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Mannitol and Hypertonic Saline Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of Intracerebral Hemorrhage

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

Repeated dosing of osmotherapeutics at regular intervals may be a useful adjunct to reduce neuroinflammation following ICH.

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Funding

This work was supported in part by a grant to DLS from the Department of Anesthesia. JMS is supported by a grant from the National Heart, Lung, and Blood Institute (HL082517).

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Authors and Affiliations

  1. Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    David L. Schreibman & Caron M. Hong

  2. Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD, 21201-1595, USA

    Kaspar Keledjian, Svetlana Ivanova, Solomiya Tsymbalyuk, Volodymyr Gerzanich & J. Marc Simard

  3. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    J. Marc Simard

  4. Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    J. Marc Simard

Authors
  1. David L. Schreibman
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  2. Caron M. Hong
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  3. Kaspar Keledjian
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Correspondence to J. Marc Simard.

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Schreibman, D.L., Hong, C.M., Keledjian, K. et al. Mannitol and Hypertonic Saline Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of Intracerebral Hemorrhage. Neurocrit Care 29, 253–263 (2018). https://doi.org/10.1007/s12028-018-0535-7

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