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. Exploratory gut microbiome analyses were also conducted (see Supplemental Materials). ResultsSaline-treated stressed rats demonstrated significantly elevated anhedonia and social avoidance compared to all other groups, while 3-AB treatment prevented these behavioral deficits. 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 these hemodynamic changes. Neurobiological analyses showed that FLX-treated stressed rats unexpectedly exhibited elevated PARP-1 expression in prefrontal cortical gray matter. Microglial morphological analysis revealed significantly more prolate (activated) microglia in the saline-treated stressed rats compared to all other treatment groups. Saline-treated stressed rats exhibited significantly increased hippocampal proinflammatory cytokines, with 3-AB treatment specifically normalizing TNF- levels. ConclusionPARP inhibition with 3-AB provides multi-system protection against chronic stress effects, preventing behavioral deficits, cardiovascular dysfunction, and neuroinflammation. These findings establish PARP-1 as a key mediator in the systemic pathophysiology of chronic stress and highlight PARP inhibition as a promising therapeutic approach for stress-related disorders with treatment-resistant features. Significant OutcomesO_LIPARP inhibition with 3-aminobenzamide (3-AB) prevented stress-induced behavioral deficits (anhedonia and social avoidance) 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_LIPARP inhibition prevented microglial activation and reduced proinflammatory cytokine expression (IL-1{beta} and TNF-) in stress-sensitive brain regions, supporting an anti-neuroinflammatory mechanism of action. C_LIO_LIFLX-treated stressed rats unexpectedly showed elevated PARP-1 expression in prefrontal cortical gray matter, suggesting a previously unrecognized interaction between serotonergic antidepressants and PARP-1 signaling that warrants further investigation. C_LIO_LIThe multi-system protective effects of PARP inhibition, spanning behavioral, cardiovascular, and neuroinflammatory domains, suggest therapeutic potential for treatment-resistant depression. 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