Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD, 21201-1595, USA.
Neurocrit Care. 2018 Oct;29(2):253-263. doi: 10.1007/s12028-018-0535-7.
Spontaneous intracerebral hemorrhage (ICH) leaves most survivors dependent at follow-up. The importance of promoting M2-like microglial responses is increasingly recognized as a key element to ameliorate brain injury following ICH. The osmotherapeutic agents, mannitol and hypertonic saline (HTS), which are routinely used to reduce intracranial pressure, have been shown to reduce neuroinflammation in experimental ischemic and traumatic brain injury, but anti-inflammatory effects of osmotherapies have not been investigated in ICH.
We studied the effects of iso-osmotic mannitol and HTS in rat models of ICH utilizing high-dose and moderate-dose collagenase injections into the basal ganglia, associated with high and low mortality, respectively. We studied the effects of osmotherapies, first given 5 h after ICH induction, and then administered every 12 h thereafter (4 doses total). Immunohistochemistry was used to quantify microglial activation and polarization.
Compared to controls, mannitol and HTS increased plasma osmolarity 1 h after infusion (301 ± 1.5, 315 ± 4.2 and 310 ± 2.0 mOsm/kg, respectively), reduced mortality at 48 h (82, 36 and 53%, respectively), and reduced hemispheric swelling at 48 h (32, 21, and 17%, respectively). In both perihematomal and contralateral tissues, mannitol and HTS reduced activation of microglia/macrophages (abundance and morphology of Iba1 + cells), and in perihematomal tissues, they reduced markers of the microglia/macrophage M1-like phenotype (nuclear p65, TNF, and NOS2), increased markers of the microglia/macrophage M2-like phenotype (arginase, YM1, and pSTAT3), and reduced infiltration of CD45 + cells.
Repeated dosing of osmotherapeutics at regular intervals may be a useful adjunct to reduce neuroinflammation following ICH.
自发性脑出血（ICH）使大多数幸存者在随访时依赖于他人。促进 M2 样小胶质细胞反应的重要性越来越被认为是改善 ICH 后脑损伤的关键因素。渗透性治疗剂甘露醇和高渗盐水（HTS）通常用于降低颅内压，已被证明可减轻实验性缺血性和创伤性脑损伤中的神经炎症，但渗透性治疗对 ICH 的抗炎作用尚未得到研究。
我们使用高剂量和中剂量胶原酶注射到基底节来建立大鼠 ICH 模型，研究了等渗甘露醇和 HTS 的作用，分别与高死亡率和低死亡率相关。我们研究了渗透性治疗的作用，首先在 ICH 诱导后 5 小时给予，然后每 12 小时给予一次（共 4 次）。免疫组织化学用于定量小胶质细胞激活和极化。
与对照组相比，甘露醇和 HTS 输注后 1 小时增加了血浆渗透压（分别为 301±1.5、315±4.2 和 310±2.0 mOsm/kg），降低了 48 小时的死亡率（分别为 82%、36%和 53%），并降低了 48 小时的半球肿胀（分别为 32%、21%和 17%）。在血肿周围和对侧组织中，甘露醇和 HTS 减少了小胶质细胞/巨噬细胞的激活（Iba1+细胞的丰度和形态），在血肿周围组织中，它们减少了小胶质细胞/巨噬细胞 M1 样表型的标志物（核 p65、TNF 和 NOS2），增加了小胶质细胞/巨噬细胞 M2 样表型的标志物（精氨酸酶、YM1 和 pSTAT3），并减少了 CD45+细胞的浸润。
定期重复给予渗透性治疗可能是一种有用的辅助治疗方法，可减少 ICH 后的神经炎症。
