Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.
Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.
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DOI：
10.1002/btm2.10259
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发表时间：
2022-01
影响因子：
7.4
通讯作者：
Thakor NV
中科院分区：
文献类型：
--
作者：
Modi HR;Wang Q;Olmstead SJ;Khoury ES;Sah N;Guo Y;Gharibani P;Sharma R;Kannan RM;Kannan S;Thakor NV
心脏骤停（CA），即有效心脏泵血功能的突然停止，仍然是一个主要的临床问题，早期和长期死亡率很高。心脏骤停后综合征（PCAS）可能与早期全身炎症反应有关，导致过度和持续的神经炎症。因此，通过靶向药物递送进行早期干预以减轻神经炎症可能会大大改善治疗结果。使用临床相关的窒息CA模型，我们证明，一个单一的（i. p.）剂量的树枝状聚合物-N-乙酰半胱氨酸缀合物（D-NAC）可以靶向CA后的“活化”小胶质细胞，导致与盐水相比CA后存活率的改善（86%对45%）。D-NAC治疗还在治疗4小时内显著改善了大体神经系统评分（p < 0.05），并在48小时继续显示改善（p < 0.05）。具体而言，CA后运动反应存在实质性损害，随后通过D-NAC治疗得到改善（p < 0.05）。D-NAC还减轻了CA后在CA 1和CA 3亚区中观察到的海马细胞密度损失（p < 0.001）。这些结果表明，即使使用单次D-NAC推注进行早期治疗干预，也可在长期生存、短期运动缺陷和神经恢复方面实现稳健的可持续改善。我们目前的工作为治疗CA后综合征的临床相关治疗方法奠定了基础。
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.
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DOI：
10.1016/j.bbi.2015.03.005
发表时间：
2015-08
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Grace PM;Shimizu K;Strand KA;Rice KC;Deng G;Watkins LR;Herson PS
通讯作者：
Herson PS
影响因子：
6.5
作者：
Janata A;Magnet IA;Uray T;Stezoski JP;Janesko-Feldman K;Tisherman SA;Kochanek PM;Drabek T
通讯作者：
Drabek T
影响因子：
3.4
作者：
Langdon, Kristopher D.;Granter-Button, Shirley;Corbett, Dale
通讯作者：
Corbett, Dale
影响因子：
2.6
作者：
Bhalala US;Koehler RC;Kannan S
通讯作者：
Kannan S
影响因子：
17.1
作者：
Kannan S;Dai H;Navath RS;Balakrishnan B;Jyoti A;Janisse J;Romero R;Kannan RM
通讯作者：
Kannan RM