Intracerebral hemorrhage (ICH) accounts for 10-15% of strokes, and is associated with significant mortality, morbidity, and economic cost. Therapy is currently limited to hematoma evacuation when indicated, reversal of anticoagulation, antihypertensive therapy, and supportive care. The inadequacy of this approach is demonstrated by mortality statistics, which are unchanged over the past two decades. A growing body of experimental evidence suggests that toxins produced by the hematoma may contribute in delayed fashion to this poor outcome. One likely toxin is hemin, which is released from methemoglobin and is present in a hematoma in high micromolar concentrations. The primary defense against extracellular hemin is provided by hemopexin (Hx), a glycoprotein that binds it with extraordinary affinity and mitigates its pro-oxidant effect. Recent studies in the PIs laboratory have demonstrated that mice lacking Hx sustain more severe peri-hematomal injury and neurological deficits after ICH than their wild-type counterparts. However, no published studies have assessed the therapeutic potential of exogenous Hx therapy after ICH, likely due to its limited availability and prohibitive cost. The broad goal of this project, made feasible by n unrestricted gift of purified human Hx from CSL Behring, is to test the efficacy of Hx therapy in two established mouse ICH models. Preliminary experiments indicate that Hx has a robust protective effect on perihematomal cells when administered by i.p. injection after hemorrhage.
Specific aims are as follows: 1) Induce striatal ICH by stereotactic collagenase or autologous blood injection in 4-6 month old male and female mice. Two or four hours later, randomly assign mice to treatment with purified human Hx or PBS vehicle control administered i.p. Quantify striatal cell viability, water and hemin content, hematoma size, inflammatory cell populations, blood-brain barrier integrity, perihematomal blood flow, and behavioral deficits 3 and 8 days later. 2) Guided by dose and time window results in younger mice, test efficacy of Hx therapy in 18-20 month old mice, quantifying the same outcome measures as in younger mice and also mortality rate. It is hoped that the results of this project will help to define the benefit of Hx therapy after ICH, and ultimately lead to clinical trials for a disease process that currently has few therapeutic options.
The results of these proposed experiments may lead to identification of a new treatment for patients who suffer from a stroke that is caused by hemorrhage into the brain. It is hoped that hemopexin will reduce cell injury in tissue surrounding the blood clot by reducing the toxicity of hemin released from the clot and also by mitigating the inflammatory response. The death rate for this type of stroke may then be reduced, and the chance of returning to an independent and productive life may be increased.
| Chen-Roetling, Jing; Regan, Kathleen A; Regan, Raymond F (2018) Protective effect of vitreous against hemoglobin neurotoxicity. Biochem Biophys Res Commun 503:152-156 |
| Chen-Roetling, Jing; Ma, Sheng-Kai; Cao, Yang et al. (2018) Hemopexin increases the neurotoxicity of hemoglobin when haptoglobin is absent. J Neurochem 145:464-473 |
| Chen-Roetling, Jing; Regan, Raymond F (2017) Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage. Curr Pharm Des 23:2226-2237 |
| Chen-Roetling, Jing; Regan, Raymond F (2016) Haptoglobin increases the vulnerability of CD163-expressing neurons to hemoglobin. J Neurochem 139:586-595 |
| Elphinstone, Robyn E; Riley, Frank; Lin, Tian et al. (2015) Dysregulation of the haem-haemopexin axis is associated with severe malaria in a case-control study of Ugandan children. Malar J 14:511 |
