Microglial depletion using intrahippocampal injection of liposome-encapsulated clodronate in prolonged hypothermic cardiac arrest in rats

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Article

Drabek, Tomas^1,2  Janata, Andreas^1,3  Jackson, Edwin K.^1,4  End, Brad¹  Stezoski, Jason¹  Vagni, Vincent A.¹  Janesko-Feldman, Keri¹  Wilson, Caleb D.¹  van Rooijen, Nico⁵  Tisherman, Samuel A.^1,3,6  Kochanek, Patrick M.^1,3 

[1] Univ Pittsburgh, Safar Ctr Resuscitat Res, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA 15260 USA

[3] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15260 USA

[4] Univ Pittsburgh, Dept Pharmacol & Clin Biol, Pittsburgh, PA 15219 USA

[5] Vrije Univ, VUMC, Dept Mol Cell Biol, Fac Med, NL-1081 BT Amsterdam, Netherlands

[6] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA

关键词: Inflammation;    Iba-1;    Cardiac arrest;    Brain ischemia;    Resuscitation;    Emergency preservation;    Hypothermia;   

DOI  :  10.1016/j.resuscitation.2011.09.016

来源: Elsevier

【 摘 要 】

Trauma patients who suffer cardiac arrest (CA) from exsanguination rarely survive. Emergency preservation and resuscitation using hypothermia was developed to buy time for resuscitative surgery and delayed resuscitation with cardiopulmonary bypass (CPB), but intact survival is limited by neuronal death associated with microglial proliferation and activation. Pharmacological modulation of microglia may improve outcome following CA. Systemic injection of liposome-encapsulated clodronate (LEC) depletes macrophages. To test the hypothesis that intrahippocampal injection of LEC would attenuate local microglial proliferation after CA in rats, we administered LEC or PBS into the right or left hippocampus, respectively. After rapid exsanguination and 6 min no-flow, hypothermia was induced by ice-cold (IC) or room-temperature (RT) flush. Total duration of CA was 20 min. Pre-treatment (IC, RTpre) and post-treatment (RTpost) groups were studied, along with shams (cannulation only) and CPB controls. On day 7, shams and CPB groups showed neither neuronal death nor microglial activation. In contrast, the number of microglia in hippocampus in each individual group (IC, RTpre, RTpost) was decreased with LEC vs. PBS by similar to 34-46% (P < 0.05). Microglial proliferation was attenuated in the IC vs. RT groups (P < 0.05). Neuronal death did not differ between hemispheres or IC vs. RT groups. Thus, intrahippocampal injection of LEC attenuated microglial proliferation by similar to 40%, but did not alter neuronal death. This suggests that microglia may not play a pivotal role in mediating neuronal death in prolonged hypothermic CA. This novel strategy provides us with a tool to study the specific effects of microglia in hypothermic CA. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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