activity-dependent dendritic spine pruning or spine head enlargement; ROCK indeed inhibits cofilin-mediated actin cycling, the process of change in size and shape of dendrites controlled by actin filaments (Shapiro et al, 2019). Compared to this mechanism which appears particularly innovative, the other mentioned ones involve alternative pathways to induce anti-inflammatory and/or neuroprotective/antioxidant effects which showed promising results in animal models of depression (Ordway et al, 2017) (Zhang et al, 2020).…”