Mannitol and Hypertonic Saline Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of Intracerebral Hemorrh
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ORIGINAL ARTICLE
Mannitol and Hypertonic Saline Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of Intracerebral Hemorrhage David L. Schreibman1, Caron M. Hong1, Kaspar Keledjian2, Svetlana Ivanova2, Solomiya Tsymbalyuk2, Volodymyr Gerzanich2 and J. Marc Simard2,3,4* © 2018 Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society
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. Keywords: Intracerebral hemorrhage, Mannitol, Hypertonic saline, Microglia, Brain swelling Introduction Spontaneous intracerebral hemorrhage (ICH) accounts for 15% of all strokes and leaves most survivors dependent at follow-up. Numerous mechanisms of secondary injury adversely affect outcomes in this type of stroke [1]. *Correspondence: [email protected] 2 Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD 21201‑1595, USA Full author information is available at the end of the article
Osmotic agents such as mannitol and hypertonic saline (HTS) are mainstays of treatment to mitigate brain swelling and decrease intracranial pressure (ICP) following ICH [2]. Apart from brain swelling, outcomes after ICH also depend on the inflammatory response of the brain
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