PARP inhibition with 3-aminobenzimide attenuates behavioral, cardiovascular, and neuroinflammatory effects of chronic stress
BackgroundMajor depressive disorder (MDD) affects approximately 20% of the population, with over 30% of cases demonstrating treatment resistance. Postmortem analyses have revealed increased poly (ADP-ribose) polymerase 1 (PARP-1) expression in prefrontal cortical white matter of individuals with MDD, suggesting PARP-1 as a potential therapeutic target. Chronic stress, a major risk factor for depression, affects multiple physiological domains including behavior, cardiovascular function, neuroinflammation, and gut-brain axis signaling. MethodsWe conducted a comprehensive multi-system investigation of PARP inhibition effects on stress-induced pathophysiology using the social defeat stress/chronic unpredictable stress (SDS+CUS) rodent model. In the primary study, male Sprague-Dawley rats (N=32) underwent 10 days of SDS+CUS while receiving daily treatment with the PARP inhibitor 3-aminobenzamide (3-AB; 40mg/kg), selective serotonin reuptake inhibitor fluoxetine (FLX; 10mg/kg), or saline (0.9% NaCl), with non-stressed controls included. Behavioral outcomes were assessed via sucrose preference and social interaction tests. Neurobiological analyses examined PARP-1 expression, microglial morphology, and proinflammatory cytokine levels (IL-1{beta}, TNF-, IL-6) in relevant brain regions. In a parallel cardiovascular study, a separate cohort of stressed rats (N=8) received either saline or 3-AB treatment while hemodynamic parameters were monitored via telemetry before, during, and after stress exposure. ResultsSaline-treated stressed rats demonstrated significantly elevated anhedonia compared to the 3-AB/Stress rats and social avoidance compared to the 3-AB/Stress and Control/ No-Stress groups. Cardiovascular monitoring revealed that stressed saline-treated rats developed significant elevations in systolic and mean blood pressure with decreased heart rate compared to baseline, whereas 3-AB treatment prevented changes in systolic and mean blood pressure. Neurobiological analyses of PARP-1 expression in PFC did not reveal significant group differences. Microglial morphological analysis revealed a shift toward more prolate (activated) soma morphology in the saline-treated stressed rats compared to the non-stressed controls. Additionally, 3-AB-treated rats showed significantly more oblate (quiescent) microglia than saline-treated rats. Saline-treated stressed rats exhibited significantly increased hippocampal proinflammatory cytokines, with 3-AB treatment specifically attenuating TNF- and IL-1{beta} levels. Conclusion3-AB treatment provided multi-system protection against chronic stress effects, preventing behavioral deficits and cardiovascular dysfunction, and attenuating select markers of neuroinflammation. These findings suggest that 3-AB, and potentially PARP-1 inhibition, warrants further investigation as a therapeutic approach for stress-related disorders. Significant OutcomesO_LI3-aminobenzamide (3-AB) treatment was associated with reduced stress-induced behavioral anhedonia and social avoidance relative to saline-treated stressed rats in a validated rodent model combining social defeat and chronic unpredictable stress. C_LIO_LI3-AB treatment prevented stress-induced increases in arterial blood pressure. C_LIO_LI3-AB treatment prevented the stress-induced shift toward a more prolate microglial morphology and significantly attenuated the stress-induced increase in hippocampal TNF- and IL-1{beta}. C_LIO_LIThe multi-domain protective effects of 3-AB, spanning behavioral, cardiovascular, and neuroinflammatory measures, support further investigation of PARP inhibition as a potential therapeutic strategy for stress-related disorders. C_LI LimitationsO_LIThis study examined only male rats, limiting generalizability to female subjects despite the higher prevalence of MDD in women. C_LIO_LIBehavioral assessments were limited to anhedonia and social interaction; additional tests of other depression-relevant behaviors would provide a more comprehensive phenotypic profile. C_LIO_LILong-term effects of 3-AB treatment beyond the 10-day stress paradigm remain unexplored. C_LI