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Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.

ABSTRACT: 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.

SUBMITTER: Modi HR

PROVIDER: S-EPMC8780014 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.

Modi Hiren R HR Wang Qihong Q Olmstead Sarah J SJ Khoury Elizabeth S ES Sah Nirnath N Guo Yu Y Gharibani Payam P Sharma Rishi R Kannan Rangaramanujam M RM Kannan Sujatha S Thakor Nitish V NV

Bioengineering & translational medicine 20211013 1

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 dem ...[more]

PMID: 35079634

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Project description:BackgroundEach year, 200,000 patients undergo an in-hospital cardiac arrest (IHCA), with approximately 15-20% surviving to discharge. Little is known, however, about the long-term prognosis of these patients after discharge. Previous efforts to describe out-of-hospital survival of IHCA patients have been limited by small sample sizes and narrow patient populationsMethodsA single institution matched cohort study was undertaken to describe mortality following IHCA. Patients surviving to discharge following an IHCA between 2008 and 2010 were matched on age, sex, race and hospital admission criteria with non-IHCA hospital controls and follow-up between 9 and 45 months. Kaplan-Meier curves and Cox PH models assessed differences in survival.ResultsOf the 1262 IHCAs, 20% survived to hospital discharge. Of those discharged, survival at 1 year post-discharge was 59% for IHCA patients and 82% for controls (p<0.0001). Hazard ratios (IHCA vs. controls) for mortality were greatest within the 90 days following discharge (HR=2.90, p<0.0001) and decreased linearly thereafter, with those surviving to one year post-discharge having an HR for mortality below 1.0. Survival after discharge varied amongst IHCA survivors. When grouped by discharge destination, out of hospital survival varied; in fact, IHCA patients discharged home without services demonstrated no survival difference compared to their non-IHCA controls (HR 1.10, p=0.72). IHCA patients discharged to long-term hospital care or hospice, however, had a significantly higher mortality compared to matched controls (HR 3.91 and 20.3, respectively; p<0.0001).ConclusionAmong IHCA patients who survive to hospital discharge, the highest risk of death is within the first 90 days after discharge. Additionally, IHCA survivors overall have increased long-term mortality vs.ControlsSurvival rates were varied widely with different discharge destinations, and those discharged to home, skilled nursing facilities or to rehabilitation services had survival rates no different than controls. Thus, increased mortality was primarily driven by patients discharged to long-term care or hospice.

Project description:BACKGROUND:Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome. METHODS:To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc-) is upregulated in Mecp2-null glia when compared to WT, the role of Xc- in the uptake of NAC and L-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan. RESULTS:We demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc- was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc- for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival. CONCLUSIONS:These results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT.

Project description:BackgroundMitochondrial transplantation (MTx) is an emerging but poorly understood technology with the potential to mitigate severe ischemia-reperfusion injuries after cardiac arrest (CA). To address critical gaps in the current knowledge, we test the hypothesis that MTx can improve outcomes after CA resuscitation.MethodsThis study consists of both in vitro and in vivo studies. We initially examined the migration of exogenous mitochondria into primary neural cell culture in vitro. Exogenous mitochondria extracted from the brain and muscle tissues of donor rats and endogenous mitochondria in the neural cells were separately labeled before co-culture. After a period of 24 h following co-culture, mitochondrial transfer was observed using microscopy. In vitro adenosine triphosphate (ATP) contents were assessed between freshly isolated and frozen-thawed mitochondria to compare their effects on survival. Our main study was an in vivo rat model of CA in which rats were subjected to 10 min of asphyxial CA followed by resuscitation. At the time of achieving successful resuscitation, rats were randomly assigned into one of three groups of intravenous injections: vehicle, frozen-thawed, or fresh viable mitochondria. During 72 h post-CA, the therapeutic efficacy of MTx was assessed by comparison of survival rates. The persistence of labeled donor mitochondria within critical organs of recipient animals 24 h post-CA was visualized via microscopy.ResultsThe donated mitochondria were successfully taken up into cultured neural cells. Transferred exogenous mitochondria co-localized with endogenous mitochondria inside neural cells. ATP content in fresh mitochondria was approximately four times higher than in frozen-thawed mitochondria. In the in vivo survival study, freshly isolated functional mitochondria, but not frozen-thawed mitochondria, significantly increased 72-h survival from 55 to 91% (P = 0.048 vs. vehicle). The beneficial effects on survival were associated with improvements in rapid recovery of arterial lactate and glucose levels, cerebral microcirculation, lung edema, and neurological function. Labeled mitochondria were observed inside the vital organs of the surviving rats 24 h post-CA.ConclusionsMTx performed immediately after resuscitation improved survival and neurological recovery in post-CA rats. These results provide a foundation for future studies to promote the development of MTx as a novel therapeutic strategy to save lives currently lost after CA.

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Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.

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Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.

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