Cardiac arrest (CA), the sudden cessation of effective cardiac pumping function, is still a major clinical problem with a high rate of early and long‐term mortality. Post‐cardiac arrest syndrome (PCAS) may be related to an early systemic inflammatory response leading to exaggerated and sustained neuroinflammation. Therefore, early intervention with targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes. Using a clinically relevant asphyxia CA model, we demonstrate that a single (i.p.) dose of dendrimer‐N‐acetylcysteine conjugate (D‐NAC), can target “activated” microglial cells following CA, leading to an improvement in post‐CA survival rate compared to saline (86% vs. 45%). D‐NAC treatment also significantly improved gross neurological score within 4 h of treatment ( p < 0.05) and continued to show improvement at 48 h ( p < 0.05). Specifically, there was a substantial impairment in motor responses after CA, which was subsequently improved with D‐NAC treatment ( p < 0.05). D‐NAC also mitigated hippocampal cell density loss seen post‐CA in the CA1 and CA3 subregions ( p < 0.001). These results demonstrate that early therapeutic intervention even with a single D‐NAC bolus results in a robust sustainable improvement in long‐term survival, short‐term motor deficits, and neurological recovery. Our current work lays the groundwork for a clinically relevant therapeutic approach to treating post‐CA syndrome.

IntroductionSelective serotonin reuptake inhibitor (SSRI) antidepressants represent first-line pharmacological treatment for a variety of neuropsychiatric illnesses, including major depressive disorder (MDD), anxiety, and post-traumatic stress disorder (PTSD), which show high rates of comorbidity. SSRIs have a delayed onset of action. Most patients do not show significant effects until 4–8 weeks of continuous treatment, have impairing side effects and as many as 40% of patients do not respond. Methylone (3,4-methylenedioxy-N-methylcathinone; MDMC, βk-MDMA, M1) is a rapid-acting entactogen that showed significant benefit in a clinical case series of PTSD patients and was well-tolerated in two Phase 1 studies of healthy volunteers. Based on these early observations in humans, in the current study we tested the hypothesis that methylone has antidepressant-like and anxiolytic effects in preclinical tests.MethodsFor all studies, 6–8-week-old male Sprague Dawley rats (N = 6–16) were used. We employed the Forced Swim Test (FST), a classic and widely used screen for antidepressants, to explore the effects of methylone and to probe dose-response relationships, durability of effect, and potential interactions with combined SSRI treatment. We compared the effect of methylone with the prototypical SSRI fluoxetine.ResultsThree doses of fluoxetine (10 mg/kg) given within 24 h before FST testing caused a 50% reduction in immobility compared with controls that lasted less than 24 h. In contrast, a single dose of methylone (5–30 mg/kg) administered 30 min prior to testing produced a rapid, robust, and durable antidepressant-like response in the FST, greater in magnitude than fluoxetine. Immobility was reduced by nearly 95% vs. controls and effects persisted for at least 72 h after a single dose (15 mg/kg). Effects on swimming and climbing behavior in the FST, which reflect serotonergic and noradrenergic activity, respectively, were consistent with studies showing that methylone is less serotoninergic than MDMA. Fluoxetine pretreatment did not change methylone’s antidepressant-like effect in the FST, suggesting the possibility that the two may be co-administered. In addition, methylone (5–30 mg/kg) exhibited anxiolytic effects measured as increased time spent in the center of an open field.DiscussionTaken together, and consistent with initial clinical findings, our study suggests that methylone may have potential for treating depression and anxiety.