Haemoglobin causes neuronal damage in vivo which is preventable by haptoglobin. Issue 1 (3rd January 2020)

• Record Type: Journal Article
• Authors: Garland, Patrick; Morton, Matthew J; Haskins, William; Zolnourian, Ardalan; Durnford, Andrew; Gaastra, Ben; Toombs, Jamie; Heslegrave, Amanda J; More, John; Okemefuna, Azubuike I; Teeling, Jessica L; Graversen, Jonas H; Zetterberg, Henrik; Moestrup, Soren K; Bulters, Diederik O; Galea, Ian
• Is Part Of: Brain communications. Volume 2:Issue 1(2020)
• Publication Date: 2020-01-03
• Subjects: subarachnoid haemorrhage -- haptoglobin -- haemoglobin -- neurofilament light chain -- outcome; 616
• DOI: 10.1093/braincomms/fcz053
• Languages: English
• ISSNs: 2632-1297

Abstract

Abstract: After subarachnoid haemorrhage, prolonged exposure to toxic extracellular haemoglobin occurs in the brain. Here, we investigate the role of haemoglobin neurotoxicity in vivo and its prevention. In humans after subarachnoid haemorrhage, haemoglobin in cerebrospinal fluid was associated with neurofilament light chain, a marker of neuronal damage. Most haemoglobin was not complexed with haptoglobin, an endogenous haemoglobin scavenger present at very low concentration in the brain. Exogenously added haptoglobin bound most uncomplexed haemoglobin, in the first 2 weeks after human subarachnoid haemorrhage, indicating a wide therapeutic window. In mice, the behavioural, vascular, cellular and molecular changes seen after human subarachnoid haemorrhage were recapitulated by modelling a single aspect of subarachnoid haemorrhage: prolonged intrathecal exposure to haemoglobin. Haemoglobin-induced behavioural deficits and astrocytic, microglial and synaptic changes were attenuated by haptoglobin. Haptoglobin treatment did not attenuate large-vessel vasospasm, yet improved clinical outcome by restricting diffusion of haemoglobin into the parenchyma and reducing small-vessel vasospasm. In summary, haemoglobin toxicity is of clinical importance and preventable by haptoglobin, independent of large-vessel vasospasm. Abstract : Extracellular haemoglobin is toxic; its contribution to neuronal damage in vivo was unknown. Garland et al show that exposing the brain to haemoglobin recapitulates the clinicopathological features of subarachnoid haemorrhage. These features are preventable by administration of haptoglobin, which keeps haemoglobin out of the brain tissue, limiting neuronal damage. Graphical Abstract: