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Role of Heme Oxygenase as a Modulator of Heme-Mediated Pathways
Open AccessArticle

Neuroprotection after Hemorrhagic Stroke Depends on Cerebral Heme Oxygenase-1

1
Department of Anesthesiology and Critical Care Medicine, Medical Center—University of Freiburg, 79106 Freiburg, Germany
2
Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
3
Department of Neurology, Medical Center—University of Freiburg, 79106 Freiburg, Germany
4
Department of Neurosurgery, Medical Center—University of Freiburg, 79106 Freiburg, Germany
*
Author to whom correspondence should be addressed.
Antioxidants 2019, 8(10), 496; https://doi.org/10.3390/antiox8100496
Received: 26 September 2019 / Revised: 14 October 2019 / Accepted: 18 October 2019 / Published: 19 October 2019
(1) Background: A detailed understanding of the pathophysiology of hemorrhagic stroke is still missing. We hypothesized that expression of heme oxygenase-1 (HO-1) in microglia functions as a protective signaling pathway. (2) Methods: Hippocampal HT22 neuronal cells were exposed to heme-containing blood components and cell death was determined. We evaluated HO-1-induction and cytokine release by wildtype compared to tissue-specific HO-1-deficient (LyzM-Cre.Hmox1 fl/fl) primary microglia (PMG). In a study involving 46 patients with subarachnoid hemorrhage (SAH), relative HO-1 mRNA level in the cerebrospinal fluid were correlated with hematoma size and functional outcome. (3) Results: Neuronal cell death was induced by exposure to whole blood and hemoglobin. HO-1 was induced in microglia following blood exposure. Neuronal cells were protected from cell death by microglia cell medium conditioned with blood. This was associated with a HO-1-dependent increase in monocyte chemotactic protein-1 (MCP-1) production. HO-1 mRNA level in the cerebrospinal fluid of SAH-patients correlated positively with hematoma size. High HO-1 mRNA level in relation to hematoma size were associated with improved functional outcome at hospital discharge. (4) Conclusions: Microglial HO-1 induction with endogenous CO production functions as a crucial signaling pathway in blood-induced inflammation, determining microglial MCP-1 production and the extent of neuronal cell death. These results give further insight into the pathophysiology of neuronal damage after SAH and the function of HO-1 in humans. View Full-Text
Keywords: cerebrovascular stroke; heme oxygenase; microglia; neuroprotection; subarachnoid hemorrhage cerebrovascular stroke; heme oxygenase; microglia; neuroprotection; subarachnoid hemorrhage
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Kaiser, S.; Frase, S.; Selzner, L.; Lieberum, J.-L.; Wollborn, J.; Niesen, W.-D.; Foit, N.A.; Heiland, D.H.; Schallner, N. Neuroprotection after Hemorrhagic Stroke Depends on Cerebral Heme Oxygenase-1. Antioxidants 2019, 8, 496.

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