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.

Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in an Alzheimer’s disease mouse model

“…To determine whether HDs can be used as a pharmacological tool to target PAMs in an AD mouse model, we utilized HDs conjugated to a Cy5 fluorophore (referred to as D-Cy5) as previously described [ 44 , 45 , 47 – 49 , 66 ] (Fig. 1 a).…”

“…Other non-invasive delivery methods such as nasal drug administration, exosome delivery, and nanoparticle delivery represent promising avenues for drug delivery to the brain, but these methods have their own caveats as well such as toxicity problems, dosing limitations, and drug conjugation problems [ 11 , 21 , 52 , 57 ]. Previous research has shown that HDs can bypass a partially impaired blood-brain barrier and be phagocytosed by activated microglia and macrophages [ 44 , 45 , 47 – 49 , 66 ]. However, to our knowledge, this is the first study to assess the ability of HDs to target and treat PAMs specifically in the context of AD.…”

“…HDs consist of a hydrophobic core, repeating branches that expand outward, and hydrophilic functional groups at the outer surface. Importantly, the high density of surface hydroxyls provides a neutral charge allowing HDs to easily cross the blood brain barrier (BBB) in regions of inflammation and be selectively internalized by activated microglia and macrophages [ 44 , 45 , 47 – 49 , 66 ].…”

“…Traditional dendrimers alone do not bypass the BBB​ with high efficiency without resorting to invasive approaches such as carotid artery injections [ 63 , 74 ]. Recently, however, systemic administration of HDs have shown promise in bypassing slightly impaired BBB and were shown to be taken up specifically by microglia and macrophages in regions of neuroinflammation in rodent models of cerebral palsy, glioblastoma, Rett syndrome, AD, ALS, and multiple sclerosis (MS) [ 44 , 45 , 47 – 49 , 59 , 60 , 66 ]. In the AD brain, PAMs are the primary phagocytic macrophages; therefore, HDs theoretically have the capacity to bypass the BBB and become specifically engulfed by PAMs.…”

Rat model of asphyxia-induced cardiac arrest and resuscitation

“…Rat neurologic function changes dynamically across the first few days post-resuscitation. Modi et al (2022) used an NDS of 0–80 with a cutoff of 60 to distinguish mild and severe neurologic impairment. In their study, 24 h NDS scores were <60, which lowered at 48 h. That is, neurologic function deteriorated.…”